ABSTRACT

The global epidemic of type 2 diabetes remains one of the greatest health challenges of our time. The collective human and economic costs are staggering and rising. Widespread initiatives now exist to prevent diabetes wherever possible. These initiatives are singularly focused on preventing diabetes in the very highest risk group: people with prediabetes. Plasma glucose concentrations can exist over a continuum with normoglycemia on one side and diabetes mellitus on the other. Nevertheless, the concept of “prediabetes” – a state of neither normoglycemia or bonafide diabetes – has been in the clinical purview since the first formal diagnostic criteria of diabetes itself. Most can agree that prediabetes represents a high-risk state for diabetes (and for the sake of this review, high-risk for type 2 diabetes, specifically), but consensus is lacking for much else, including the diagnostic thresholds, if, when, or what to initiate as to pharmacotherapy for diabetes prevention, and whether prediabetes is actually just an earlier form of diabetes warranting similarly aggressive risk factor modification for diabetes-related complications. In this chapter, PREDIABETES, we will review the recommendations for screening, diagnosis, and intervention, largely according to the American Diabetes Association (ADA).  We will also look at the pathogenesis of this highly heterogeneous dysglycemic state as well as an increasing body of evidence that treatment of prediabetes back to normoglycemia should be the goal for people with prediabetes. Lastly, the scientific evidence reviewed will be distilled into an example of a conversation intended to engage patients in this process.

INTRODUCTION

In 1979-1980, the National Diabetes Data Group and World Health Organization introduced the first formal diagnostic criteria for diabetes (1,2). Cross sectional observations that the presence of both microvascular disease (MVD) (3-6)and cardiovascular disease (CVD) (7,8) were higher when fasting plasma glucose (FPG) was >140 mg/dl and/or 2-hour post-challenge glucose (2h-PG) was >200 mg/dl were confirmed in longitudinal population studies, providing rationale for these cut points (9-11). Nevertheless, clear evidence that lowering plasma glucose could prevent diabetic complications was not available until the 1993 publication of the Diabetes Complications and Control Trial (DCCT) (12). The DCCT noted an inflection point between A1c 6.5-7.0% (48-53 mmol/mol) and risk for retinopathy, as well as a 76% reduction in retinopathy, in participants with type 1 diabetes randomized to intensive treatment (12). Hence, the A1c goal of <6.5-7.0% soon became – and has remained – the major benchmark of care for people with diabetes (type 1 and 2) (13).  

Diagnostic criteria for diabetes have evolved over the years, lowering plasma glucose thresholds (14) and even advocating use of the A1c for diagnosis (15), while continuing to calibrate these thresholds against risk for retinopathy. Far less well known than the landmark publication of the DCCT is the re-analysis of the original data demonstrating a flaw in the models with no inflection point in A1c and risk for retinopathy noted (16). Instead, reduction in retinopathy was appreciated across the A1c range, including what is now considered the pre-diabetic A1c range. The first formal diagnostic criteria for “pre”-diabetes (i.e. impaired glucose tolerance) were introduced concurrently with those for diabetes itself (1). Diagnostic thresholds for prediabetes have been more moveable (14,15,17) and more controversial. Despite evidence demonstrating higher MVD and CVD in people with prediabetes compared to their normoglycemic peers (18-21), treatment of people with prediabetes is uncommon (22,23) as the notion of a “pre” disease presents a clinical and regulatory conundrum. 

SCREENING

Much ado has been made about the cost-effectiveness of screening for prediabetes.  Nevertheless, because roughly one-quarter of people with diabetes in the U.S. remain undiagnosed (24), numerous guidelines do advocate screening for dysglycemia (e.g. diabetes and prediabetes). According to the American Diabetes Association (ADA) together with the European Association for the Study of Diabetes (EASD), an informal assessment of risk factors or use of a risk assessment tool (e.g. www.diabetes.org/socrisktest) can guide who should undergo blood testing (25). Children >10 years old or who have gone through puberty (whichever occurs first) who are >85^th% weight for height, with one or more risk factors (Table 1), should be screened. Non-pregnant adults >35 years without risk factors, or adults of any age who are overweight (BMI>25 kg/m² or BMI >23 kg/m², if Asian ethnicity) and have one or more risk factors (Table 1), should be screened. The screening test should be A1c, fasting glucose, or 2-hour glucose, and repeated at least at 3-year intervals for those whose screening reveals normoglycemia and once yearly in those diagnosed with prediabetes (26).

DIAGNOSIS

According to the ADA and EASD, the diagnosis of prediabetes is made when the fasting plasma glucose (FPG) is 100-125 mg/dl (5.6-6.9 mmol/l; “impaired fasting glucose” (IFG)), plasma glucose concentration is 140-199 mg/dl (7.8-11.1 mmol/l; “impaired glucose tolerance” (IGT)) 2 hours after a 75 g oral glucose tolerance test (OGTT), and/or A1c 5.7-6.4% (26) (Table 2).  Unlike diagnostic criteria for diabetes that are based on their predictive value for retinopathy (14), diagnostic thresholds for prediabetes are based on the likelihood of developing overt diabetes (27-30).  However, discussion regarding the existing cut points is ongoing. Longitudinal data from a cohort of Israeli soldiers suggest that a fasting glucose above 87 mg/dl (4.8 mmol/l) is associated with an increased risk of future diabetes (31). Further, misclassification is common given the day-to-day variability in the fasting (15%) and 2-hour (46%) glucose concentrations (32). A1c can be confounded by a number of comorbid conditions like renal disease, anemia, and hemoglobinopathies (see www.ngsp.org/interf.asp)  and must be done using a method certified by the National Glycohemoglobin Standardization Program (NGSP).  Use of the 1-hour glucose value (i.e., >155 mg/dl post-OGTT), fructosamine, 5-androhydroglucitol among others have also been proposed, but none are standardized hence none currently recommended (33,34). Despite the fact that A1c-defined prediabetes appears to confer worse outcomes than prediabetes defined by fasting or 2-hour glucose criteria (35), the use of the A1c is not supported by the World Health Organization (WHO) for the diagnosis of prediabetes (36).

PREVALENCE

The changes in diagnostic criteria over the past years make it difficult to estimate exact trends in the global burden of prediabetes. However, by combining recent data from diverse sources, the prevalence of prediabetes can roughly be approximated. In 2021, the Centers for Disease Control (CDC) estimated that 96 million Americans – 38% of the adult population – had prediabetes demonstrating an increase in the percent of the population that has prediabetes that had previously been stable (24). Discordance in the diagnostic criteria for prediabetes, regional differences in surveillance and reporting for chronic diseases, and other cultural nuances pose challenges in estimating the global burden of prediabetes. To this point, the literature is currently devoid of any estimate of global prevalence of IFG, specifically. In 2017, the International Diabetes Federation (IDF) estimated the worldwide prevalence of IGT at 318 million - a number expected to increase to 482 million by 2040 (www.diabetesatlas.org) – with no further update in 2021. Data from the National Health and Nutrition Examination Survey (NHANES) would contend that the prevalence of IFG is twice that of IGT (37) (using ADA criteria), suggesting that the worldwide prevalence of prediabetes (IFG and/or IGT) may exceed 1 billion. Most alarming is that roughly one- third of people with IGT (and possibly IFG) are between 20 and 39 years old, thus are expected to spend many years at risk for or with diabetes (www.diabetesatlas.org).

RISK FOR DIABETES

Screening for and diagnosis of prediabetes is advocated as it represents a high-risk state for the development of overt type 2 diabetes. A recent meta-analysis showed that the yearly progression rate to diabetes in individuals with prediabetes is 3.5-7.0% (vs. 2%/year in their normoglycemic counterparts) (28), with highest rates in those with combined IFG and IGT and the lowest in those with IFG by ADA (vs. WHO) definition (38). Increasing A1c is also associated with increased risk of diabetes with yearly incidence rates approximating 5% for those with an A1c of 5.7-6.0% and up to 10% for those with an A1c of 6.1-6.4% (39).  Adding non-glycemic risk factors (Table 1) to the diagnosis of prediabetes markedly increases risk for diabetes, approaching 30% per year (40).  Decompensation from prediabetes to diabetes appears rapid in the later stages (41) and may warrant closer monitoring for people close to the thresholds for diabetes as well as earlier risk factor modification.

A recent study looked at the prevalence of prediabetes and risk of developing diabetes in 3412 individuals between 71 and 90 years of age (42). The prevalence of diabetes in this population was very high with 44% meeting the criteria based on A1C, 59% based on fasting glucose, 73% based on either A1c or fasting glucose, and 29% based on both A1c and fasting glucose. After a median 5-year follow-up only 9% of individuals with prediabetes based on A1c developed diabetes and only 8% of individuals with prediabetes based on fasting glucose developed diabetes. In individuals with prediabetes based on both A1c and fasting glucose levels 12% developed diabetes during the 5-year follow-up period. Many of the individuals with prediabetes regressed to normal glycemia. Thus, in the elderly the risk of progressing from prediabetes to diabetes appears to be lower than in middle aged individuals.  

SUBTYPES & PATHOGENESIS

Not long ago, the universal teaching was that post-prandial hyperglycemia always preceded fasting hyperglycemia in the evolution of diabetes (Figure 1).  The past decade has ushered in compelling evidence that this is not always the case. IFG can be isolated or precede IGT, IGT can be isolated or precede IFG, or they can be concurrent in the prediabetic state (27,29,43) (Figure 1).  This realization has sparked rigorous investigations into the pathogenesis of the subtypes - IFG, IGT and IFG/IGT - as discreet prediabetic states. Early studies used the homeostasis model assessment (HOMA) to delineate IFG from IGT, concluding that IFG was more insulin resistant than IGT (43).  Most noteworthy is the fact that this conclusion is inherently flawed since HOMA relies on FPG (i.e., HOMA-IR = FPG x FPI / 22.5) and IFG is defined by FPG.  Fortunately, more rigorous investigations have followed.

Figure 1. A) Former concept as to the pathophysiology of prediabetes and diabetes >10 years ago; B) Current knowledge as to the pathophysiology of prediabetes and diabetes <10 years

In some individuals, type 2 diabetes seems to develop as a consequence of inherent beta cell dysfunction (44). In others, development of insulin resistance precedes defects in the pancreatic beta cells (44,45). These findings underscore that prediabetes (like type 2 diabetes) is not a single disease entity, but rather multiple diseases with different pathologies (Table 3) and trajectories for disease development. This notion is supported by longitudinal data from the Whitehall II Study illustrating that the underlying disease mechanisms for individuals developing type 2 diabetes differ depending on whether diabetes is diagnosed by increased fasting or 2-hour plasma glucose levels (44). Further, this heterogeneity in the disease process is present decades before the clinical onset of diabetes.  Defects unique to IFG and IGT may be collective or unique when IFG and IGT exist in combination (46).

Impaired Fasting Glucose (IFG)

THE ROLE OF THE LIVER

In healthy humans, circulating plasma glucose concentration is maintained in a narrow range by the liver’s ability to regulate its direction of glucose flux (47).  By virtue of hepatic insulin resistance (48), decreased hepatic glucose clearance (49), or lower glucose effectiveness (50), endogenous glucose production (EGP) becomes abnormal in the development of isolated IFG (48,51-54).  EGP, as measured by glucose rate of appearance (Ra), has been reported as 8-25% higher in people with IFG vs. normal glucose tolerant (NGT) controls in some studies (46,54), or “inappropriately” comparable to NGT (given the higher circulating glucose and insulin levels in IFG) in others (48,55). It is clear that the liver, rather than muscle, plays a distinctive role in the pathogenesis of IFG.

THE ROLE OF THE BETA CELL

Unique defects in beta cell function are seen in concert with the defects in the liver in people with isolated IFG. Collective data suggest that beta cell function may be intrinsically impaired, vs. acquired, in IFG. This notion is supported by epidemiologic studies showing diminished insulin response to glucose in normoglycemic individuals who later develop isolated IFG (56) and that this defect may be seen as long as 18 years before they are diagnosed with diabetes (44).  Furthermore, beta cell dysfunction has been demonstrated in individuals with isolated IFG and normal peripheral insulin sensitivity (48,51). 

The exact manner of beta cell dysfunction in IFG appears specific to 1^st vs. 2^nd phase insulin secretion (55,57).  It should be pointed out, however, that 1^st phase insulin secretion is only appreciated in response to an intravenous glucose challenge bringing its physiologic relevance into question. Studies carefully examining insulin secretion in IFG (vs. NGT or IGT) have uniformly noted decrements in response to intravenous, but not oral, glucose challenges (46,48,51,54,55). Collectively, these data imply a dependence on the incretin hormones to maintain normal insulin secretion in IFG that may diverge from the role of the incretin hormones to facilitate insulin secretion in IGT.

OTHER DISTINGUISHING AND NON-DISTINGUISHING FEATURES OF IFG

Despite the implication of different roles for the incretin hormones in conferring IFG vs. IGT, existing data are conflicting (51,58). Likewise, plasma glucagon concentrations (51), adipose tissue mass and function (59) do not appear different, and other pathogenic features such as intramuscular lipids have not been compared between the subtypes of prediabetes. Of note, people with IFG tend to be male and younger – whereas those with IGT female and older - and have slight differences in their risk factors for CVD (43,60,61).

Impaired Glucose Tolerance (IGT)

THE ROLE OF SKELETAL MUSCLE

Despite reports of greater hepatic fat in people with IGT vs. IFG (62), skeletal muscle, rather than liver, has been implicated as the site of insulin resistance in isolated IGT. Glucose rate of disappearance (Rd; a measure of muscle insulin sensitivity) has been shown to be 42-48% lower in IGT vs. NGT (48,55) with only minimal impairments seen in IFG (54).  Because of the larger contribution of muscle (vs. liver) to whole-body insulin sensitivity, people with isolated IGT demonstrate on average 15-30% lower whole body insulin sensitivity compared to those with isolated IFG(51,52,57).

THE ROLE OF THE BETA CELL

In contrast to IFG, beta cell dysfunction appears to be acquired rather than intrinsic in IGT. For example, long-term population studies have not noted early defects in people destined to develop isolated IGT (56).  Nevertheless, beta cell dysfunction has been repeatedly observed in people with established IGT, particularly when significant whole body and skeletal muscle insulin resistance co-exists (51,56,63,64).  The exact manner of beta cell dysfunction in IGT appears specific to 2nd vs. 1st phase insulin secretion (55,57) and is observed whether or not the incretin-axis is invoked during the assessment. 

A1c-Defined Prediabetes

Recent trends in medical practice have seen the 2-hour OGTT fall from grace and be replaced by the A1c, even for the diagnosis and surveillance of prediabetes. Being that A1c is a composite of fasting and post-prandial glucose concentrations, it cannot delineate IFG from IGT nor any of the pathology unique to either. Alpha-hydroxybuytric acid, linoleoyl-glycerophosphocholine, and oleic acid have been shown predictive of 2-hour glucose values in three European cohort studies (65), hence may hold value if the pathophysiologic differences between IFG and IGT are to guide clinical decision-making in the future.  Currently, the strategies for diabetes prevention do not discriminate between the subtypes of prediabetes.

CLINICAL TRIALS AIMED AT PREVENTING OR DELAYING DIABETES

With the global surge in the prevalence of type 2 diabetes, focus on its prevention has intensified. Clinical trials for diabetes prevention around the globe have universally enrolled participants with untreated prediabetes (mostly IGT) due to their high risk for acquiring overt diabetes (28). Approaches for the prevention of diabetes have included intensive lifestyle modification (66-68) (Figure 2) or drug therapy using glucose-lowering medications (69-76)  (Figure 3) or anti-obesity medications (77-81) (Figure 4). Lifestyle interventions have utilized a low fat (<30% calories from fat; <10% from saturated fat) hypocaloric diet and moderate intensity exercise ~150 minutes per week for the purpose of 5-7% weight reduction. With the exception of the NAVIGATOR Trial (75), collective results demonstrate that diabetes incidence can be reduced by 20-89% over 2.4-6 years in a wide range of ethnic groups. 

Figure 2. Major trials using intensive lifestyle interventions for diabetes prevention

Figure 3. Major trials using glucose-lowering medications for diabetes prevention

Figure 4. Major trials using anti-obesity medications for diabetes prevention

Despite success amongst the various strategies employed, only intensive lifestyle modification has been universally advocated. The lifestyle curriculum designed for the U.S. Diabetes Prevention Program (DPP) serves as the foundation for the National DPP (NDPP) – the translational effort of bringing clinical trial results to the real world (www.cdc.gov/diabetes/prevention). A recent meta-analysis of 63 publications stemming from international real-world translations of clinical trial lifestyle curriculum demonstrated a 3% reduction in absolute risk and 29% reduction in relative risk for active participants, even when weight loss was modest (82). Likewise, the National Health Service Diabetes Prevention Programme (NHS DPP) began implementation across the United Kingdom in 2016 (83).  Evaluation of the program showed a consistent ~40% reduction in onset of diabetes over 13.4 months, including when the curriculum was delivered by lay volunteers (84). Initiation of metformin in people with pre-diabetes is recommended for those younger than 65 years old with a body mass index (BMI) >25 kg/m² (85). To date, only ~0.7% of people with prediabetes in the U.S. are treated with metformin (23). It should be noted that no medication is approved by the U.S. Food and Drug Administration (FDA) for the treatment of prediabetes – not even metformin – as the FDA does not recognize prediabetes as a disease. In fact, the mere notion of a “pre” disease creates a clinical and regulatory conundrum. In 2008, the FDA issued guidance for industry developing drugs for the treatment or prevention of diabetes stating that it would consider approving pharmacotherapy for prediabetes if the drug could show “clinical benefit” (e.g. a delay or lessening in micro- or macrovascular complications) (https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf).  Increasing evidence shows this may be possible.

COMPLICATIONS OF PREDIABETES

It is alluring to imagine an A1c threshold below which patients are fully protected from diabetic complications (86). This quest has proven less straightforward than is widely acknowledged.  People with prediabetes can suffer the same micro-, macrovascular, and non-vascular complications as people with diabetes, just at a lower incidence rate. Further, data exist and studies ongoing to show clear benefit from early intervention for people with prediabetes (www.clinicaltrials.gov/prediabetes).

Microvascular

Diabetes remains a leading cause of blindness, kidney failure, and amputations around the world. Benchmarks for diabetes care are explicitly based on the prevention of such microvascular complications (13). Nonetheless, complications of diabetes increase with increasing glycemia, even in the prediabetic glucose range. For example, nearly 10% of DPP participants had diabetic retinopathy, without diabetes, in a cross sectional analysis (19).  Moreover, data from NHANES suggests the steepest increase in risk for retinopathy occurs at an A1c of 5.5% (18), which would be considered normoglycemia by current ADA and WHO criteria. Polyneuropathy has also been reported as more prevalent in prediabetes, affecting 13% of people with IGT and 11.3% with IFG compared to 7.4% with NGT (21). Lastly, microalbuminuria doubles in prevalence with the onset of IFG or IGT, whereas its progression appears slower at the diagnostic threshold for overt diabetes (87). Recent trends reveal chronic kidney disease (defined as a glomerular filtration rate (GFR) < 60 ml/min/1.73 m²) is now as prevalent in people with prediabetes as diabetes itself (88). 

Perhaps more surprising than the incidence and prevalence of microvascular disease in people with prediabetes are data showing benefit from early interventions.  For example, the DPP Outcomes Study (DPPOS) demonstrated a 21% lower prevalence of the composite microvascular endpoint (retinopathy, nephropathy and/or neuropathy) in women who had been randomized to the intensive lifestyle intervention and followed 15 years post-randomization and a 28% lower prevalence across the treatment groups when diabetes was prevented (89).  In the roughly 600 participants with prediabetes that entered the Swedish Obesity Study (SOS), the composite microvascular endpoint was 82% lower in those who underwent bariatric surgery a median of 19 years after their procedure – an effect size that was much greater than for those who entered the study with either diabetes or normoglycemia (90).  Lastly, retinopathy was shown reduced by 40% in the 30-year follow-up of the Da Qing Study – a study that rendered a meager average of 1.8 kg weight loss during the intervention period (91).  Altogether, there is increasing evidence that people with prediabetes are at risk for classic complications of diabetes and these can be prevented with early intervention (Figure 5).

Figure 5. Trials demonstrating a reduction in microvascular disease in people with prediabetes

Macrovascular

In 2010, a meta-analysis by Ford et al. illustrated an approximate 20% increased risk of cardiovascular disease (CVD) in people with prediabetes, irrespective of type (IFG or IGT), criteria used to define it, or the development of diabetes (20). As a continuous variable, however, CVD risk appears more closely related to 2-hour than fasting glucose (92).  In 2018, serial cross sectional data from NHANES showed surprising similarity in the prevalence of myocardial infarction and stroke in people with prediabetes vs. diabetes (88) likely due to the dramatic fall in incident myocardial infarction and stroke in people with diabetes (93).  This finding implies that CVD may now be as common in people with prediabetes as with diabetes (recently reviewed by (94)). It should be recognized that whether the elevated glucose is causing the increased risk of CVD in individuals with prediabetes is uncertain as prediabetes is associated with other factors such as obesity, insulin resistance, dyslipidemia, hypertension, hypercoagulation, and inflammation that could be playing important roles in increasing the risk of CVD.

As with microvascular disease, data do exist that early intervention also prevents macrovascular disease in people with prediabetes (Figure 6).  The first study to contend that this may be the case came from a post-hoc analysis of STOP-NIDDM – a trial that used acarbose to prevent or delay diabetes in people with prediabetes.  This analysis showed a highly unexpected 49% lower probability of any CV event in the group randomized to acarbose (95).  Interestingly, the trial was repeated, powered with benefit as the a priori hypothesis and did not succeed at recapitulating the prior findings (73). Differences in medication dosage and ethnic admixture may or may not explain the discrepancy. Nevertheless, pioglitazone has been shown to reduce CV events over 4.8 years in insulin-resistant people 6 months post-stroke with an average A1c of 5.8% (96).  Likewise, the Da Qing Study revealed a 33% lower CV mortality and 26% lower all-cause mortality, whilst still preventing diabetes, 30 years into the post-randomization follow-up (91).  CV data from the DPPOS is expected shortly with great anticipation that prediabetes may finally be recognized as an earlier form of diabetes warranting intervention. While the effect of lowering glucose levels in individuals with prediabetes is uncertain given the high risk of CVD in this population aggressive treatment of dyslipidemia and hypertension is indicated given the large number of studies showing benefits.

Figure 6. Trials demonstrating a reduction in macrovascular disease in people with prediabetes

Not Necessarily Vascular

Although risk factor modification largely focuses on preventing the classic complications of diabetes, greater attention is being paid to a much larger scope of possible comorbidities.  A recent study elaborated on structural brain abnormalities in people with prediabetes that are linked to dementia, stroke, and depression and hypothesized that glucose-lowering may reverse the abnormalities (97).  Functionally, these brain changes lead to slower processing speeds and cognitive deficits (98).  Mild cognitive impairments are accelerated by the presence of prediabetes leading to frank dementia (99). Unequivocally, cognitive impairments and dementia dramatically reduce quality of life for both patients and their care-takers.  Fortunately, patient-reported outcomes are becoming increasing revered as a scientific endpoint and may provide additional rationale for treating prediabetes. The much-anticipated long term outcomes from the DPPOS (expected 2020-2025) also include examining treatment effect on cognition, aspects of aging, quality of life, health care utilization and cancer.

RESTORATION OF NORMOGLYCEMIA

In clinical trials to date, interventions were deemed successful if diabetes was prevented or delayed, yet many participants remained with prediabetes. Arguably, prevention of diabetes and its complications lies in the restoration of normoglycemia rather than in the maintenance of prediabetes.  This was confirmed by a post-hoc analysis from the Diabetes Prevention Program Outcomes Study (DPPOS) (100). This analysis demonstrated a 56% lower risk of diabetes 10 years from randomization among those who were able to achieve normoglycemia during DPP vs. those who remained with prediabetes. Additionally, restoration of normoglycemia reduced prevalence of microvascular disease (101) and CV risk factors despite less use of medication to lower lipids and blood pressure (102).  The concept that diabetes and CV risk can be significantly reduced over the long-term through the pursuit of normoglycemia represents a major shift in our current thinking and has quickly gained consensus as the goal for people with prediabetes (103,104). Clinical predictors (105) and calculators as to the likelihood of regression (106)can be used to select and activate patients. Importantly, restoration of normoglycemia – as opposed to “diabetes prevention” – is clinically actionable. 

Exactly how normoglycemia should be achieved is far less clear. Data from the DPP would contend that only lifestyle modification, not metformin, is useful in achieving normoglycemia in people with prediabetes (105) (Figure 7). Of note, lifestyle modification has been shown particularly effective in women (107) and the elderly (108). The thiazolidinediones (TZD’s) have also demonstrated their ability to restore normoglycemia in people with prediabetes (71,72,109) and may gain greater acceptance in this population now that their CV safety has been established.  An increasing number of trials are focused on the ability of medication or lifestyle to not only prevent or delay onset of diabetes, but restore normoglycemia (79,110,111).

TRANSLATING INFORMATION INTO CONVERSATION

As we follow the recommended steps for screening and diagnosis of prediabetes outlined above, the next step in beginning the conversation with a patient with prediabetes is educating them about what the diagnosis means.  An A1c of 5.7-6.0% carries up to a 25%/5-year risk, whereas an A1c 6.0-6.4% carries up to a 50%/5-year risk, and prediabetes period carries up to a 70% lifetime risk of diabetes.  Further, people with prediabetes can suffer complications of diabetes even if they never convert. Early intervention can prevent diabetes by more than 50% if normoglycemia can be attained – even if transiently. Intensive lifestyle modification and a number of glucose-lowering and anti-obesity medications have been shown as capable to achieve this.  Metformin is recommended for younger, overweight people with prediabetes even though it may not achieve normoglycemia as readily. Micro- and macrovascular risk factor modification is critical.  Plasma glucose concentrations should be followed and re-screening for diabetes done annually.

CONCLUSION

In the light of the global burden of prediabetes affecting close to one billion people, the high progression rates to type 2 diabetes, and the increased risk of both micro- and macrovascular complications and death (112), efforts focused on preventing progression to diabetes and its complications are crucial. Although both intensive lifestyle intervention and various medications have proven to be effective for prevention or delay of diabetes in people with prediabetes, their uptake has been slow. This is true even in light of emerging data showing the vast benefits of early interventions.  Our best bet to recognize prediabetes as a disease is probably by calling it what it is: early diabetes (94) and treat it as such, eradicating the term “prediabetes” for good.

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ABSTRACT

Diabetes mellitus is a strong, independent risk factor for the development of atherosclerotic cardiovascular disease (ASCVD) and therefore for atherothrombotic events. Compared to those without diabetes, individuals with diabetes are also at increased risk of cardioembolic stroke in the presence of atrial fibrillation (AF) and of venous thromboembolism. Activation of platelets and the coagulation cascade are the central mechanisms of thrombosis. A range of antiplatelet and anticoagulant drugs are now available. Antithrombotic therapy should be considered in all those with diabetes and established ASCVD or AF. Intensification of antithrombotic therapy is typically indicated during the acute phase of an atherothrombotic event or in those with chronic coronary syndromes who are at high ischemic risk, provided this outweighs bleeding risk. Clinical decisions regarding antithrombotic therapy should be made by assessing an individual’s ischemic and bleeding risks, in consultation with the recipient and reviewed upon any change in circumstances.

LIST OF ABBREVIATIONS

INTRODUCTION

Despite a century of advances in understanding and management of diabetes mellitus (DM), it continues to increase in prevalence and, furthermore, remains an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), leading to a significant burden of premature mortality and morbidity (1).

ASCVD includes a spectrum of clinical syndromes. This can include acute presentations such as acute coronary syndromes (ACS, including myocardial infarction [MI] or unstable angina [UA]), thrombotic stroke, or acute limb ischemia (ALI) (Figure 1). Similarly, ASCVD can lead to chronic conditions such as chronic coronary syndromes (CCS, for example those with stable angina or a history of MI >1 year previously) or chronic lower extremity arterial disease (LEAD) (2).

Most acute events in ASCVD are caused by thrombosis. The hemostatic response has an important physiological role in the response to trauma but, if it becomes activated inappropriately, thrombosis can be triggered (3). The clinical effects of thrombosis arise primarily from its location, such as in the coronary arteries leading to acute coronary syndrome (ACS, including myocardial infarction [MI] and unstable angina [UA]), cerebral arteries leading to thrombotic stroke, peripheral arteries leading to acute limb ischemia or deep limb veins leading to deep vein thrombosis (DVT). Alternatively, a thrombus formed at a site can embolize, leading to presentations such as acute pulmonary embolism (typically embolism of a DVT to the pulmonary arteries) or embolic stroke (typically left atrial thrombus to the cerebral arteries) (2,4). In addition to atherosclerotic diseases, individuals with DM who have atrial fibrillation are at higher risk of stroke, secondary to atrial thrombosis and subsequent cardioembolic events (5).

There are clear links between pathological processes associated with DM and those responsible for atherogenesis and thrombosis, including inflammation, platelet activation, and coagulation (6,7). Alongside control of glucose levels and optimization of other risk factors, such as dyslipidemia, hypertension, and smoking cessation, antithrombotic therapy (ATT), including antiplatelet therapy (APT) and oral anticoagulation (OAC), has become a key component of the treatment and prevention of atherothrombotic and cardioembolic events. ATT has evolved greatly in the last decades, both in terms of the range of drugs available but also our understanding of how best to deploy them (8).

Whilst ATT reduces thrombotic risk, in particular reducing the composite of major adverse cardiovascular events (MACE, typically defined as cardiovascular death, stroke or MI), it also leads to an increased risk of bleeding. Balancing these risks is central to interpretation of clinical trial data and development of treatment recommendations, including in those with DM (9).

In this chapter, we will review the underlying pathophysiological mechanisms of thrombosis and the pharmacology of commonly prescribed drugs during ATT. With specific reference to individuals with DM, we will appraise evidence for ATT in a broad range of clinical settings, highlighting current treatment recommendations and particular areas in which more data are needed.

Figure 1. The spectrum of acute cardiovascular events relating to thrombosis and hemostasis in DM.

THE THROMBOTIC RESPONSE AND ITS PHARMACOLOGY

As described in Virchow’s triad, prothrombotic changes in the blood flow, constituents and/or vessel wall can trigger thrombosis (10). Broadly, thrombosis involves the activation of platelets and the coagulation cascade (Figure 2). Understanding these processes provides insights into how pharmacological modulation may improve ischemic risk and increase bleeding risk as well as how the individual components of combination ATT interact, including in those with DM.

Platelet Activation

Platelet activation typically occurs upon endothelial injury and atherosclerotic plaque rupture or erosion, resulting in exposure of blood constituents to prothrombotic substances such as collagen. Collagen exposure leads to platelets adhering to the vessel wall via the glycoprotein (GP) Ia receptor and activation via GPVI (11,12). GPIb forms a complex with clotting factors IX, V and von Willebrand Factor (vWF), strengthening adhesion (13).

Platelet activation involves several key processes. Alterations in the cytoskeleton lead to shape change with the formation of filopodia, which increase surface area to volume ratio and may facilitate mechanical adhesion to the vessel wall, other platelets and fibrin strands (14). Platelet activation also involves the release of arachidonic acid from the cell membrane, which is then locally converted to thromboxane A₂ (TXA₂) by cyclo-oxygenase (COX) 1 and TXA₂synthase. TXA₂, via the platelet TP-α receptor, contributes further to platelet activation (15). Aspirin (acetylsalicylic acid) irreversibly inhibits COX1, thereby blocking the downstream release of TXA₂ for the platelet’s lifespan (around 8-10 days in healthy individuals) as, unlike nucleated cells, platelets cannot regenerate the enzyme (8). Endothelial COX1 and 2 generate the antiplatelet and vasodilatory substance prostacyclin (PGI₂). The facts that aspirin is short-lived in the systemic circulation, that platelets are exposed to higher levels of aspirin than endothelium, due to travel through the portal circulation, and that aspirin has relative selectivity for COX1 over COX2 leads to aspirin’s net antiplatelet effect at low doses (16).

Platelets also undergo degranulation on activation; a granules contain procoagulant and proinflammatory factors, including platelet P-selectin (also known as CD62P), the surface expression of which is therefore increased. P-selectin mediates platelet-leukocyte aggregation and therefore contributes to an associated inflammatory response (17). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP) and 5-hydroxytryptamine (5HT, also known as serotonin). In particular, ADP stimulates platelet activation via P2Y₁ and, most significantly, P2Y₁₂ receptors (18,19).

Stimulation of the P2Y₁₂ receptor leads to central amplification of the response to a range of agonists and contributes significantly to activation of platelet surface GPIIb/IIIa receptors, the final pathway of platelet aggregation (20). Via vWF and fibrinogen bridges, GPIIb/IIIa mediates platelet-platelet interaction (21).

Figure 2. Pathophysiology of the thrombotic response showing targets for antithrombotic drugs discussed in this chapter. 5HT, 5-hydroxytryptamine (serotonin); AA, arachidonic acid; ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca2+, calcium; COX1, cyclo-oxygenase 1; GP, glycoprotein; IXa, activated factor IX; P2X1, platelet ATP receptor; P2Y1/P2Y12, platelet ADP receptors; PAR, protease activated receptor; PLA2, phospholipase A2; PSGL1, P-selectin glycoprotein ligand 1; TF, tissue factor; TPα, thromboxane receptor α; TXA2, thromboxane A2; TXA2s, thromboxane A2 synthase; Va, activated factor V; VIIa, activated factor VII; VIIIa, activated factor VIII; VASP, vasodilator-stimulated phosphoprotein; vWF, von Willebrand factor; Xa, activated factor X; XIa, activated factor XI; XIIa, activated factor XII; XIIIa, activated factor XII. Modified from (22).

Several oral platelet P2Y₁₂ receptor antagonists (‘P2Y₁₂ inhibitors’) are currently available (23). Clopidogrel and prasugrel are irreversibly-binding thienopyridines (8). As pro-drugs, they require hepatic metabolism to be activated. In the case of prasugrel this pathway is reliable, whereas there is interindividual variation in the metabolism of clopidogrel meaning around one-third of recipients have poor response when assessed using aggregometry (22). Ticagrelor is a reversibly-binding cyclopentyl-triazolopyrimidine that does not require metabolism to be active. Prasugrel or ticagrelor provide more potent and reliable platelet inhibition compared with clopidogrel (24).

Parenterally administered P2Y₁₂ inhibitors have also been developed. Cangrelor is a reversibly-binding ATP analogue that is potent and has rapid onset and offset (25). Selatogrel is a novel, parenterally-active, reversibly-binding P2Y₁₂ inhibitor formulated for subcutaneous administration, but has not yet completed phase III trials and is yet to be marketed (26).

Activation of the Coagulation Cascade

Although likely an oversimplification of the in vivo state, the coagulation cascade can be summarized as two key pathways made up of factors that converge on a final pathway (27).

Loss of endothelium leads to exposure of subendothelial extracellular matrix and contact activation of factor XII, triggering the chain of clotting factor activation known as the intrinsic pathway (28). Tissue factor, expressed on subendothelial cells and released in microparticles from atheromatous plaques, can activate factor IX when in a complex with factor VII: this is the extrinsic pathway (29).

Initiation of either pathway can lead to activation of factor X, which associates with activated factor V, calcium (released from damaged tissue) and phospholipids to form the prothrombinase complex (30). Prothrombin (II) is thus broken down to thrombin (IIa), which completes the process through cleavage of fibrinogen to fibrin, the latter being insoluble and forming strands. Tissue factor pathway inhibitor and antithrombin limit this response, but, as recruitment of activated platelets contributes to higher levels of thrombin generation, this endogenous inhibition is quickly overwhelmed (31). Once fibrin is formed, factor XIIIa, activated by thrombin, stabilizes the structure of clot by forming crosslinks between strands and by crosslinking anti-fibrinolytic proteins into the clot (32).

Fibrin is lysed by plasmin, a proteolytic enzyme that degrades into variously termed fragments (33). Plasmin is cleaved from its precursor, plasminogen, by tissue plasminogen activator, and is endogenously inhibited by antiplasmin.

A number of drugs target the coagulation cascade. During chronic administration, vitamin K antagonists (VKA) such as warfarin reduce the biological activity of prothrombotic vitamin-K-dependent factors (II, VII, IX, X) more than antithrombotic factors (e.g., proteins C and S) (34). Non-vitamin K antagonist oral anticoagulants (NOACs) include the Xa inhibitors apixaban, edoxaban and rivaroxaban and the thrombin inhibitor dabigatran (35).

Crosstalk Between Platelets and the Coagulation Cascade

Despite the fact that platelets and coagulation are often considered separately when discussing physiology and pharmacology, there is significant crosstalk between the two. Thrombin is generated upon activation of coagulation, and is able to stimulate platelet activation via action on protease-activated receptor (PAR) 1 and, at higher concentrations, PAR4 (36). Conversely platelets can contribute to thrombin generation, increasing coagulability, via scramblase activity that leads to greater surface expression of phosphatidylserine, supporting the assembly of prothrombinase complex on the activated platelet surface, which potentiates thrombin generation (37).

SPECIAL PATHOPHYSIOLOGICAL CONSIDERATIONS IN DIABETES

DM is an independent risk factor for atherothrombosis and also thrombosis after vascular interventions (38).  Individuals with DM have greater average atherosclerotic plaque burden than those without (39), and onset is at an earlier age (40). There is also some evidence that atherosclerosis in people with DM is more likely to involve distal vessels than those without DM (41). The reasons for this are not completely understood and are likely multifactorial, but a number of relevant pathological processes such as hyperglycemia, chronic inflammation, and oxidative stress are prominent in DM. These contribute to both endothelial injury/dysfunction and increased platelet reactivity, resulting in a prothrombotic milieu (42-44).

Platelet activation markers are enhanced in people with DM (45). Effects of hyperglycemia on platelets include increased expression of GPIba, GPIIb/IIIa, and P2Y₁₂, and reduced platelet membrane fluidity (46,47).Hyperglycemia-induced changes in intracellular magnesium and calcium signaling increase sensitivity of platelets to agonists such as ADP, epinephrine and thrombin (48). TXA₂ and F2-isoprostane synthesis is increased, the latter via oxidative stress, leading to increased TPa receptor stimulation (49). Reduced sensitivity to PGI₂, nitric oxide and insulin, which inhibit platelet activation, also contributes to hyper-reactivity (50,51).

Platelet turnover is accelerated in those with DM compared to those without (52). This increased activity in the creation and destruction of circulating platelets means a higher proportion of immature platelets, which are hyper-reactive, are present at any time (53). As well as increasing baseline platelet reactivity, the more frequent appearance of aspirin-naïve platelets in the circulation means more have uninhibited COX1 between doses (54).

There is also evidence that DM affects expression of platelet-associated microRNAs (miR-223, miR-26b, miR-126, miR-140), which play a role in the expression in a wide range of genes including those encoding the P2Y₁₂ receptor and P-selectin, though the significance of this remains to be fully established (55,56).

As well as platelet activation, DM may affect coagulation and fibrinolysis (57). Changes include increased levels of tissue factor, prothrombin, factor VII and fibrinogen leading to impaired anticoagulant and fibrinolytic activity (58). Increased levels of fibrinogen and its levels of glycation and oxidation lead to more compact, densely-packed fibrin networks and reduced fibrinolysis (59). Hyperglycemia inhibits the fibrinolytic activity of plasminogen through inducing qualitative changes (60). Fibrinolysis is further impaired by elevated levels of plasminogen activator inhibitor 1 and thrombin-activatable fibrinolysis inhibitor as well as incorporation into clot of complement C3 and plasmin inhibitor (59,61).

DM also appears to enhance the crosstalk between platelets and clotting factors, leading to tendency to more externalization of phosphatidylserine in the outer platelet membrane, promoting clotting factor assembly and tissue factor activation (62).

Finally, individuals with DM frequently have other metabolic conditions such as obesity, dyslipidemia, and increased systemic inflammation. These may interact with diabetes to further enhance platelet reactivity and impair fibrinolysis (59).

CURRENT EVIDENCE AND TREATMENT RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY IN DIABETES

The Need for Therapeutic Oral Anticoagulation

Broadly, when considering the need for antithrombotic therapy (ATT), including in people with DM, it is helpful to make first a distinction between those with an indication for therapeutic anticoagulation and those without. The most common indication is for prevention of cardioembolic stroke in those with current or previous atrial fibrillation (AF). Individuals with atrial flutter are typically regarded as having similar thrombotic risk to those with AF so similar recommendations are followed (63).

DM increases the risk of developing AF by around 40% (64,65). Whilst difficult to completely exclude the effects of confounders such as obesity and hypertension, epidemiological data suggest a causal association between DM and AF, including that poor glycemic control and longer diabetes duration increase AF risk (66). A raised level of HbA1c is also associated with a higher chance of AF recurrence after catheter ablation (67). Hyperglycemia and glycemic fluctuations may contribute to the development of AF though exact mechanisms remain to be determined. Disappointingly, however, there is no clear evidence that intensive glycemic control reduces AF risk, though prospective trials are lacking (66). Treatment with metformin, thiazolidinediones, or dapagliflozin is associated with lower AF risk, suggesting that hypoglycemia avoidance may play a role but adequately designed studies to investigate this possibility are lacking (68-71). AF is often clinically silent and screening with simple pulse checking or using wearable devices should be considered in those over 65 years old (72).

Presence of DM is incorporated into the CHA₂DS₂VASc score used to assess stroke risk when determining whether to recommend oral anticoagulation in people with AF (Table 1 and 2) (73). Long-term oral anticoagulation is strongly recommended in those with AF/atrial flutter and a CHA₂DS₂VASc score of ³2 (if male) or ³3 (if female), and should be considered when the score is 1 (male) or 2 (female). Individuals with DM, technically defined for the purposes of calculating the score as treatment with oral hypoglycemic drugs and/or insulin or fasting blood glucose >7.0 mmol/L (126 mg/dL), will have a score of at least 1 (males) or 2 (females), therefore OAC should be considered in all people with DM and concurrent AF (63). Bleeding risk should also be considered when weighing the benefits and risks of OAC, but there is no concrete evidence that DM itself increases this, including in those with complications such as retinopathy (74). For people with non-valvular AF (i.e., those without at least moderate mitral valve stenosis or a mechanical valve prothesis), there is now good evidence that, unless contraindicated, a NOAC should be preferred over a VKA, offering better stroke prevention whilst leading to less bleeding, including in individuals with DM (75).

Components of the CHA2DS2VASc score are shown in Table 1 and the relation of the score with stroke risk is shown in table 2 (76-78).

LVEF, left ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral artery disease; TIA, transient ischemic attack.

When choosing between individual non-vitamin K antagonist oral anticoagulants (NOACs), beyond considering specific drug interactions, there is little evidence to support the use of one agent over another as these have never undergone head-to-head clinical outcome-driven randomized controlled trials (RCTs), although observational data have emerged to provide some insights. In a large retrospective observational study of 434,046 participants with non-valvular AF comparing treatment with apixaban, dabigatran, rivaroxaban and warfarin, apixaban led to a lower risk of stroke against both dabigatran (HR 0.72 [ 95% CI 0.60-0.85]) and rivaroxaban (0.80 [0.73-0.89]), whilst also leading to less bleeding (major bleeding: vs. dabigatran 0.78 [0.70-0.87]; vs. rivaroxaban 0.80 [0.55-0.59]) (79). These findings remain hypothesis-generating, however, and prospective trials would clarify this issue more definitively.

Although not discussed in detail in this chapter, OAC may also be indicated for the treatment and prevention of venous thromboembolism. Whilst DM is regarded as a weak risk factor for VTE, beyond this there are no particular considerations relating to DM and usual clinical guidelines as for non-DM individuals should generally be followed (4). Of specific note, however, is that people with DM who are experiencing hyperosmolar states such as ketoacidosis or hyperosmolar hyperglycemic syndrome are at particular risk of VTE. There is ongoing debate around the intensity of anticoagulation that is appropriate for thromboprophylaxis in this group. Consensus is that at least prophylactic doses of low molecular weight heparin, for example, are warranted, with others advocate therapeutic doses (80,81). A robustly-powered clinical outcomes-driven RCT would be welcome to definitively address this issue.

Where indications for both anti-platelet therapy (APT) and therapeutic levels of oral anticoagulant therapy (OAC) exist, the general principle is to prioritize continuation of OAC. Co-prescription of APT and OAC should in general be reserved for those with acute coronary syndrome (ACS), recent percutaneous coronary intervention (PCI) or indication for long-term therapy in selected individuals with chronic coronary syndromes (CCS) where ischemic risk is felt to significantly outweigh bleeding risk (22).

Treating Acute Atherothrombotic Events

ACUTE CORONARY SYNDROMES (ACS)

Current guidelines recommend 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor, including in those with DM, as the default antithrombotic strategy for ACS (72,82-84).

There is robust evidence for aspirin therapy in ACS. For example, ISIS-2 demonstrated that aspirin led to an odds reduction in 30-day vascular mortality of 23% in those with acute MI (85). Current recommendations advise a loading dose of around 300 mg followed by maintenance therapy with 75 mg once daily, including in those with DM. However, because of higher platelet turnover in people with DM, 24-hour platelet inhibition is greater with twice-daily compared with once-daily aspirin administration (86-88). Any effects of clinical outcomes are yet to be determined, but are being studied in the ANDAMAN trial that aims to recruit 2573 participants (NCT02520921) and is estimated to finish in December 2023.

In ACS, the newer P2Y₁₂ inhibitors prasugrel and ticagrelor are recommended in preference to clopidogrel due to their greater pharmacodynamic and clinical efficacy (83,84). Post-hoc analysis of the TRITON-TIMI trial suggested an impressive benefit of prasugrel over clopidogrel in people with DM (89). Similar findings were noted with regards to ticagrelor over clopidogrel in the PLATO trial, for which post-hoc analysis showing that the absolute benefit of was greatest in individuals with both DM and chronic kidney disease (90).

ACS, acute coronary syndrome; ARR, absolute risk reduction; CV, cardiovascular; DM, diabetes mellitus; HR, hazard ratio; MI, myocardial infarction; NR, not reported; NSTE-ACS, non-ST elevation ACS; OR, odds ratio; PCI, percutaneous coronary intervention; PPCI, primary PCI; PPM, permanent pacemaker; RR, relative risk; STEMI, ST elevation MI; NR, not recorded

The recent ISAR-REACT-5 study demonstrated superiority of a prasugrel-based strategy over a ticagrelor-based strategy in reducing cardiovascular events in ACS patients but was an open-label trial with limited power (97,98). Furthermore, data from the pre-specified subgroup with DM suggested there was no difference between the drugs (99).

Early de-escalation from dual antiplatelet therapy (DAPT) to ticagrelor monotherapy after PCI, including for ACS, has recently been trialed as an alternative strategy. In the TWILIGHT study, de-escalation from aspirin and ticagrelor to ticagrelor monotherapy at 3 months after PCI for ACS or stable coronary artery disease (CAD) was compared with continued DAPT in 7,119 participants (100). De-escalating to ticagrelor monotherapy led to a lower incidence at 12 months of the primary end point of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding compared with DAPT (4.0% vs 7.1%, HR 0.56 [95% 0.45-0.68], p<0.001). This finding appeared similar regardless of DM status. There was no evidence of an increase in the secondary combined endpoint of death, MI or stroke. Conversely, 1 month of DAPT followed by ticagrelor alone for 23 months was not superior to 12 months of standard DAPT followed by 12 months of aspirin alone in reducing the primary endpoint of all-cause mortality or new Q-wave MI following PCI in the GLOBAL LEADERS trial, in which 47% of participants had ACS (101). Antiplatelet strategy had no significant effect on BARC type 3 or 5 bleeding in those with and without DM (102). Currently, de-escalation of DAPT may be an option for individuals with high bleeding risk and relatively low risk of vascular re-occlusion but guidelines are yet to recommend more widespread adoption.

In summary, following ACS in individuals with diabetes, DAPT for 12 months with aspirin and prasugrel or aspirin and ticagrelor is recommended by the majority of guidelines/experts and early de-escalation should be reserved to those at high bleeding risk. Longer term DAPT should be considered in those at high thrombosis/low bleeding risk, which is further detailed below. 

ACUTE ISCHEMIC STROKE

If no contraindications exist, the first-line treatment for significant acute ischemic stroke is thrombolysis with an intravenous tissue plasminogen activator, or percutaneous mechanical thrombectomy (103). Antiplatelet therapy (APT), typically aspirin monotherapy, is then administered from 24 hours later (104,105).

In those with minor stroke (National Institutes of Health Stroke Score <3), high-risk transient ischemic attack (TIA) (Age, blood pressure, clinical feature, duration and presence of diabetes score>4) or TIA not requiring thrombolysis or thrombectomy, APT can be initiated as soon as hemorrhagic stroke is excluded. The current regimen of choice may be dual antiplatelet therapy (DAPT) with aspirin 75-100 mg once daily and clopidogrel 75 mg once daily, based on findings from the CHANCE and POINT trials (106,107). After 21 days, DAPT should be de-escalated to clopidogrel monotherapy (105).

Both ticagrelor monotherapy and aspirin plus ticagrelor have also been compared to aspirin alone after acute non-severe ischemic stroke or high-risk TIA. The SOCRATES trial narrowly failed to demonstrate statistically-significant difference in the primary endpoint of stroke, MI or death (6.7% vs. 7.5%, HR 0.89 [95% CI 0.78-1.01], p=0.07) between participants receiving ticagrelor vs. aspirin (108). However, exploratory analysis suggested those who received both aspirin and ticagrelor in the peri-event period appeared to gain more benefit compared to individuals not having aspirin pre-randomization (HR 0.76 [95% CI 0.61-0.95], p=0.02; vs. 0.96 [0.82-1.12]). This was explored further in the THALES trial, which demonstrated a significant reduction in the primary composite endpoint of stroke or death at 30 days (5.5% vs. 6.6%, HR 0.83 [95% CI 0.71-0.96, p=0.02) when receiving aspirin plus ticagrelor compared to aspirin alone, but at the expense of more frequent severe bleeding (0.5% vs. 0.1%, HR 3.99 [95% CI 1.74-9.14], p=0.001), defined using the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial criteria (109). Findings from SOCRATES appeared similar in the subgroups with and without DM, whereas in THALES there was less signal of benefit of DAPT in those with DM vs. those without (HR 0.93 [95% CI 0.72-1.20] vs. 0.78 [0.64-0.94]).

In summary, following major stroke requiring thrombolysis or thrombectomy, aspirin monotherapy should be administered 24 hours later. In minor stroke or high-risk TIA, DAPT should be initiated as soon as intracerebral bleeding is ruled out and continued for 21 days with aspirin then withdrawn and individuals treated with long-term clopidogrel monotherapy.

Preventing Atherothrombotic Events in Individuals with Diabetes and Established Cardiovascular Disease

CORONARY ARTERY DISEASE

In those with established CAD, even without an ACS event in the last 12 months, the benefits of antiplatelet therapy (APT) are well-established. Robust evidence for vs. against use of APT in patients with ASCVD, including CAD comes, for example, from the Antithrombotic Trialists Collaboration, who performed a meta-analysis including 135,000 individuals (110). This demonstrated clear benefit, mainly with aspirin as single-antiplatelet therapy (SAPT), in reducing MACE by around a quarter (110).  The incidence of diabetes in these studies, many of which are now several decades old, was relatively low, however.

There is evidence from trials with both pharmacodynamic and clinical outcomes that increasing daily aspirin dose beyond 75-100 mg in patients with DM leads to neither greater platelet inhibition nor improved outcomes (111,112).

Daily doses of aspirin in the range 75-100 mg and no higher are recommended for use as APT. Recent data on clinical outcomes relating to aspirin dosing comes from the ADAPTABLE trial, in which the regimens 81 mg OD and 325 mg OD were compared in 15,076 patients with ASCVD (113). After a median of 26 months, there was no significant difference in the rates of a composite primary endpoint of all-cause death, hospitalization for myocardial infarction or hospitalization for stroke (7.28% [81 mg] vs. 7.51% [325 mg], HR 1.02, 95% CI 0.91-1.14; p=0.75). Furthermore, this finding appeared replicated in the subgroup (n=5676) with diabetes (HR 0.99 [0.84-1.17]). This is supported by pharmacodynamic data showing that, whilst individuals with DM have reduced response to aspirin 75 mg once daily compared with healthy controls, increasing the dose to 300 mg does not alter the response (111).

In the CAPRIE study, clopidogrel 75 mg once daily was compared with aspirin 325 mg once daily (114). There was a slightly lower rate of MI, ischemic stroke or CV death with clopidogrel (5.32% vs. 5.83%, RRR 8.7% [95% CI 0.3-16.5], p=0.043) as well as less gastrointestinal bleeding. A fifth of participants in CAPRIE had diabetes and a retrospective subgroup analysis suggested an amplified benefit of clopidogrel over aspirin compared to those without diabetes. Clopidogrel monotherapy is currently recommended in those people with chronic coronary syndromes (CCS) who are unable to take aspirin, or, based on pre-specified subgroup analyses of CAPRIE suggesting particular benefit, as a first-line agent in those with either concurrent CAD and cerebrovascular disease or PAD.

Beyond single antiplatelet therapy (SAPT), there is good evidence for intensification of antithrombotic therapy in select people with CAD who are at high risk of ischemic events but without high risk of bleeding. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study randomized 19,185 stable aspirin-treated individuals with established atherothrombotic disease or multiple risk factors to receive clopidogrel 75 mg once daily or placebo (115). Though the point estimate of the hazard ratio was below 1, there was no significant reduction in the primary efficacy endpoint of MACE when receiving dual antithrombotic therapy (DAPT) vs. aspirin alone (HR 0.93, [95% CI 0.83-1.05], p=0.22). However, in the subgroup with prior MI, prior stroke or PAD, there was some evidence of benefit (0.77 [0.61-0.98], p=0.031) (116). Around 30% of the participants in CHARISMA had DM and there was in fact a trend towards less benefit of DAPT over SAPT in this group compared to those without DM.

The DAPT study similarly showed that 30 vs. 12 months of clopidogrel (65%) or prasugrel (35%) given to aspirin-treated individuals undergoing PCI significantly reduced death, MI or stroke in those with prior MI (HR 0.56 [95% CI 0.42-0.76], p<0.001), but not those without (0.83 [0.68-1.02], p=0.08) (117). Like CAPRIE, there was some evidence that those in the trial with DM gained less benefit in reduction of MACE from continued thienopyridine vs. placebo, when compared to those without DM (6.6% vs. 7.0% in those with DM, p=0.55; 3.3% vs. 5.2% in those without, p<0.001; interaction-p=0.03). Conversely, DM did not appear to be an interacting factor with regards to stent thrombosis or bleeding.

There is perhaps more convincing evidence, particularly in those with DM, for use of long-term ticagrelor-based DAPT. In the PEGASUS-TIMI 54 study, DAPT with aspirin plus ticagrelor, either 60 mg or 90 mg twice-daily, reduced MACE vs. aspirin alone (e.g. 60 mg twice-daily vs. placebo: HR 0.84 [95% CI 0.74-0.95], p=0.008) in participants with prior MI (>1 year ago) and an additional risk factor (age ≥65 years, DM, recurrent MI, multivessel CAD or non-end stage CKD) (118). Thrombolysis In Myocardial Infarction (TIMI)-major bleeding was significantly more frequent in ticagrelor-treated individuals, but serious events such as intracranial hemorrhage, hemorrhagic stroke or fatal bleeding showed no increase. In contrast to the thienopyridine trials, the 6806 participants with diabetes demonstrated a significant benefit of DAPT over SAPT in reducing MACE (HR 0.84 [95% CI 0.72-0.99], p=0.035) with a greater absolute risk reduction than in the cohort without diabetes (1.5% vs. 1.1%) (119). Patients without a history of anemia or hospitalization for bleeding, important risk factors for bleeding, appeared to derive greater benefit from long-term DAPT (120).

As well as in those with prior MI, ticagrelor-based DAPT has also been tested against aspirin alone in people with type 2 DM and chronic coronary syndromes (CCS) but without prior MI. THEMIS included 19,220 participants randomized to receive ticagrelor (90 mg twice daily, reduced to 60 mg during the trial) or placebo, on a background of aspirin treatment (121). After an average follow-up of 40 months, there was a lower incidence of MACE in those receiving ticagrelor when compared to placebo (HR 0.90 [95% CI 0.81-0.99], p=0.04).  Notably, however, there was a relatively greater increase in TIMI-major bleeding (2.32 [1.82-2.94], p<0.001). Whilst meeting its primary endpoint, the net clinical benefit has not supported adoption in European practice, although subgroup analysis has suggested this may have been more favorable in those patients with prior PCI (122). Furthermore, based on the THEMIS data, the US Food and Drug Administration has recently extended the licensed indication for ticagrelor to include the prevention of a first MI or stroke in people with CCS at high risk of MI or stroke, including in those with DM (123).

An alternative to long-term DAPT is low-dose dual antithrombotic therapy (DATT) with aspirin 75-100 mg once daily and rivaroxaban 2.5 mg twice daily.  The COMPASS trial included randomization of 27,395 participants with prior MI or multivessel CAD (38% with DM) or PAD to receive either low-dose DATT, rivaroxaban 5 mg twice daily alone or aspirin alone (124). Compared to aspirin alone, low-dose DATT led to a significantly reduced incidence of MACE [4.1% vs 5.4%, HR 0.76 [95% CI 0.66-0.86], p<0.001], people with DM gaining an even greater absolute net benefit.

Current guidelines recommend long-term DAPT or low-dose dual antithrombotic therapy (DATT) in those individuals with CCS without an indication for therapeutic oral anticoagulant (OAC) who are at high ischemic risk but not high bleeding risk (22).

In those undergoing PCI for stable CAD, including in those individuals with DM, the standard DATT regimen is DAPT with aspirin and clopidogrel for 6 months (125).

In summary, individuals with DM who have CCS should be treated with at least one antiplatelet agent, usually aspirin, although clopidogrel can be used if aspirin is contraindicated. However, more recent evidence indicates that those with a previous MI benefit from long-term DAPT (aspirin and ticagrelor) or a combination of antiplatelet and anticoagulant (DATT with aspirin and rivaroxaban) provided they have a low bleeding risk. Individuals with significant CAD but without a previous MI may also benefit from DAPT or DATT, which is best reserved for people with high vascular risk but low bleeding risk. 

CEREBROVASCULAR DISEASE  

There is good evidence for use of APT with aspirin, clopidogrel, ticlopidine or aspirin and dipyridamole in combination for secondary prevention in people with cerebrovascular disease, including those who also have DM (126). Aspirin plus dipyridamole offers better long-term protection than aspirin alone, but has a frequent adverse effect of headache that can limit its use (127). Clopidogrel monotherapy, without this side effect, offers similar levels of secondary prevention to aspirin plus dipyridamole and is the current preferred agent. In the first 3 months after an ischemic stroke, if reperfusion therapy has been given, aspirin alone is typically prescribed. In cases where reperfusion therapy has not been given, there is good evidence for using either aspirin and clopidogrel or aspirin and ticagrelor over aspirin alone (128,129).  After 3 months, typically clopidogrel monotherapy is then given long-term, though aspirin and dipyridamole or aspirin alone are used instead at some centers (127,130,131).

PERIPHERAL ARTERY DISEASE

The effectiveness of APT for secondary prevention of ASCVD, including in those with symptomatic PAD, was established by the Antithrombotic Trialists’ Collaboration as discussed above. Similarly, in the CAPRIE trial, P2Y₁₂inhibitor monotherapy with clopidogrel was compared with aspirin, including in people with PAD (114). Whilst in the overall trial population there was only a modest reduction in MACE, there was evidence of greater efficacy in the subgroup with PAD, meaning clopidogrel may be preferred to aspirin. Current ESC guidelines recommend either aspirin or clopidogrel for patients with symptomatic PAD and/or those who have required revascularization, including in individuals with DM (132).

In those with symptomatic PAD, ticagrelor monotherapy has also been compared with clopidogrel in the EUCLID trial (133). There was no significant difference in the primary composite endpoint of MACE during a median follow-up period of 30 months and therefore ticagrelor monotherapy is not licensed for use in PAD. Prasugrel monotherapy has not been well tested in clinical-outcome studies but may offer pharmacodynamic advantages over clopidogrel, including in individuals with DM (134).

Comparison of DAPT (aspirin plus clopidogrel) with aspirin alone in people with PAD was included in CHARISMA (n=3,096 with PAD, 36.2% with DM). There was no significant difference in MACE (7.6% vs 8.9%, HR 0.85 [0.66–1.08], p=0.18) (135).

Conversely, there is good evidence for intensification of aspirin monotherapy to low-dose DATT with aspirin 75-100 mg once daily and rivaroxaban 2.5 mg twice daily in people with PAD, supported by the analysis of 7,470 participants with PAD in the COMPASS trial (136). The combination of rivaroxaban and aspirin reduced incidence of MACE over a median follow up of 21 months versus aspirin alone [5.1% vs 6.9%, HR 0.72 (0.57-0.90); p=0.0047]. Particularly important benefits observed included a lower incidence of major adverse limb events [1% vs 2%, HR 0·63 [95% CI 0.41–0.96], p=0·032], and lower incidence of major amputation [0.30 [0.11–0.80], p=0.011].

Subsequently, the evidence base for low-dose DATT in people PAD has been enhanced by the results of the VOYAGER-PAD trial, which randomized 6564 individuals with PAD treated by revascularization to receive either low-dose DATT or aspirin alone (137). After a median follow-up of 28 months (interquartile range 22-34), the primary composite endpoint of acute limb ischemia, amputation, MI, ischemic stroke or CV death occurred in 17.3% vs. 19.9% (HR 0.85 [0.76-0.96], p=0.009) without a significant increase in the incidence of TIMI major bleeding (2.65% vs. 1.87%, HR 1.43 [0.97-2.10, p=0.07). Forty percent of the trial population had DM with a similar response observed in this group.

It should be noted that DM individuals with symptomatic PAD are likely to have extensive vascular pathology and therefore DATT is likely to offer benefit in more than one vascular bed. Discussion of antithrombotic therapy for those people with DM and asymptomatic PAD is included in the next section.

Preventing First Atherothrombotic Event in Patients with Diabetes and No Symptomatic Atherosclerotic Cardiovascular Disease

It is rational to hypothesize that antithrombotic therapy (ATT) therapy may reduce the chance of a first atherothrombotic event or limit its severity by preventing thrombosis or reducing its impact.  ATT in several distinct groups with DM but without symptomatic ASCVD have been investigated in a number of trials. The largest individual-level meta-analysis was performed in 2009 and included 95,000 participants from 6 trials (138). In individuals with DM, though aspirin led to a 12% proportional reduction in the rate of serious vascular events, this did not reach statistical significance. However, the point estimate was consistent with the statistically significant benefit of aspirin in the non-DM population and the DM population showed an identical trend. Three further trials have been added to the literature since this meta-analysis was performed. Two, JPAD (n=2539) and POPADAD (n=1276) were not adequately powered to draw firm conclusions (139,140). However, most recently ASCEND provided data from 15,480 individuals with DM but without symptomatic ASCVD who were randomized to receive aspirin 100 mg once daily or placebo (141). After a mean follow up of 7.4 years, those randomized to aspirin had a significantly reduced rate of serious vascular events (MI, stroke or TIA, or vascular death excluding intracranial hemorrhage) (RR 0.88 [95 % CI 0.79-0.97], p=0.01). However, major bleeding was significantly more frequent when receiving aspirin (1.24 [1.09-1.52], p=0.003), the majority being gastrointestinal. The investigators concluded that the absolute benefits were largely counterbalanced by the risks, despite a favorable, albeit modest, risk-benefit ratio.

Antiplatelet drugs other than aspirin have not been widely studied for primary prevention in individuals with DM and this remains an area for future research.

CONCLUSIONS

DM leads to a prothrombotic milieu that increases the risk of atherothrombotic and thromboembolic events compared to the non-DM population. Changes in platelets, coagulation, and inflammation appear central to this increased risk. Antithrombotic therapy (ATT) can help treat or prevent thrombotic events but increases bleeding risk. In those with a history of symptomatic ASCVD, long-term antiplatelet therapy (APT) with aspirin or clopidogrel is indicated. Intensification to long-term dual antiplatelet therapy (DAPT) or low-dose dual antithrombotic therapy (DATT) should be considered in those with chronic coronary syndromes (CCS) who have high ischemic risk but not high bleeding risk. Low-dose DATT can also be beneficial to people with symptomatic PAD. Therapeutic levels of oral anticoagulant (OAC) should be considered in all individuals with DM who develop AF. Accurately assessing and balancing a patient’s risk of ischemic and bleeding events is key to making rational treatment recommendations for ATT in DM (Figure 3).

Looking to the future, further work to determine more precisely an individual’s thrombotic and bleeding risk would greatly enhance our ability to make the best treatment recommendations for patients with DM. Whether this is achieved by more complex statistical modelling, novel imaging techniques, and/or better appreciation of circulating biomarkers remains to be determined. This would allow a greater move towards personalized strategies in order to more appropriately balance the benefits and risks of ATT. People with DM often have complex co-morbidities meaning choosing the best regimen is difficult, but is at the same time crucial to ensure an optimal outcome.

Emerging strategies such as early de-escalation of DAPT are encouraging new tools giving more options for subtle adjustment of ATT intensity, but require definitive proof they lead to no significant ischemic penalty and ratification by guideline committees before wider adoption can be recommended. No doubt further clarity will follow in the coming years.

The lack of an ability of ATT to meaningfully improve net clinical outcomes in those with DM without established ASCVD is a source of disappointment and demands future attention. Trials have focused on aspirin but it is clear that people with DM may have a poor response (111). As well as trials exploring novel regimens of aspirin, trials testing P2Y₁₂ inhibitor monotherapy, which may offer pharmacodynamic advantages over aspirin in this group, are warranted (134).

Finally, targeting the pathological abnormalities that cause hypofibrinolysis in diabetes, such as inhibition of PAI-1 activity, may offer an alternative management strategy to further reduce vascular occlusive disease in diabetes, while keeping the risk of bleeding to a minimum.

Figure 3. Principles to consider when deciding on the optimal regimen of antithrombotic therapy in a person with diabetes. ACS, acute coronary syndrome; AF, atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CI, contraindication; DAPT, dual antiplatelet therapy; DATT, dual antithrombotic therapy; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; OAC, oral anticoagulation; PAD, peripheral artery disease; PCI, percutaneous coronary intervention.

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ABSTRACT

While most patients with diabetes have Type 1 diabetes (T1D) or Type 2 diabetes (T2D) there are other etiologies of diabetes that occur less frequently. In this chapter we will discuss a number of these less-common causes of diabetes. It is clinically very important to recognize these uncommon causes of diabetes as treatment directed towards the underlying etiology can at times result in the remission of the diabetes (for example Cushing’s Syndrome) or be required to avoid other complications of the underlying disorder (for example hemochromatosis, which in addition to causing diabetes can lead to severe liver disease and congestive heart failure). In this chapter the following disorders that are associated with diabetes are discussed: 1) genetic disorders of insulin action (Type A insulin resistance, Donohue Syndrome/Leprechaunism, Rabson-Mendenhall syndrome); 2) maternally inherited diabetes mellitus and deafness syndrome; 3) disorders of the exocrine pancreas (pancreatitis, trauma/pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis); 4) endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, primary hyperaldosteronism); 5) drug induced; 6) infections; 7) immune mediated (stiff-man syndrome, anti-insulin receptor antibodies); 8) ketosis prone diabetes (Flatbush diabetes); and 9) genetic disorder sometimes associated with diabetes (Down syndrome, Klinefelter syndrome, Turner syndrome, Wilsons syndrome, Wolfram syndrome, Friedreich ataxia, Huntington chorea, Bardet-Biedl syndrome (Laurence-Moon-Biedl syndrome), myotonic dystrophy, porphyria, Prader-Willi syndrome, Alström syndrome). Gestational diabetes, monogenic diabetes (maturity onset diabetes of the young (MODY) and neonatal diabetes), lipodystrophy, fibrocalculous pancreatic disease, diabetes associated with HIV infection, diabetes due to the autoimmune polyglandular syndromes, and post-transplant diabetes are not discussed in this chapter as they are discussed in other Endotext chapters.

INTRODUCTION

While most patients with diabetes have Type 1 diabetes (T1D) or Type 2 diabetes (T2D) there are other etiologies of diabetes that occur less frequently. In this chapter we will discuss a number of these less-common causes of diabetes (see table 1). Note that gestational diabetes, monogenic diabetes (maturity onset diabetes of the young (MODY) and neonatal diabetes), lipodystrophy, fibrocalculous pancreatic disease, diabetes associated with HIV infection, diabetes due to the autoimmune polyglandular syndromes, and post-transplant diabetes are discussed in separate Endotext chapters (1-7). It is clinically very important to recognize these uncommon causes of diabetes as treatment directed towards the underlying etiology can at times result in the remission of the diabetes (for example Cushing’s Syndrome) or be required to avoid other complications of the underlying disorder (for example hemochromatosis, which in addition to causing diabetes can lead to severe liver disease and congestive heart failure).

MATERNALLY INHERITED DIABETES MELLITUS AND DEAFNESS (MIDD)

Maternally inherited diabetes mellitus and deafness is a mitochondrial disorder characterized by diabetes and progressive sensorineuronal hearing loss (8,9). Mitochondrial DNA is only transmitted from the mother as the sperm lacks mitochondrial DNA (8). Therefore, over 50% of affected individuals with MIDD have a mother with diabetes.  A mother with this disorder transmits the mutation to almost all of her offspring (10). However, the proportion of somatic cells with the mutation can vary considerably, a condition called heteroplasmy (9). The higher the number of somatic cells with a mutation the greater is the penetrance of symptoms and disease severity. Additionally, the proportion of somatic cells with a mutation can vary from tissue to tissue and explains the variability in the manifestations of this disorder (9). The prevalence of mitochondrial diabetes in the diabetes population depends on ethnic background and ranges between 0.2% and 2%, with the highest prevalence in Japan (10).

MIDD is associated with a point mutation in a transfer ribonucleic acid (tRNA) gene at position 3243 with an A to G transition (8,9). In addition to diabetes and auditory impairment, the m.3243A>G mutation can cause other clinical manifestations including central neurological and psychiatric disorders, eye disease, myopathy, cardiac disorders, renal disease, endocrine disease, and gastrointestinal disease (8,9). Other point mutations in mitochondrial DNA can also result in diabetes and deafness but these mutations are rare in comparison to m.3243A>G (8-10).

It is thought that defects in mitochondrial function result in the decreased production of ATP following glucose uptake by beta cells resulting in decreased insulin secretion in response to elevated glucose levels (8,9). Additionally, mitochondrial dysfunction in the highly metabolically active pancreatic islets ultimately results in the loss of B‐cell mass further compromising insulin secretion (9). Insulin sensitivity is usually normal (10). Other tissues that are metabolically active may also be adversely effected by the inability of the mitochondria to produce ATP including the cells in the cochlea (9).

The clinical syndrome of MIDD can phenotypically resemble either T1D or T2D (9,10). The age of onset varies between childhood and mid-adulthood. Approximately 20% of patients present acutely with high glucose levels and even ketoacidosis (9). Most patients do not have islet cell antibodies but they are present in a small number of patients (9). This could be due to concomitant T1D or to the development of antibodies secondary to beta cell destruction due to mitochondria dysfunction. Patients tend to be thin rather than obese (9). This disorder can be distinguished from MODY by the presence of multi-organ involvement, particularly sensorineural hearing loss, and maternal rather than autosomal dominant transmission. Initially patients may be treated with diet and/or oral agents but overtime most patients with MIDD progress to requiring insulin therapy (8-10).

As the name implies this disorder is recognized by the presence of diabetes and deafness and a family history of these conditions in maternal relatives (9,10). Hearing loss is present in approximately 75% of patients and typically precedes the development of diabetes (9). Hearing loss is more common and severe in males (9). Approximately 10-15% of patients, in addition to having diabetes and deafness, also have the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (9). The m.3243A>G mutation can cause a wide spectrum of abnormalities that include neurological abnormalities (strokes, dementia, seizures), psychiatric disorders including recurrent major depression, schizophrenia and a variety of phobias, macular retinal dystrophy with pigmentation, proximal myopathy, cardiomyopathy, renal failure, short stature, endocrine dysfunction, and gastrointestinal complaints (9). The finding of classical retinal dystrophy and hyperpigmentation on routine eye exam should suggest the diagnosis of maternally inherited diabetes mellitus and deafness. Once suspected the diagnosis of MIDD should be confirmed by genetic testing for the mitochondrial DNA point mutation at position 3243 (A>G). This is usually initially carried out on blood cells but if negative urinary cells or skeletal muscle can be tested and if necessary one can test for other mutations that cause similar phenotypes (11). Once a diagnosis is confirmed first-degree family members at risk should be screened for the mutation and provided with genetic counseling. For those carrying the mutation without clinical manifestations, screening for diabetes and monitoring of kidney function, hearing, and cardiac function should be carried out.

GENETIC DEFECTS IN INSULIN ACTION

Overview of Insulin Receptor Defects

Mutations in the insulin receptor can cause different degrees of insulin resistance but do not need to be associated with diabetes per se (12). A large number of different mutations have been described and they can be classified as mutations that prevent synthesis of the receptor, inhibit transport of the receptor to the plasma membrane, decrease insulin binding to the receptor, impair transmembrane signaling, or increase receptor degradation (13). Pancreatic beta cell hyperplasia and hyperinsulinemia can compensate for the insulin resistance preventing hyperglycemia. Fasting hypoglycemia and postprandial hyperglycemia may be observed. Overtime the beta cells’ ability to secrete insulin diminishes and frank diabetes usually develops. Treatment of the diabetes may require very high doses of insulin (14). Unfortunately, insulin sensitizers have not been very effective in patients with insulin receptor defects. In contrast to the typical patients with insulin resistance, obesity, dyslipidemia, hypertension, and fatty liver are not usually present (14,15). Acanthosis nigricans, pigmentation in the neck or axillae, is a visible sign of severe insulin resistance (12,14). In females, severe insulin resistance is usually associated with hyperandrogenism, oligomenorrhea or amenorrhea, anovulation, hirsutism, acne, and masculinization (12,14). It is hypothesized that the ovarian dysfunction and acanthosis nigricans is due to high levels of insulin acting via the IGF1 receptors (15). The amount of residual insulin receptor function determines the specific syndrome in patients with insulin receptor mutations (Figure 1).

Figure 1. Insulin Receptor Mutation Syndromes (Modified from reference (12)). Severe disorders are usually homozygous or compound heterozygous mutations while milder forms are often heterozygotes.

Type A Insulin Resistance

This autosomal dominant disorder includes patients with severe insulin resistance and acanthosis nigricans (12,14). Patients have normal growth and females show ovarian hyperandrogenism that typically presents in the peripubertal period (14). In females, hyperglycemia develops after ovarian hyperandrogenism and acanthosis nigricans. Males display only acanthosis nigricans and they often remain undiagnosed even after the development of symptomatic diabetes, which may not occur until the patients are adults. These patients have mutations in the insulin receptor gene that decreases the activity of the insulin receptor (13,14). In addition, mutations in transcription factors that stimulate the expression of insulin receptors can lead to a similar phenotype as mutations in the insulin receptor (10). Inherited defects in pathways downstream of the insulin receptor can also lead to clinical abnormalities similar to mutations in the insulin receptor (10,11).

Donohue Syndrome (Leprechaunism)

Donohue syndrome is a rare congenital, autosomal recessive syndrome characterized by very severe insulin resistance due to mutations in the insulin receptor gene, dysmorphic features such as protuberant and low-set ears, flaring nostrils and thick lips, growth retardation, failure to thrive, and early death (13). The name leprechaunism relates to the elfin features of those affected. Clinical features include in addition to acanthosis nigricans, hypertrichosis, hirsutism, dysmorphic facies, breast enlargement, abdominal distension, and lipoatrophy. Patients have extremely high levels of insulin and can develop impaired glucose tolerance or overt diabetes. The prognosis for infants with this condition is very poor and most will die in the first year of life. When parents, who are heterozygous for mutations in the insulin receptor are studied, many of these individuals are insulin resistant (13).

Rabson-Mendenhall Syndrome

The Rabson-Mendenhall syndrome represents another disorder of extreme insulin resistance (14). This autosomal recessive syndrome is associated with mutations in the insulin receptor gene (12). Initially fasting hypoglycemia, postprandial hyperglycemia, and marked hyperinsulinemia may be observed (12). When beta-cells decompensate, hyperglycemia may become very difficult to treat. Clinical features include in addition to acanthosis nigricans, phallic enlargement, precocious pseudopuberty, short stature, and abnormal teeth, hair and nails (13,14). Hyperplasia of the pineal gland is an unusual feature (13). Prognosis is poor as diabetes is difficult to control even with high insulin doses (13). Hyperglycemia leads to microvascular disease and/or diabetic ketoacidosis resulting in death in the second and third decades of life (12). Leptin administration has resulted in an improvement in this syndrome (16,17).

DISEASES OF THE EXOCRINE PANCREAS

Diseases that destroy the pancreas can cause DM even in individuals who do not have risk factors for diabetes (18). In the medical literature this is often referred to as Type 3C diabetes. Acquired causes of damage to the pancreas include pancreatitis, trauma, infection, pancreatic carcinoma, and pancreatectomy. Inherited disorders that affect the endocrine pancreas, such as hemochromatosis, thalassemia, and cystic fibrosis, can also cause insulin deficiency and diabetes. The distribution of causes for diabetes secondary to pancreatic disorders in one study was chronic pancreatitis (79%), pancreatic ductal adenocarcinoma (8%), hemochromatosis (7%), cystic fibrosis (4%), and previous pancreatic surgery (2%) (19). The prevalence of diabetes secondary to pancreatic disease is estimated to range from 1% to 9% and likely will depend on the patient population studied (20). In a population study carried out in New Zealand the prevalence of diabetes secondary to pancreatic disorders was close to that of T1D (21).

Pancreatitis

Pancreatitis may lead to the destruction of the beta cells due to inflammation and irreversible fibrotic damage  (22). In addition to destroying the beta cells, pancreatitis also leads to the destruction of glucagon secreting alpha-cells and pancreatic polypeptide secreting cells (22). The decrease in insulin secretion is the primary mechanism leading to hyperglycemia. In addition, the decrease in secretion of pancreatic polypeptide leads to a decrease in hepatic insulin sensitivity resulting in increased hepatic glucose production (23). Nutrient malabsorption that occurs secondary to pancreatitis leads to impaired incretin secretion that can result in diminished insulin release by the remaining beta-cells (24). Acute pancreatitis can induce transient hyperglycemia that can last for several weeks or permanent hyperglycemia (20,25,26). Predictors of the development of diabetes include obesity, a family history of diabetes, exocrine pancreatic insufficiency, history of pancreatic surgery, pancreatic calcifications, and long duration of pancreatitis (27).

The prevalence of diabetes secondary to pancreatitis varies greatly with studies in North America estimating a prevalence of 0.5%-1.15% whereas in Southeast Asia, where tropical or fibrocalcific pancreatitis is endemic, a prevalence of approximately 15%-20% has been reported (22) (see chapter in Tropical Endocrinology Section of Endotext entitled “Fibrocalculous Pancreatic Diabetes” for an in depth discussion of this entity (7). Recently, data from the UK Royal College of General Practitioners Research and Surveillance Centre found 559 cases of diabetes following pancreatic disease in 31,789 cases of adults newly diagnosed with diabetes (1.8%) (28). Most cases of diabetes following pancreatic disease were classified as T2D (28). In another study approximately 50% of the patients with diabetes secondary to pancreatitis were not recognized and were incorrectly thought to have T2D (5). It is very likely that many cases of diabetes secondary to pancreatitis are not recognized to be due to pancreatic disease.

The prevalence of diabetes in patients with diagnosed pancreatitis has ranged between 26-80%, depending on the cohort and duration of follow up (20,22,29). The prevalence of diabetes increases with the duration of pancreatitis and early onset of calcific disease (22). Because of the high risk of diabetes in patients with pancreatitis these patients should be periodically screened for the presence of diabetes with measurement of fasting glucose and/or A1c levels.

At times it can be difficult to distinguish diabetes secondary to pancreatitis from T1D or T2D. The following diagnostic criteria have been proposed (Table 2) (22).

It should be recognized that these proposed criteria have not been rigorously tested nor are all criteria available in routine clinical practice. In addition, there are a number of key considerations. First, long-standing T1D and T2D are associated with exocrine pancreatic failure (30). It has been estimated that 26% to 74% of patients with T1D and 28% to 36% of patients with T2D have evidence of exocrine pancreatic insufficiency (18). Second, patients with diabetes are at a higher risk for developing acute and/or chronic pancreatitis (31). Lastly, patients with previous episodes of pancreatitis may also develop T1D or T2D independently of their exocrine pancreatic disease. When diabetes occurs in patients with a pre-existing diagnosis of chronic pancreatitis it is likely that the pancreatitis is an important contributor to the development of the diabetes.

Testing for T1D associated autoimmune markers can be helpful in separating T1D from diabetes secondary to pancreatic disease. The presence of islet cell antibodies supports the diagnosis of T1D. The pancreatic polypeptide response to insulin-induced hypoglycemia, secretin-infusion, or a mixed nutrient ingestion can be helpful in separating T2D from diabetes secondary to pancreatic disease. Patients with diabetes secondary to pancreatitis have an absent or reduced pancreatic polypeptide response while patients with T2D have an elevated pancreatic polypeptide response (22,29). Studies have shown that pancreatic polypeptide regulates hepatic insulin sensitivity and the absence of pancreatic polypeptide leads to hepatic insulin resistance and enhances hepatic glucose production, which could contribute to the abnormal glucose metabolism that occurs with pancreatic disease (20).

In patients with diabetes secondary to pancreatitis hyperglycemia can be mild to very severe depending upon the degree of pancreatic destruction leading to impaired insulin production and secretion (18,20,22). Glycemic control may be unstable due to the loss of glucagon secretion in response to hypoglycemia, carbohydrate malabsorption, and inconsistent food intake due to pain and/or nausea secondary to pancreatitis (i.e., “brittle diabetes”) (18,20,22). Whether glycemic control is worse in patients with diabetes secondary to pancreatitis is uncertain as older studies reported worse glycemic control and more recent studies have reported that glycemic control was similar to other patients with diabetes (18). The ability to obtain good glycemic control is likely to be related to the degree of pancreatic insufficiency with patients with a total absence of pancreatic function being more difficult to control.

In patients with relatively mild diabetes treatment with metformin is indicated. The GI side effects (nausea, abdominal complaints, diarrhea) of metformin may not be tolerable in some patients with pancreatitis. In observational studies metformin therapy has been associated with a reduction in the development of pancreatic cancer in patients with diabetes (32). Given the increased risk of pancreatic cancer in patients with diabetes and/or pancreatitis a reduction in the development of pancreatic cancer would be a potential added benefit of metformin therapy (33-35). There are conflicting data on whether treatment with DPP4-inhibitors or GLP1-analogues can cause pancreatitis, but until this issue has been unequivocally settled, it is wise to refrain from using these drugs in patients who have had pancreatitis without a clear reversible etiology (for example, gallstone pancreatitis status post cholecystectomy). Thiazolidinediones should probably be avoided as patients with pancreatitis and malabsorption are at increased risk for osteoporosis and thiazolidinediones may potentiate this problem.

Chronic pancreatitis is a progressive disease and therefore it is likely that glycemic control will worsen overtime and most patients will eventually require insulin therapy (22). Many patients will have severe insulin deficiency and will need to be treated with insulin therapy using regimens employed in patients with T1D. Because of the absence of glucagon secretion patients with diabetes secondary to pancreatitis are more susceptible to severe hypoglycemia with insulin therapy but diabetic ketoacidosis is not commonly observed due to the absence of glucagon.

Patients with diabetes secondary to pancreatitis are at risk for microvascular complications and lower extremity arterial disease and therefore routine testing for eye disease, kidney disease, foot ulcers, and neuropathy should be instituted (36-39).

Finally, it should be recognized that patients with diabetes secondary to pancreatitis will almost always have exocrine pancreatic insufficiency (29). Many patients with chronic pancreatitis manifest fat malabsorption without symptoms and therefore a thorough evaluation is required. Oral pancreatic enzyme replacement is beneficial in these patients. Of note, pancreatic enzyme supplementation can improve incretin secretion and thereby may benefit glycemic control (20,24,40). Fat soluble vitamin deficiency commonly occurs (Vitamin A, D, and K) and many patients will require supplementation with fat-soluble vitamins.

Pancreatectomy

The metabolic abnormalities that occur after pancreatic surgery depend on the amount and area of the pancreas removed and whether the remaining pancreas is normal or diseased (23). The basis for this variability is due to the distribution of β and non-β islet cell types in the pancreas. Islet density is relatively low in the head of the pancreas and gradually increases through the body toward the tail region by greater than 2-fold and thus α- and β-cells predominate in the tail. In contrast, the cells that secrete pancreatic polypeptide are mainly localized in the head of the pancreas. Distal pancreatectomy usually causes little change in the metabolic status unless more than 50% of parenchyma is excised in patients with diffuse disease or more than 80% in patients with normal pancreatic function (23). Approximately 4.8 to 38% of patients develop diabetes after a distal pancreatectomy (23). Resection of the head of the pancreas results in a decrease in pancreatic polypeptide, hepatic insulin resistance, and fasting hyperglycemia. Approximately 20% of patients develop diabetes after resection of the head of the pancreas (23). It should also be recognized that removal of pancreatic tissue can accelerate the development of T2D by decreasing insulin secretion in patients with impaired glucose metabolism (41).

Patients who have undergone total surgical pancreatectomy have a deficiency of insulin, glucagon, and pancreatic polypeptide and require insulin treatment. In general, there are several differences from typical T1D, including exocrine deficiency, low insulin requirements, and a higher risk of hypoglycemia due to the decrease in glucagon, which stimulates hepatic glucose production (glycogenolysis and gluconeogenesis). Pancreatectomized patients are prone to hypoglycemia and a delayed recovery from hypoglycemia. In an evaluation of 180 patients post pancreatectomy 42% experienced one or more hypoglycemic events on a monthly basis (42). In addition to treatment with insulin, pancreatic enzyme supplements are always needed. Intraportal islet auto transplantation has been used to prevent the development of diabetes with total pancreatectomy and/or reduce the risk of developing difficult to control diabetes (43-45).

Pancreatic Cancer

A high percentage of patients with pancreatic carcinoma have diabetes (20,46). In one study 68% of patients with pancreatic cancer also had diabetes (47). The prevalence of diabetes in patients with pancreatic cancer is much higher than in other common malignancies (46,47). In patients with pancreatic cancer who also have diabetes, the diagnosis of diabetes occurred less than 2 years prior to the diagnosis of pancreatic cancer in 74% of patients (48). In a population-based study 0.85% of patients over the age of 50 years with newly diagnosed diabetes were diagnosed with pancreatic cancer within 3 years (49). In a study of 115 patients over 50 years of age who were hospitalized for new-onset diabetes 5.6% were found to have a pancreatic cancer (50). Many patients with pancreatic cancer lose weight and therefore deteriorating glycemic control in conjunction with weight loss and anorexia should raise the possibility of an occult pancreatic cancer (46,51). Other clues to the presence of pancreatic cancer in a patient with new onset diabetes are the lack of a family history of diabetes, a BMI < 25, and the absence of features of the metabolic syndrome such as dyslipidemia and hypertension. Given the high incidence of diabetes relative to the incidence of pancreatic cancer the routine screening of all patients who develop diabetes is not cost effective. However, in selected patients with the features described above screening is appropriate.

Conversely, long standing T2D increases the risk of developing pancreatic cancer by approximately 1.5 to 2-fold indicating a bidirectional relationship (23,46,52). This risk may persist even after adjustment for obesity and smoking, risk factors for pancreatic cancer. Diabetes is both a risk factor for the development of pancreatic cancer and a complication of pancreatic cancer.

As discussed above diabetes may develop secondary to chronic pancreatitis. Chronic pancreatitis increases the risk of pancreatic cancer. Thus, patients with diabetes secondary to chronic pancreatitis are at a higher risk of developing pancreatic cancer (53).  

The strongest evidence linking pancreatic cancer with incident diabetes is the beneficial effects of cancer resection on glycemic control (46). In a small study in 7 patients, Permert and colleagues reported an improvement in diabetes status and glucose metabolism after subtotal pancreatectomy (54). Similarly, Pannala and colleagues in a larger study reported that after pancreaticoduodenectomy, diabetes resolved in 17 of 30 patients (57%) with new-onset diabetes but was unaffected in patients with longstanding diabetes (48). Litwin and colleagues noted similar improvements in glucose metabolism after surgery in patients with pancreatic cancer but a deterioration in patients with chronic pancreatitis (55). Finally, studies have also shown that a good response to chemotherapy in patients with pancreatic cancer can also improve glucose levels (56). Taken together these results demonstrate a benefit from tumor removal and suggest that new-onset diabetes associated with pancreatic cancer may be a paraneoplastic phenomenon.

The mechanism accounting for the development of new onset diabetes by pancreatic cancers is unknown (46). In contrast to other pancreatic disorders the etiology of diabetes is not due to destruction of the pancreas as patients with new onset diabetes and pancreatic cancer have hyperinsulinemia rather than low insulin levels and as noted above the diabetes improves after resection (20). Additionally, the pancreatic cancers may be very small and thus unlikely to cause pancreatic insufficiency. Pancreatic cancer is associated with insulin resistance but the factors leading to insulin resistance are unknown (20).

In patients with pancreatic cancer the main goal of the treatment of diabetes is to prevent the short- term metabolic complications and facilitate the ability of the patient to tolerate treatment of the pancreatic cancer (surgery and chemotherapy). Given the poor survival of patients with pancreatic cancer prevention of the long-term sequelae of diabetes is not a major focus. Metformin is a preferred hypoglycemic agent because there are observational studies suggesting that metformin may improve survival in patients with pancreatic cancer (57-59). However, randomized trials have failed to demonstrate a benefit of metformin therapy in patients with pancreatic cancer (60,61).

Hemochromatosis

Hemochromatosis is an autosomal recessive disorder characterized by increased iron absorption by the GI tract and increased total body iron stores (62). The excess iron is sequestered in many different tissues including the liver, skin, heart, and the pancreas. The classic triad of hemochromatosis is diabetes mellitus, hepatomegaly, and increased skin pigmentation (“bronze diabetes”), but clinical features also include gonadal failure, arthropathy, and cardiomyopathy (62).

In early studies diabetes was present in over 50% of patients with hemochromatosis (63,64). More recently the prevalence of diabetes in patients with hemochromatosis has decreased to approximately 20% of patients, presumably due to the early diagnosis and treatment of hemochromatosis due to genetic testing (63-66). In patients with hemochromatosis screening for the presence of diabetes should be periodically carried out.

Diabetes was typically observed in persons who also had severe iron overload and cirrhosis (64). In recent studies with lower rates of diabetes impaired glucose tolerance was observed in approximately 30% of patients with hemochromatosis (63,66). It should be noted that iron overload from any cause can result in diabetes (67). For example, patients with thalassemia develop iron overload due to the need for frequent transfusions (68,69). The prevalence of diabetes in patients with thalassemia has been declining since the more aggressive and widespread use of iron chelation therapy (69).

There are two abnormalities that lead to abnormal glucose metabolism in patients with hemochromatosis and iron overload (63). First, iron overload leads to beta cell damage with decreased insulin production and secretion. Pathologic examination revealed hemosiderin deposition and iron-induced fibrosis of the islets (64). The decrease in insulin secretion is the primary defect leading to the development of diabetes (63,64,66). Of note glucagon secretion does not appear to be deficient in patients with diabetes and hemochromatosis suggesting that the iron overload has a preferential toxicity for beta cells compared to alpha cells (64,70,71). Similarly, basal and stimulated pancreatic polypeptide levels are also not decreased in diabetic patients with hemochromatosis (72). Thus, the hormonal abnormalities differ in patients with iron overload induced diabetes compared to patients with pancreatitis induced diabetes. The second abnormality is insulin resistance that occurs due to iron overload hepatic damage and/or secondary to obesity (63,64). In addition, a genetic predisposition to diabetes potentiates the development of metabolic dysfunction. Many patients with hemochromatosis and diabetes have a relative with diabetes (73).

The typical micro and macrovascular complications of diabetes occur in patients with hemochromatosis (64,73). In a study by Griffiths and colleagues, 11 of 49 patients with hemochromatosis and diabetes had diabetic retinopathy (74). Sixty percent of the patients with hemochromatosis who had diabetes for greater than 10 years had retinopathy. The incidence of retinopathy is similar to that observed in the general diabetes population (73,74). Similarly, Becker and Miller observed that 7 of 22 patients with diabetes and hemochromatosis had pathologic evidence of diabetic glomerulopathy (75).

The treatment of hemochromatosis by phlebotomy has a variable impact on glucose metabolism (63). In patients who do not yet have complications or organ damage an improvement of insulin secretory capacity and normalization of glucose tolerance has been observed (63,64). Glucose metabolism often improves in patients with impaired glucose tolerance (63,76). In patients with diabetes improvement in glucose metabolism by phlebotomy may occur but is not as common as in “pre-diabetics” (63,76,77). In one study 28% of patients with diabetes and hemochromatosis on insulin or oral agents showed improved glucose control following phlebotomy therapy (78).

Cystic Fibrosis

Cystic Fibrosis is an autosomal recessive disorder due to a defect in the chloride transport channel (79). Cystic fibrosis related diabetes is rare in children but is present in approximately 20% of adolescents and 40-50% of adults with cystic fibrosis (80,81). As patients with cystic fibrosis live longer it is likely that the number of patients with cystic fibrosis and diabetes will increase. The development of diabetes is associated with more severe cystic fibrosis gene mutations, increasing age, worse pulmonary function, undernutrition, liver dysfunction, pancreatic insufficiency, a family history of diabetes, female gender, and corticosteroid use (80,81).

The primary defect in patients with cystic fibrosis related diabetes is decreased insulin production and secretion due to fibrosis and atrophy of the pancreas with a reduction of islet mass (80). In addition, mutations in the cystic fibrosis transmembrane conductance regulator gene may have direct effects on the ability of beta cells to secrete insulin (81,82). Beta cell dysfunction is not complete with residual insulin secretion and thus patients with cystic fibrosis related diabetes do not typically develop ketosis (80). Reduced alpha cell mass also occurs so while fasting glucagon levels are normal, glucagon secretion in response to hypoglycemia is impaired (80). Peripheral and hepatic insulin resistance may also occur secondary to infections and inflammation (81).

Some of the clinical features of cystic fibrosis related diabetes are similar to T1D as patients are young, not obese, insulin deficiency is the primary defect, and features of the metabolic syndrome (hyperlipidemia, hypertension, visceral adiposity) are not usually present (80). However, cystic fibrosis related diabetes is not an autoimmune disease (islet cell antibodies are not present) and ketosis is rare because endogenous insulin is still produced (80). Fasting glucose levels are often normal initially with elevated postprandial glucose levels due to a reduced and delayed insulin response to carbohydrates while basal insulin is often adequate to maintain normal glucose levels (83). Patients with cystic fibrosis related diabetes are not at high risk to develop atherosclerosis and heart disease is not a major issue (80-82). This is likely due to malabsorption leading to life-long low plasma cholesterol levels and the shortened length of life (80,81). As life expectancy increases the risk of macrovascular disease may increase. Microvascular complications do occur in cystic fibrosis related diabetes and are related to the duration of diabetes and glycemic control (80,81,83). The American Diabetes Association recommends screening for complications of diabetes beginning 5 years after the diagnosis of cystic fibrosis related diabetes (84)

Lung disease is a major cause of morbidity and mortality in patients with cystic fibrosis and both insulin insufficiency and hyperglycemia negatively affect cystic fibrosis lung disease (85). Numerous studies have shown that the occurrence of diabetes in patients with cystic fibrosis is associated with more severe lung disease and increased mortality and this adverse effect disproportionately affects women (80,83,85). In patients with cystic fibrosis lung function is critically dependent on maintaining normal weight and lean body mass. Insulin deficiency leads to a catabolic state with the loss of protein and fat (80). Multiple studies have shown that insulin replacement therapy improves nutritional status and pulmonary function in patients with cystic fibrosis related diabetes (80). In addition, elevated blood glucose levels result in elevated blood glucose levels in the airways, which promotes the growth of pathogenic microorganisms and increase pulmonary infections (80,83). Of note recent studies have shown that the marked increase in mortality in patients with cystic fibrosis related diabetes compared to patients with cystic fibrosis only has diminished (86). It is likely that early diagnosis and aggressive treatment has improved survival in patients with cystic fibrosis related diabetes.

Because of the adverse effects of diabetes on lung function in patients with cystic fibrosis routine screening for diabetes is recommended (85). It is recommended that annual screening begin at age 10 (85). While fasting glucose and A1c levels are routine screening tests for diabetes, in patients with cystic fibrosis these tests are not sensitive enough (85). Fasting glucose and A1c testing will fail to diagnose approximately 50% of patients with cystic fibrosis related diabetes (82,85). However, recent studies have suggested that a screening A1c >5.5% would detect more than 90% of patients with diabetes and therefore with further confirming studies measuring A1c levels could become an initial screening approach (84).  As noted above, abnormalities in postprandial glucose characterizes cystic fibrosis related diabetes and it is therefore recommended that an oral glucose tolerance test (OGTT) be utilized for the diagnosis of diabetes in patients with cystic fibrosis (85). Studies have shown that the diagnosis of diabetes by OGTT correlates with clinically important cystic fibrosis outcomes including the rate of lung function decline, the risk of microvascular complications, and the risk of early death (85). Moreover, the OGTT identified patients who benefited from insulin therapy (85). Additional screening recommendations are shown in Table 3 and the interpretation of these tests are shown in Table 4.

CF= cystic fibrosis; CRFD= cystic fibrosis related diabetes; OGTT= oral glucose tolerance test, SMBG= self-monitored blood glucose

CF= cystic fibrosis; CRFD= cystic fibrosis related diabetes; OGTT= oral glucose tolerance test

There is evidence that elevations in glucose below the levels typically used to diagnose diabetes result in adverse effects on the lungs (83). Thus, some experts recommend that treatment should be considered for individuals with abnormal glucose levels which do not meet the criteria for diabetes if there is evidence of declining lung function or weight loss (83).

A unique feature in the treatment of patients with cystic fibrosis related diabetes is that insulin is the treatment of choice in all patients (85). Studies have shown that cystic fibrosis patients on insulin therapy who achieve good glycemic control demonstrate improvement in weight, protein anabolism, pulmonary function, and survival (85). No specific insulin treatment regimen is recommended and the regimen should be individualized for the patient. For example, a patient with elevated postprandial glucose levels will benefit from meal time rapid acting insulin. It should be noted that patients with cystic fibrosis induced diabetes still have endogenous insulin production, which allows for the achievement of good glycemic control. Oral diabetes agents are not as effective as insulin in improving nutritional and metabolic outcomes and therefore are not recommended (85). For most patients with cystic fibrosis related diabetes an A1c < 7% is recommended but the A1c goal can be higher or lower for certain patients based on clinical judgement. Also of note is that cystic fibrosis patients require a high-calorie, high-salt, high-fat diet.

Ivacaftor, a cystic fibrosis transmembrane conductance regulator modulator, is a relatively new agent to treat cystic fibrosis and has been shown to partially reverse the disease. Interestingly in case reports ivacaftor has been shown to markedly improve glycemic control (81,87). In a recent retrospective observation study approximately 1/3 of patients with CFRD had either a resolution of their diabetes or marked improvement with ivacaftor therapy (88). Additionally, the risk of developing CFRD is decreased in patients treated with ivacaftor (89). This beneficial effect is likely due to an improvement in insulin secretion (81,90).

INFECTIONS

Viral Infections

Viral infections, particularly enterovirus and herpes virus infections, have been postulated to play a role in triggering the autoimmune reaction that leads to the development of T1D (91-93). This phenomenon is discussed in detail in the Endotext chapter on the pathogenesis of T1D and the Endotext chapter on changing the course of the disease in T1D (94,95). In rare instances a viral infection has been associated with the fulminant development of diabetes due to the destruction of beta cells (96).

Congenital Rubella

Congenital rubella infection has been shown to predispose to the development of T1D that usually presents before five years of age (97). It has been estimated that approximately 1-6% of individuals with the rubella syndrome will develop diabetes in childhood or adolescence (97,98). The mechanism for this association is unknown. In addition, studies have also shown that patients with congenital rubella also develop T2D (98). In one series 22% of individuals with congenital rubella developed diabetes later in life (98). Fortunately, with increased vaccinations, congenital rubella has become a disease of the past in developed countries.

Hepatitis C Virus (HCV)

Meta-analyses and large data base studies have demonstrated that HCV infection is associated with an increased risk of T2D (99-104). In a meta-analysis of 34 studies the risk of diabetes in patients with HCV infection was increased by approximately 70% (99). Moreover, HCV infection is associated with an increased risk of T2D independent of the severity of the associated liver disease (i.e. occurs in patients without liver disease) but the risk of T2D was higher in HCV patients with cirrhosis (100). As expected, the risk of diabetes is increased in HCV patients if the BMI is increased, there is a family history of diabetes, older age, more severe liver disease, and male sex. Conversely, the prevalence of HCV infection in patients with T2D is higher than in non-diabetic controls (100,104,105). In a meta-analysis of 22 studies with 78,051 individuals it was found that patients with T2D were at a higher risk of HCV infection than non-diabetic patients (OR = 3.50; CI = 2.54-4.82) (105). Finally, diabetes is a significant risk factor for the development of liver cirrhosis and hepatocellular carcinoma in HCV infected patients (104,106-109).

Given the increased risk of diabetes in HCV infected patients it seems prudent to routinely screen HCV positive patients for diabetes. Conversely, screening patients with diabetes for HCV infection seems reasonable given the availability of drugs that can effectively treat HCV infections.

Patients with diabetes and HCV infection are insulin resistant in the liver and peripheral tissues (104,109,110). Insulin resistance is present in HCV infection in the absence of significant liver dysfunction and prior to the development of diabetes (110). Treatment that reduces viral load decreases insulin resistance and the risk of developing diabetes in HCV (104,110,111). The insulin resistance in individuals with HCV infections may be due to inflammation induced by cytokines such as TNF-alpha or monocyte chemoattractant protein-1, released from HCV-induced liver inflammation (104,109). Additionally, HCV may directly activate the mTOR/S6K1 signaling pathway, inhibiting IRS-1 protein function and thereby down-regulating GLUT-4 and up-regulating the gluconeogenic enzyme phosphoenolpyruvate carboxykinase-2 (104,109).

Studies have shown that direct-acting antiviral agents that eradicate HCV infection are associated with improved glycemic control in patients with diabetes indicated by decreased A1c levels and decreased insulin use (109,112). Additionally, in a database study of anti-viral treatment for HCV infection, a decrease in end-stage renal disease, ischemic stroke, and acute coronary syndrome was reported (113). These beneficial results on key outcomes need to be confirmed in randomized trials (this may be impossible as withholding treatment of HCV is not appropriate). Treatment of diabetes with metformin or thiazolidinediones is preferred as studies have suggested that these drugs may lower the risk of hepatocellular carcinoma, liver-related death, or liver transplantation in patients infected with HCV (114,115).

COVID-19

Studies have shown that COVID-19 infections are associated with hyperglycemia and new onset diabetes (116). In a meta-analysis of 8 studies with a total of 3711 COVID-19

patients 492 cases of newly diagnosed diabetes were found (14.4%) (117). There are a number of possibilities that could explain this association (116):

• The diabetes could be secondary to acute illness and stress induced hyperglycemia. Stress induced hyperglycemia has been observed after other acute conditions including other infections.
• Pre-existing diabetes could be first recognized during a COVID-19 infection
• SARS-CoV-2 virus could directly damage the beta cells leading to decreased insulin secretion and hyperglycemia.
• SARS-CoV-2 virus could lead to pancreatitis indirectly effecting beta cell function
• The strong immune response that is seen in COVID-19 infections (cytokine storm) could indirectly lead to beta cell dysfunction.
• The use of high dose glucocorticoids in patients with severe COVID-19 could lead to hyperglycemia and diabetes.

Hopefully, future studies will better characterize the mechanisms leading to new onset diabetes in patients with COVID-19 infections and determine whether there is a unique mechanism for this association.

ENDOCRINOPATHIES

A number of endocrine disorders are associated with an increased occurrence of diabetes.  Increased levels of GH, glucocorticoids, catecholamines, glucagon cause insulin resistance and increased levels of catecholamines, somatostatin, and aldosterone (by producing hypokalemia) decrease insulin secretion and hence can adversely affect glucose homeostasis. The disturbance in glucose metabolism occurring secondary to endocrine disorders may vary from a moderate degree of glucose intolerance to overt diabetes with symptomatic hyperglycemia. Additionally, the endocrine disorders can worsen glycemic control in patients with pre-existing diabetes.

Acromegaly

This condition is caused by excessive production of growth hormone (GH) from the pituitary (118). The prevalence of DM in patients with acromegaly is between 10-40%; the prevalence of diabetes and glucose intolerance effects more than 50% of patients (118-120). As expected, there is an increased prevalence of diabetes mellitus with age, elevated BMI, a family history of diabetes, and longer duration of acromegaly (119). Diabetes may be present at the time of the diagnosis of acromegaly (121). Higher plasma IGF-1 concentrations correlate with an increased risk of diabetes suggesting that the biochemical severity of acromegaly influences the risk of developing abnormalities of glucose metabolism (122). Patients with acromegaly should be screened for abnormalities in glucose metabolism (120). The prevalence of acromegaly in patients with diabetes is unknown but is likely to be very low given that acromegaly is an uncommon disorder (60 per million) and diabetes is very common (118).

GH is a counter regulatory hormone to insulin and is secreted during hypoglycemia (123,124). In patients with acromegaly insulin resistance is the major abnormality leading to disturbances in glucose metabolism (119,121,125). The insulin resistance is driven primarily through GH induced lipolysis, which results in glucose-fatty acid substrate competition leading to decreased glucose utilization in muscle (119,121,125). Additionally, inhibition of post receptor signaling pathway of the insulin receptor also likely plays a role in the insulin resistance (125). Increased hepatic gluconeogenesis also contributes to the hyperglycemia (119,125). Lipolysis increases the delivery of glycerol and fatty acids to the liver, which serve as a substrate and energy source for gluconeogenesis. In some patients with acromegaly increased insulin secretion compensates for the insulin resistance and glucose metabolism remains normal (119). If insulin secretion cannot increase sufficiently to compensate for the insulin resistance glucose intolerance or diabetes develops (119).

Treatment is directed at the cause of the acromegaly (118). Successful surgical removal of the pituitary adenoma improves hyperglycemia and glucose metabolism has been reported to normalize in 23–58% of people with pre-operative diabetes after surgical cure of acromegaly (119-121). Lower IGF-1 and growth hormone levels post operatively correlate with remission of diabetes (126). A meta-analysis of 31 studies with 619 patients treated with somatostatin analogues for acromegaly reported a decrease in insulin levels and glucose levels during a glucose tolerance test but no change in fasting glucose or A1c levels (127). The absence of greater benefit in glucose homeostasis with somatostatin analogues could be secondary to somatostatin analogues inhibiting insulin secretion (118). Of note, while first generation somatostatin analogues appear to have mild or neutral effects on glucose metabolism in patients with acromegaly, treatment with pasireotide, a second-generation somatostatin analogue, aggravated glucose metabolism leading to the development of diabetes in some instances (128,129). The adverse effect of pasireotide is due to inhibiting insulin secretion and decreasing the incretin effect. There are little data on the impact of cabergoline on glucose homeostasis in patients with acromegaly but the available studies suggest that it modestly improves glucose metabolism (120). Studies have shown that bromocriptine can improve glucose homeostasis (119,120,130).  Finally, treatment with the growth hormone receptor antagonist, pegvisomant, has beneficial effects on glucose homeostasis (131,132).

The treatment of diabetes in patients with acromegaly is similar to the treatment in other patients with diabetes (119). Patients with acromegaly are often lean with low body fat and therefore dietary recommendations may need to be modified. Additionally, since insulin resistance is the primary defect in patients with acromegaly the use of insulin sensitizers may be especially effective but there are no studies comparing the efficacy of various hypoglycemic agents in patients with acromegaly (119). Data suggest that active acromegaly with elevated GH levels enhances the development of microvascular disease (121). The effect of acromegaly on the development of macrovascular disease is unclear (121). Ketoacidosis is uncommon in patients with diabetes and acromegaly.   

Cushing’s Syndrome

Cushing’s syndrome is due to elevated glucocorticoids that can be caused by the overproduction of ACTH by pituitary adenomas or ectopic ACTH producing tumors, overproduction of glucocorticoids by the adrenal glands due to adenomas or hyperplasia, or the exogenous administration of glucocorticoids (133). In patients with Cushing’s syndrome diabetes is present in 20-47% of the patients, while impaired glucose tolerance (IGT) is present in 21-64% of cases (134). Risk factors for the development of diabetes in patients with Cushing syndrome include age, obesity, and a family history of diabetes (134). The prevalence of diabetes varies depending on the etiology of Cushing’s syndrome (pituitary 33%, ectopic 74%, adrenal 34%) (135). In patients with endogenous Cushing’s syndrome the relationship of the degree of hypercortisolism and abnormalities in glucose metabolism has been inconsistent with some studies showing a correlation and other studies no relationship (136). For example, in one study, in patients with endogenous Cushing’s syndrome the prevalence of abnormalities in glucose metabolism and diabetes did not differ in patients with slightly elevated (not greater than 2x the upper limit of normal), moderately elevated (2-5X the ULN), and severely elevated (>5x the ULN) levels of urinary free cortisol (137). In patients with exogenous Cushing’s syndrome high doses of glucocorticoids and longer duration of treatment are more likely to cause diabetes (120,136). Elevated glucocorticoids are more likely to cause high glucose levels in the afternoon or evening and in the postprandial state (120). Hyperglycemia resulting from exogenous steroids occurs in concert with the time-action profile of the steroid regimen employed, such that once daily morning administration of an intermediate acting steroid (prednisone or methylprednisone) causes peak hyperglycemia within 12 hours (post-prandial) while long-acting or frequently administered steroids cause both fasting and postprandial hyperglycemia.

Patients with Cushing’s syndrome should be screened for the presence of abnormalities in glucose metabolism (136). It should be noted that fasting glucose levels are often normal with abnormalities present during an oral glucose tolerance test (134,136). Screening with A1c levels or with an oral glucose tolerance test are therefore preferred. The abnormalities in glucose metabolism may contribute to the increased risk of atherosclerosis in patients with Cushing’s syndrome.

The prevalence of Cushing’s syndrome in patients with diabetes is uncertain with studies reporting very different results ranging from 0 to 9% (136). The selection process used and the criteria used to determine the presence of Cushing’s syndrome likely greatly influences the results with studies that select patients with marked obesity, poor glycemic control, and poorly controlled hypertension finding a higher percentage of patients with diabetes having Cushing’s syndrome. A recent meta-analysis of 14 studies with a total of 2827 patients with T2D reported that 1.4% had Cushing’s syndrome based on biochemical analysis (138). In a multicenter study carried out in Italy between 2006 and 2008, 813 patients with known T2D without clinically overt hypercortisolism were evaluated for Cushing’s syndrome (139). After extensive evaluation 6 patients (0.7%) were diagnosed to have Cushing’s syndrome. Four patients had an adrenal adenoma and their diabetes was markedly improved with the disappearance of diabetes in three patients and discontinuation of insulin therapy in the remaining patient. One patient had bilateral macronodular adrenal hyperplasia and one patient had ACTH dependent Cushing’s syndrome with a normal pituitary MRI. In approximately 15-35% of patients with an incidental adrenal nodule mild autonomous cortisol secretion with T2D is present (140,141). After surgical removal of the adenoma in patients with autonomous cortisol secretion diabetes normalized or improved in 62.5% of patients (5 of 8) (142). However, not all studies have seen such dramatic improvements in diabetes after adenoma removal (143). Clearly additional studies (preferably large randomized trials) are required to better define the prevalence of mild subclinical Cushing’s syndrome in patients with diabetes and whether treating the subclinical Cushing’s syndrome in these patients will improve their glycemic control. For a detailed discussion of autonomous cortisol secretion see the chapter on Adrenal Incidentalomas in the Adrenal section of Endotext (144).

Currently, routinely screening patients with T2D for Cushing’s syndrome is not recommended (136). Nevertheless, clinicians should be aware of the possibility of Cushing’s syndrome and screen appropriate patients with T2D (young patients, negative family history of diabetes, patients with physical findings suggestive of Cushing’s syndrome, patients with difficult to control diabetes or hypertension) (136).    

Glucocorticoids function as a counter regulatory hormone to insulin and increase in response to hypoglycemia (145). Glucocorticoids disrupt glucose metabolism primarily by inducing insulin resistance in liver and muscle and by stimulating hepatic gluconeogenesis (134,136). The increase in hepatic gluconeogenesis is mediated by several mechanisms including a) directly stimulating the expression of gluconeogenic enzymes b) stimulating proteolysis and lipolysis leading to an increase delivery of amino acids, glycerol, and fatty acids to the liver that provides substrates and energy sources for gluconeogenesis c) inducing insulin resistance and d) enhancing the action of glucagon (134,136). The glucocorticoid induced increase in insulin resistance is due to inhibition of the post-receptor signaling pathway of the insulin receptor, which will result in a decrease in the uptake of glucose by skeletal muscle and adipose tissue (134). In addition to the above glucocorticoids can accelerate the degradation of Glut4 in beta cells, which impairs the ability of beta cells to secrete insulin in response to glucose (146).

Treatment of Cushing’s syndrome by removal of a pituitary tumor, an ectopic ACTH producing tumor, or an adrenal lesion result in a marked improvement in glucose metabolism and in many patients a remission of the diabetes (134,136). In patients with persistent Cushing’s syndrome drug therapy may be needed to normalize cortisol levels. Studies have shown that ketoconazole (200–1200 mg/day), metyrapone (250–4500 mg/day), mifepristone (300–2000 mg/day), or cabergoline (1-7mg/day) improves glucose metabolism in patients with Cushing’s syndrome (120,136).  In contrast, pasireotide has been shown to significantly worsen glucose tolerance, despite control of hypercortisolism, in patients with Cushing’s syndrome (120,136). In patients with exogenous Cushing’s syndrome it is important to use as low a dose as possible of glucocorticoids for the shortest period of time to avoid complications of therapy including disrupting glucose homeostasis (147).

The management of diabetes in patients with Cushing’s disease is similar to the treatment of other patients with diabetes (120). Since insulin resistance is a key defect in patients with Cushing’s syndrome the use of insulin sensitizers may be especially effective but there are no studies comparing the efficacy of various hypoglycemic agents in patients with Cushing’s syndrome (120). Pioglitazone and rosiglitazone can increase the risk of osteoporosis and it should be noted that patients with Cushing’s syndrome also have a high risk of osteoporosis. As noted above, postprandial glucose levels are preferentially increased in Cushing’s syndrome and therefore drugs that lower postprandial glucose levels, such as DPP4 inhibitors, GLP1 receptor agonists, alpha glucosidase inhibitors, and rapid acting insulin may be very useful (120). In glucocorticoid-treated patients requiring a basal-bolus insulin regimen, a higher requirement of short-acting insulin than basal insulin is frequently required (usually approximately 70% of total insulin dose as prandial and 30% as basal) (120). Because of the insulin resistance in patients with Cushing’s syndrome higher doses of insulin are often required to achieve glycemic control. Patients with Cushing’s syndrome are at higher risk for developing macrovascular disease and therefore the treatment of dyslipidemia and hypertension is required (148,149).  

Pheochromocytoma

Pheochromocytomas are rare neuroendocrine tumors that secrete norepinephrine, epinephrine, and dopamine (150). In pheochromocytomas the prevalence of diabetes mellitus has been estimated to be between 15-40% and impaired glucose tolerance as high as 50% (151-153). Patients with diabetes were older, had a longer known duration of hypertension, higher plasma epinephrine levels, increased urinary metanephrine excretion, and larger tumors (152,153). Surprisingly the BMI did not differ between patients with and without diabetes perhaps because more active tumors with higher catecholamine levels lead to weight loss (152,153). In most instances the diabetes is relatively mild but in rare instances can be severe with ketoacidosis (154). The association of hypertension with diabetes in a young patient who is not overweight is a clue to the presence of a pheochromocytoma (152).

Catecholamines, acting primarily by the beta-adrenergic receptors, stimulate glucose production by the liver by increasing glycogenolysis and increase insulin resistance leading to a decrease in tissue disposal of glucose, which together result in elevations in glucose levels (155-157). In addition, catecholamines acting via the alpha-adrenergic receptors, inhibit insulin secretion by the beta cells and acting via the beta-adrenergic receptors, increase glucagon secretion by the alpha cells (158). A decrease in insulin secretion and an increase in glucagon secretion would facilitate the development of hyperglycemia.

With tumor resection the diabetes resolves or markedly improves in the vast majority of patients (>90%) with a pheochromocytoma (152,153). A duration of diabetes of less than 3 years is associated with a remission of diabetes (159). It should be noted that post-surgical removal of a pheochromocytoma, hypoglycemia can occur in approximately 5% of patients (160). Most of these hypoglycemic episodes occur in the first 24 hours and are more likely to occur in patients with large tumors and high urinary metanephrine levels (160). If surgery is unsuccessful the use of alpha and beta blockers may improve insulin resistance and glucose homeostasis (161).

Hyperthyroidism 

Hyperthyroidism in patients without diabetes leads to an increase in glucose intolerance (162). Whether hyperthyroidism causes frank diabetes is unclear because much of the older literature that purports that hyperthyroidism causes diabetes used criteria for diabetes that differs greatly from current guidelines. For example, the study of Kreines and colleagues reported that 57% of patients with hyperthyroidism had diabetes but the criteria for diabetes was a 1 hour glucose >160mg/dL plus a 2 hour value >120 mg/dL during an oral glucose tolerance test (163). A study from China using oral glucose tolerance tests did not find a major difference in the prevalence of diabetes in patients with Grave’s disease (11.3%) vs controls (10.0%) (164). Additional studies using modern criteria for the diagnosis of diabetes are required to better elucidate the risk of developing diabetes in patients with hyperthyroidism. It should be noted that hyperthyroidism may worsen glycemic control in patients with diabetes by increasing hexose intestinal absorption, decreasing insulin sensitivity, and increasing glucose production (165).

T1D and Grave’s disease can occur together as part of the autoimmune polyglandular syndrome (166).

Glucagonoma

Glucagonomas are extremely rare and are associated with a characteristic rash termed necrolytic migratory erythema (82% of patients), painful glossitis, cheilitis, angular stomatitis, normochromic normocytic anemia (50-60%), weight loss (60-90%), mild diabetes mellitus (68-80%), hypoaminoacidemia, low zinc levels, deep vein thrombosis (50%), and depression (50%) (167,168). Glucagon stimulates hepatic glucose production by increasing gluconeogenesis and glycogenolysis leading to an increase in plasma glucose levels (169). Removal of the tumor results in remission of the diabetes.

Somatostatinoma

Somatostatinomas are extremely rare tumors that may present with a triad of diabetes mellitus, diarrhea/steatorrhea, and gallstones, but weight loss and hypochlorhydria also occur (170). Approximately seventy-five percent of patients with pancreatic somatostatinomas have diabetes mellitus while diabetes occurs in only approximately 10% of patients with intestinal tumors. Typically, the diabetes is relatively mild and can be controlled with diet, oral hypoglycemic agents or small doses of insulin (170). Somatostatin inhibits insulin secretion which can result in elevations in plasma glucose levels (139). Increased secretion of somatostatin by cells in the pancreas may be in closer proximity to beta cells and more effective in inhibiting insulin secretion. Somatostatin also inhibits glucagon secretion and therefore diabetic ketoacidosis is very unusual but has been reported (171). Additionally, replacement of functional islet cell tissue by pancreatic tumor may also contribute to the development of diabetes in patients with a pancreatic somatostatinoma (170). Removal of the tumor results in remission of the diabetes.

Primary Hyperaldosteronism

Hypokalemia secondary to hyperaldosteronism can impair insulin secretion and result in diabetes. Potassium replacement will improve glucose homeostasis.

Additionally, in a large meta-analysis the risk of diabetes (OR 1.33, 95% CI 1.01–1.74) and the metabolic syndrome (OR 1.53, 95% CI 1.22–1.91) was modestly increased in patients with primary hyperaldosteronism (172). Studies have shown that aldosterone independent of potassium levels reduces insulin secretion and induces insulin resistance via the impairment of post-receptor signaling (173).

DRUG- INDUCED DIABETES

A large number of different drugs have been shown to adversely affect glucose homeostasis (Table 1). Most of these drug’s act in conjunction with other risk factors for T2D and are usually not the sole cause of diabetes. Drug-induced hyperglycemia is often mild and may be clinically asymptomatic, but in some instances can result in the development of severe hyperglycemia manifesting as diabetic ketoacidosis. There are a number of mechanisms by which drugs induce alterations in glucose metabolism including inducing insulin resistance or inhibiting insulin secretion. In most cases the diabetes remits when the drug is stopped but in some instances the diabetes can be permanent. Use of a rodenticide (N-3 pyridylmethyl-N’4 nitrophenylurea, VacorÒ), structurally related to streptozotocin, was removed from the market in the 1980s because the ingestion of this compound resulted in insulin-dependent diabetes due to beta cell destruction (174). In this section we will focus on drugs that cause major changes in glucose homeostasis or drugs that are commonly used in clinical practice.

Antihypertensive Drugs

In a meta-analysis the risk of developing diabetes varied between different classes of antihypertensive drugs (175).  The odds ratios were: ARB 0.57; ACE inhibitor 0.67; CCB: 0.75; placebo 0.77; beta blocker 0.90 with the thiazide group set at 1.00. Similarly, in the ALLHAT study the risk of developing diabetes was greater in the thiazide group than in patients treated with an ACE inhibitor or a calcium channel blocker (176). In a meta-analysis of 10 studies of beta-blockers and 12 studies of diuretics in patients without diabetes it was found that beta-blockers increased fasting blood glucose concentrations by 11.5 mg/dL and diuretics by 13.9 mg/dl (177). In a meta-analysis of twelve studies with 94,492 patients beta-blocker therapy resulted in a 22% increased risk for new-onset diabetes compared with nondiuretic antihypertensive agents (178). Thus, both thiazide diuretics and beta blockers increase the risk of developing diabetes while ARBs and ACE inhibitors reduce the risk (179).

The hyperglycemia secondary to thiazide diuretics may in some instances be due to decreased insulin secretion secondary to potassium loss, which can be improved with potassium replacement (180). In addition, thiazides may directly affect insulin secretion similar to diazoxide (see below). Finally, thiazides also increase insulin resistance and enhance hepatic glucose production (180).

The effect on glucose metabolism differs between different beta-blockers and carvedilol, the third-generation beta-blocker has beneficial effects on glucose metabolism (179,180). A greater inhibition of insulin secretion occurs with non-selective beta-blocking agents (180). Beta blockers decrease insulin secretion and increase insulin resistance (179,180). In addition, beta-blockers increase weight, which could also adversely affect glucose homeostasis (181). Finally, beta-blockers increase the risk of severe hypoglycemia by decreasing the recovery from hypoglycemia and masking the symptoms of hypoglycemia (182).

Diazoxide

Diazoxide is a non-diuretic benzothiadiazine derivative, which increases plasma glucose levels by inhibiting insulin secretion through opening the potassium/ATP channels in beta cells (183). Diazoxide is used to control hypoglycemia in patients with insulinomas (184).

Statins

In a meta-analysis of 13 trials with over 90,000 subjects, there was a 9% increase in the incidence of diabetes during follow-up among subjects receiving statin therapy (185). All statins appear to increase the risk of developing diabetes. In comparisons of intensive vs. moderate statin therapy, Preiss et al observed that patients treated with intensive statin therapy had a 12% greater risk of developing diabetes compared to subjects treated with moderate dose statin therapy (186). Older subjects, obese subjects, and subjects with high glucose levels were at a higher risk of developing diabetes while on statin therapy (187). Thus, statins may be unmasking and accelerating the development of diabetes that would have occurred naturally in these subjects at some point in time. In patients without risk factors for developing diabetes, treatment with statins does not appear to increase the risk of developing diabetes.

The mechanism by which statins increase the risk of developing diabetes is unknown (187). Studies suggest that the inhibition of HMG-CoA reductase per se may be leading to the statin induced increased risk of diabetes via weight gain (187). However, a large number of studies have now shown that polymorphisms in a variety of different genes that lead to a decrease in LDL cholesterol levels are also associated with an increase in diabetes suggesting that decreases in LDL cholesterol levels per se alter glucose metabolism and increase the risk of diabetes (187). How decreased LDL cholesterol levels effect glucose metabolism is unknown.

In some studies statins have been shown to increase insulin resistance (188) and in some studies to decrease insulin secretion (189,190). Clearly further studies are required to understand the mechanisms by which statins increase the risk of developing diabetes.

Niacin

A recent meta-analysis examined the effect of niacin therapy on the development of new onset diabetes (191). In 11 trials with 26,340 non-diabetic participants, niacin therapy was associated with a 34% increased risk of developing diabetes (RR of 1.34; 95% CIs 1.21 to 1.49). This increased risk results in one additional case of diabetes per 43 initially non-diabetic individuals who are treated with niacin for 5 years (0.47% ten-year risk or 4.7 per 1000 patient years). Results were similar in patients who were receiving niacin therapy in combination with statin therapy. It has been recognized for many years that niacin induces insulin resistance (192). The mechanisms by which niacin induces insulin resistance are unknown but possible mechanisms include a rebound increase in free fatty acids with niacin therapy or the accumulation of diacylglycerol (192).

Pentamidine

Pentamidine is an antiprotozoal agent known to cause hypoglycemia and hyperglycemia (180). Pentamidine induces a direct cytolytic effect on pancreatic beta cells leading to insulin release and hypoglycemia, which is then followed by beta cell destruction and insulin deficiency resulting in diabetes (193,194).

Dilantin

Dilantin can cause hyperglycemia and there have been cases of diabetic ketoacidosis (195,196). The adverse effect of dilantin on glucose metabolism is mediated primarily by an inhibition of insulin secretion (180).

Alpha Interferon

Treatment with alpha interferon in rare instances can cause T1D. Of 987 patients treated with alpha interferon for chronic hepatitis C, 5 patients developed T1D (197). The clinical course is characterized by the abrupt development of severe hyperglycemia at times with ketoacidosis (198). High titers of anti-islet autoantibodies are present and almost all patients require permanent insulin therapy (198). Treatment with interferon alpha facilitates the development of autoimmune disorders including T1D (199). Other autoimmune disorders frequently occur, particularly thyroid dysfunction.

Checkpoint Inhibitors

There are several checkpoint inhibitors; ipilimumab a cytotoxic T-lymphocyte-associated protein 4 inhibitor (CTLA-4 inhibitor); nivolumab and pembrolizumab, programmed cell death protein 1 inhibitors (PD-1 inhibitors); atezolizumab, avelumab, and durvalumab. programmed cell death 1 ligand inhibitors (PD-L1 inhibitors) (200). Both CTLA-4 and PD-1 play a key role in the maintenance of immunological tolerance to self-antigens thereby preventing autoimmune disorders (200). Immune mediated hypothyroidism, hyperthyroidism, hypophysitis, primary adrenal insufficiency, hypoparathyroidism, and insulin-deficient diabetes have been reported as a complication of the use of these drugs (200,201). In a meta-analysis of 38 randomized clinical trials with 7551 patients, autoimmune diabetes occurred in only 0.2% of the patients and was primarily seen with the use of PD-1 inhibitors (200). In another meta-analysis of 101 studies with 19,922 patients the incidence of autoimmune diabetes was 2.0% (95% CI, 0.7–5.8) for nivolumab and 0.4% (95% CI, 0.2–1.3) for pembrolizumab (201). The occurrence of autoimmune diabetes with other checkpoint inhibitors was rare (201).

The onset of diabetes ranges from a few weeks up to one year after initiating therapy and typically presents with polyuria, polydipsia, weight loss and dehydration (201,202). Severe hyperglycemia and ketoacidosis is commonly observed (202). Because of the acute occurrence A1c levels may not be elevated. C-peptide levels are very low and approximately 50% of patients have islet cell antibodies (GAD, ICA, IAA or IA-2; GAD antibodies are the most commonly observed) (201,202). Insulin treatment is required and it is likely that the diabetes will be irreversible (201,202).

For additional information on the checkpoint inhibitor associated diabetes see the Endotext chapter “Immune Checkpoint Inhibitors Related Endocrine Adverse Events” in the Disorders that Affect Multiple Organs section (203).

Antipsychotic Drugs

A large number of studies have linked second generation antipsychotic medications with the development of T2D (Table 5) (204,205). In a meta-analysis of a large number of studies it was reported that olanzapine and clozapine treatment resulted in a greater increase in glucose than aripiprazole, quetiapine, risperidone and ziprasidone (206). Another meta-analysis has further shown that aripiprazole has a reduced risk of T2D compared to other antipsychotic agents (207). With regards to first generation antipsychotic drugs, chlorpromazine has a high risk of disrupting glucose metabolism while haloperidol, fluphenazine, and perphenazine have a low risk (204). It is thought that antipsychotic drugs induce diabetes by multiple mechanisms: (1) they inhibit insulin signalling in muscle cells, hepatocytes and adipocytes thereby causing insulin resistance; (2) they induce obesity, which can also cause insulin resistance; and (3) they cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells (205,208).

*Relative to other antipsychotics. Not all the risk of diabetes or weight gain is related to the antipsychotic. Table modified from (205)

Androgen Deprivation Therapy

A number of studies have shown that androgen deprivation therapy increases the risk of developing diabetes (209). For example, a study by Tsai reported that androgen deprivation therapy was associated with a 1.61-fold increased diabetes risk (95% CI 1.38-1.88) and the number needed to harm was 29 (210). The androgen deprivation induced diabetes typically develops after a year of treatment (209). Androgen deprivation therapy induces insulin resistance (209). The increase in insulin resistance may be due to an increase in visceral fat mass and/or an increase in pro-inflammatory adipokines such as TNF-a, IL-6, and resistin (209).

Immunosuppressive Drugs

Immunosuppressive drugs used after organ transplantations increase the risk of diabetes (211). In general, tacrolimus has been associated with a greater risk of developing diabetes compared to cyclosporine (211,212). The calcineurin inhibitors, tacrolimus and cyclosporine, decrease insulin secretion and synthesis (211,212). Additionally, tacrolimus and cyclosporine inhibit glucose uptake in human subcutaneous and omental adipocytes (212).

Mechanistic Target of Rapamycin Inhibitors (mTOR inhibitors)

mTOR inhibitors, sirolimus and everolimus, can induce diabetes (213).  The adverse effect of mTOR inhibitors on glucose metabolism is due to insulin resistance secondary to a reduction of the post receptor insulin signalling pathway and a reduction of insulin secretion via a direct effect on the pancreatic beta cells (211,213).

Asparaginase

Hyperglycemia is common with the use of asparaginase treatment ranging from 2.5% to 23% in the pediatric population and as high as 76% in adults with PEG-asparaginase use (214,215). Hyperglycemia usually resolves within 12 days after the last dose (214). Risk factors predisposing to hyperglycemia with asparaginase treatment include a history of impaired glucose tolerance, age >10 years, obesity, family history of diabetes mellitus, and history of Down syndrome (214,215). Diabetic ketoacidosis has been described with asparaginase treatment but is not a common occurrence (214). Decreased insulin secretion, increased insulin resistance, and increased glucagon secretion may contribute to the hyperglycemia observed with asparaginase. Additionally, asparaginase can induce pancreatitis, which can also lead to hyperglycemia (214).

Glucocorticoids, Somatostatin, and Glucagon

The effects of these hormones on glucose metabolism were discussed in the section on Endocrinopathies.

HIV Antiretroviral Therapy

The effect of the drugs used to treat patients living with HIV on the development of diabetes is discussed in the Endotext chapter “Diabetes in People Living with HIV” in the Diabetes section (6).

IMMUNE-MEDIATED

Latent Autoimmune Diabetes in Adults (LADA)

LADA is an autoimmune disorder that resembles T1D but shows a later onset and slower progression towards requiring insulin therapy (216-218). The ADA includes LADA as T1D whereas WHO classifies LADA as a hybrid form of diabetes (T1D and T2D) (84) (https://www.who.int/publications/i/item/classification-of-diabetes-mellitus). Epidemiological studies suggest that LADA may account for 2–12% of all cases of diabetes in the adult population (216,217,219). To differentiate LADA from T1D and T2D, the Immunology of Diabetes Society has proposed three criteria: (a) adult age of onset (> 30 years of age); (b) presence of at least one circulating autoantibody (GAD, ICA, IAA or IA-2) and; (c) insulin independence for the first 6 months after the time of diagnosis (216,217). Of the various antibodies associated with autoimmune diabetes GAD antibodies are present in most patients with LADA (216,217,219). Patients with high titers of GAD antibodies progress to requiring insulin more rapidly (218). LADA subjects appear to have a faster decline in C-peptide levels compared to autoantibody negative patients with T2D (219). It should be noted that classic T1D can occur in adults and this is defined as those adult patients with antibodies (GAD, ICA, IAA or IA-2) that require insulin therapy at diagnosis or soon after diagnosis (217,219). In contrast, patients with LADA can often go many years before requiring insulin therapy (217). Whether LADA is just a slowly progressing form of T1D or a hybrid T1D and T2D is unclear (Table 6).

In a retrospective study, Fourlanos and colleagues pointed out several features that increase the likelihood of a patient with “T2D” having LADA (220). These features include age of onset <50 years of age,  acute symptoms (polyuria, polydipsia, weight loss), BMI <25 kg/m2, personal history of autoimmune disease, and family history of autoimmune disease (220). The presence of at least two of these clinical features indicated a 90% sensitivity and 71% specificity for identifying a patient with LADA (220). As compared to patients with T2D, LADA patients have a lower rate of hypertension, lower total cholesterol levels, higher HDL cholesterol levels, and a decreased frequency of the metabolic syndrome (217,219). HLA-DQB1 risk genotypes have been consistently positively associated and protective genotypes have been negatively associated with LADA (218). However, in addition to genotypes that associate with T1D, patients with LADA also have an increased frequency of genotypes that associate with T2D (TCF7L2, FTO, and SLC30A8) (218).

Some have proposed GAD antibody testing all patients with T2D (221) to diagnose LADA but given the given the increased costs and the relatively frequent occurrence of false positive tests compared to true positives in a low-risk population this strategy is not widely accepted (222). The ADA suggests selective testing in adults without traditional risk factors for T2D and/or younger age (84). 

In LADA patients initially glycemic control can be achieved with hypoglycemic agents other than insulin but overtime patients progress to requiring insulin therapy. Sulfonylureas seem to accelerate the progress to requiring insulin therapy and therefore should be avoided (223). Because of the progressive loss of beta cell function there is an increased risk of diabetic ketoacidosis with SGLT2 inhibitors and therefore these drugs should be used with caution. Monitoring ketone levels in patient with LADA treated with SGLT2 inhibitors would be prudent. Novel therapies to preserve beta cell function would be ideal in patients with LADA but at this time there are no proven strategies to preserve beta cell function.

In a long- term follow-up (median 17.3 years) comparing microvascular outcomes in patients with LADA or T2D it was observed that the risk of renal failure/death, blindness, vitreous hemorrhage, or retinal photocoagulation was decreased in the patients with LADA during the first 9 years (adjusted HR 0.45; p<0.0001), whereas in subsequent years their risk was higher (HR 1·25; p=0.047) (224). This difference was attributed to higher A1c levels in the LADA patients. The prevalence of coronary heart disease and cardiovascular mortality is similar in patients with LADA and T2D (225,226).

Autoimmune Polyglandular Syndromes

T1D can occur as part of the autoimmune polyglandular syndromes. These disorders are discussed in the Endotext chapter “Autoimmune Polyglandular Syndromes” in the Disorders that Affect Multiple Organs section (4).

Stiff-person syndrome

Stiff-person syndrome is a rare autoimmune disorder of the nervous system with fluctuating stiffness and spasm of the skeletal muscles that occurs more frequently in females than males (approximately 2/3 women) (227). Muscle involvement is symmetrical and the lower extremities are affected more commonly than the upper extremities and proximal limb and axial muscles are affected more severely than distal muscles (227). Most patients have very high levels of anti-glutamic acid decarboxylase (GAD) antibodies (227). 30-65% of these individuals also develop beta cell destruction and T1D (228). Diabetes may occur several years prior to the development of the stiff person syndrome (60%) or after the development of the stiff person syndrome (227,228). The stiff person syndrome without GAD antibodies is not associated with diabetes (228). Other autoimmune manifestations are also common, particularly thyroid disorders and pernicious anemia (227,228).

Autoimmune Insulin Resistance Type B Syndrome

Insulin resistance can result from autoantibodies directed against the insulin receptor, which either inhibit insulin from binding to the receptor or stimulate the receptor (229). Thus, they can cause either hyperglycemia or hypoglycemia, even alternating in the same patient. The patients usually present with very high glucose levels and significant weight loss (229). The diagnosis can be confirmed by demonstrating the presence of autoantibodies to the insulin receptor. The prevalence of type B insulin resistance syndrome is unknown but is quite rare (229). Middle-aged women are most often affected and often have other manifestations of autoimmune disease such as SLE or Sjogren’s. However, this disorder can also affect males and younger patients. Patients may have signs of insulin resistance including acanthosis nigricans and ovarian hyperandrogenism. Of note the acanthosis nigricans may involve the lips and the periocular region resulted in a typical facial appearance (229). Serum testosterone levels are often elevated in females (229). Patients often need excessive amounts of insulin (1,000 U or more per day). One can add insulin sensitizers such as metformin and/or thiazolidinediones to try to reduce the insulin dose, which can in some patients be greater than 10,000U per day (229). Treatment includes immunosuppression and/or plasmapheresis to halt the autoantibody production and decrease antibody levels (230). Approximately 1/3 of patients will undergo a spontaneous remission with reversal of the hyperglycemia/hypoglycemia and the clinical manifestations (229).

DIABETES OF UNKNOWN CAUSE

Ketosis-Prone Diabetes in Adults (Flatbush Diabetes)

This syndrome is characterized by the acute onset of severe hyperglycemia with or without ketoacidosis, which after several weeks to months no longer requires insulin therapy and can be treated with diet or oral hypoglycemic agents (231,232). These patients typically have a history of polyuria, polydipsia, and weight loss for less than 4 to 6 weeks indicating an abrupt onset of the disorder in glucose metabolism and no history of an event that could have precipitated the hyperglycemia (232). The initial presentation is suggestive of T1D. While in most patients insulin therapy can be stopped there are some patients who continue to require insulin treatment (231). This syndrome occurs in black populations (African American, African-Caribbean, sub-Saharan African), Hispanic populations, and Asian (Chinese, Indian, and Japanese) populations but is not typically seen in Caucasians (231,232).  The typical patient is male, middle-aged, overweight or modestly obese with a strong family history of diabetes (231,232). Patients are negative when tested for islet cell antibodies (GAD, ICA, IAA or IA-2) (231). Recurrent episodes of ketoacidosis can occur but the clinical course is typical of patients with T2D (231,232). Treatment with hypoglycemic agents reduces the risk of recurrence (232,233). With long-term follow-up many patients eventually require insulin therapy similar to what is observed in patients with T2D (233).

During the episode of severe hyperglycemia patients with ketosis-prone diabetes have lost the ability of glucose to stimulate beta cell insulin secretion but nonglycemic pharmacologic agents (glucagon and arginine) can stimulate insulin secretion (231). After restoration of normal glycemia the ability of glucose to stimulate insulin secretion returns towards normal and by 8-12 weeks has maximally improved (231). Usually patients with this syndrome have a modest reduction in stimulated insulin secretion (231). Why these patients temporarily lose the ability for glucose to stimulate insulin secretion is unknown. Additionally, during the acute episode of hyperglycemia the patients are severely insulin resistant, which improves during a period of euglycemia (232,233).

Clinically, it is important to recognize this syndrome as some patients presenting with diabetic ketoacidosis, particularly if they are non-Caucasians, may not have T1D but rather have ketosis-prone diabetes. It is estimated that between 20% and 50% of African-American and Hispanic patients with a new diagnosis of diabetic ketoacidosis have ketosis-prone diabetes (232). After restoration of euglycemia the management of these patients is similar to the management of patients with T2D and they frequently do not require permanent insulin treatment.

OTHER GENETIC SYNDROMES SOMETIMES ASSOCIATED WITH DIABETES

There are a number of inherited monogenic disorders that secondarily can be associated with diabetes. The mechanisms linking these disorders with diabetes is often not clear.

Chromosomal Abnormalities

DOWN’S SYNDROME

Down’s syndrome is due to trisomy of chromosome 21 and occurs in 1 in every 787 liveborn babies (234). Down’s syndrome is often associated with autoimmune disorders like T1D and thyroiditis (234,235). The prevalence rate of T1D in patients with Down's syndrome has been estimated to be between 1.4 and 10.6%, which is higher than in the general population (236). In another study there was a 4-fold increased prevalence of diabetes in patients with Down’s syndrome (237). Diabetes in patients with Down’s syndrome often presents earlier in life with 22% of participants developing diabetes by 2 years of age (238). The presence of diabetes is often associated with other autoimmune disorders, particularly hypothyroidism and celiac disease (235). Anti-glutamic acid decarboxylase antibodies (GAD antibodies) are very frequently present in Down’s syndrome subjects developing diabetes (235). Down’s syndrome patients with diabetes have similar HLA genotypes as non-Down’s syndrome patients with T1D (235). Interestingly, while patients with Down’s syndrome and diabetes are typically treated with simpler regimens their glycemic control tends to be as good or better than the usual patient with T1D, perhaps related to a simpler lifestyle and acceptance of routine (235). The cause of the increased autoimmunity in patients with Down’s syndrome may be due to the abnormal expression of the AIRE gene, which regulates T-cell function and self-recognition and is located on chromosome 21 (21q22.3 region) (234,235).

KLINEFELTER SYNDROME

Klinefelter syndrome is due to an extra X chromosome in men (XXY) resulting in hypergonadotropic hypogonadism and low testosterone levels (239). The prevalence of Klinefelter syndrome is approximately 1 in 500 to 1 in 1000 males (239). Patients with Klinefelter syndrome are frequently obese, insulin resistant, and at increased risk to develop T2D (240). The prevalence of overt diabetes in Klinefelter syndrome is estimated to be between 10-39% (240,241). Additionally, the prevalence of diabetes is even higher (up to 57%) in patients with the more severe karyotypes (48, or 49 chromosomes) (240). Klinefelter syndrome patients develop diabetes earlier in life (onset around 30 years) and their BMI is lower than what is usually observed in patients with T2D (240). Whether testosterone therapy will be of benefit in preventing or treating diabetes in patients with Klinefelter syndrome is uncertain (241). Given the increased risk of developing T2D patients with Klinefelter syndrome should be periodically screened for diabetes.

Interestingly, one study reported an increased prevalence of T1D in patients with Klinefelter syndrome (242). Furthermore, a recent study reported that 8.2% of patients with Klinefelter syndrome had autoantibodies specific to T1D (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs) (243). Additional studies are required to better elucidate whether Klinefelter syndrome increases the risk of developing T1D.

TURNER SYNDROME

Turner syndrome is the most common chromosomal abnormality in girls, affecting approximately 1:2,500 of female live births (244). The condition is caused by complete or partial deletion of an X chromosome (244). The incidence of both T1D and T2D has been reported to be increased in patients with Turner syndrome (245). However, the link between T1D and Turner syndrome is not well characterized while the link with T2D is clearly established (246,247). For example, in a study of 224 patients with Turner syndrome 56 (25%) had T2D whereas only 1 patient (<0.5%) had T1D (248). Patients with Turner syndrome have an increased risk of autoimmune disorders, particularly hypothyroidism and celiac disease, but the risk of autoimmune T1D is much less (247,249). Four percent of patients with Turner syndrome have been shown to have GAD antibodies, which is greater than the 1% prevalence seen in the general population (249).

The prevalence of glucose intolerance is estimated to be from 15-50% while the prevalence of T2D is estimated to be approximately 10-25% (247,248). T2D occurs at a relatively young age in patients with Turner syndrome. Decreased beta cell function and decreased insulin sensitivity was observed in teenagers with Turner syndrome and was accompanied by an increased prevalence of impaired fasting glucose and impaired glucose tolerance compared to controls (250). Increased obesity is common in patients with Turner syndrome, which likely contributes to the abnormalities in glucose metabolism (246). Both insulin resistance and decreased insulin secretion are present in patients with Turner syndrome but the development of hyperglycemia in patients with T2D appears to be driven by decreased insulin secretion (246,247). Because of the high prevalence of diabetes, it is recommended to screen A1c with or without fasting glucose levels annually beginning at 10 years of age (247). Growth hormone therapy does not appear to increase the risk or worsen diabetes (246,247). Growth hormone therapy may lead to a decrease in adiposity and impaired glucose tolerance, which suggests it may actually improve glucose homeostasis (247). Similarly, sex steroid hormone replacement therapy also does not appear to have major adverse effects on glucose metabolism in patients with Turner syndrome (246).

WILLIAMS SYNDROME

Williams syndrome (Williams-Beuren syndrome) is a multisystem disorder characterized by transient infantile hypercalcemia, distinctive facial dysmorphism, and supravalvular aortic stenosis (251,252). In addition, gastrointestinal problems, dental anomalies, developmental delay/intellectual disability, anxiety disorders, and attention deficit disorder may occur as well as a variety of endocrine abnormalities including reduced statural growth, obesity, dyslipidemia, early pubertal development, hypothyroidism, and decreased bone density (251,253). Williams syndrome is due to a deletion on chromosome 7q, leading to the loss of 25–27 contiguous genes and thus individuals with Williams syndrome have only a single copy of these genes (252). This deletion almost always arises de novo in the affected individual. The estimated prevalence of Williams syndrome is ~1/7,500 and effects both males and females (252).

Numerous studies have shown a high prevalence of T2D and impaired glucose tolerance in patients with Williams syndrome (251). The abnormalities in glucose metabolism occur during adolescence and are not necessarily associated with obesity (251). Of note insulin resistance is observed initially followed by a loss of insulin secretion (251). Markers of islet autoimmunity are not observed (251). In a review of 7 studies with 154 participants with Williams syndrome and an average age ranging from 13 to 35 years of age it was observed that 18% had diabetes and 42% impaired glucose tolerance (251). Because of this high risk for diabetes, it is recommended that patients with Williams syndrome be screened for diabetes beginning in adolescence (251). Note-worthy is that A1c was frequently not abnormal and therefore screening should be with fasting glucose levels or an oral glucose tolerance test (251).

Diseases of the Endoplasmic Reticulum

The endoplasmic reticulum folds and modifies newly formed proteins to make them function properly. Therefore, diseases affecting the endoplasmic reticulum usually affect many organs.

WOLFRAM SYNDROME 

Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by T1D, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration (254,255). There are also rare autosomal dominant forms of this disorder (255). This syndrome is sometimes called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). The prevalence is approximately one per 770,000 but varies depending upon the specific population (254,255). The onset of the clinical picture is highly variable in both severity and clinical manifestations (255). This disorder typically has a very poor prognosis with the median age at death being 30 years (254). Diabetes mellitus is usually the first manifestation, typically diagnosed around age 6 (254). The diabetes is not immune mediated but is characterized by insulin deficiency (255). Almost all patients require insulin therapy (255). Residual beta cell function persists and therefore good glycemic control tends to be easier to achieve in Wolfram syndrome than immune mediated T1D (255). However, over time C-peptide levels decrease (256). The development of optic atrophy and hearing loss in children with diabetes are clues to the presence of this syndrome. Until the onset of optic atrophy and hearing loss these patients are usually thought to have typical T1D with an absence of antibodies (255). Confirmation of the diagnosis can be made by identifying mutations in the WFS1 gene (Wolfram syndrome type 1) (254). The WFS1 gene encodes a transmembrane protein (wolframin) localized to the ER (endoplasmic reticulum) and mutations result in ER stress leading to beta cell dysfunction and death (254).

Mutations in CISD2 gene cause a similar recessive type of Wolfram syndrome (Wolfram syndrome type 2) with patients exhibiting bleeding from upper intestinal ulcers and defective platelet aggregation without diabetes insipidus and psychiatric disorders (255). CISD2 encodes for a protein that moves between the ER and mitochondrial outer membrane (255).  

Unfortunately, there are currently no specific treatments to restore ER function and prevent the complications of this disorder.

Base Pair Repeat Syndromes     

FRIEDRICHS ATAXIA

Friedreich ataxia is a rare recessive disorder caused by triplet repeats (GAA) in the mitochondrial frataxin gene characterized by slowly progressive ataxia associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense (257). The onset usually occurs before 25 years of age (257). Cardiomyopathy occurs in 2/3 of patients and up to 30% of patients have diabetes (257). The disorder effects approximately 1 in 30,000 Caucasians.

Diabetes occurs in 8-32% of patients with Friedrichs ataxia and an even higher percentage have impaired glucose tolerance (258,259). Hyperglycemia commonly develops approximately 15 years after the manifestation of neurological symptoms often presenting acutely with patients requiring insulin therapy (258,259). In a number of instances patients presented with ketoacidosis (259). Both insulin deficiency and insulin resistance have been reported in patients with Friedreich ataxia (259). It is hypothesized that mutations in frataxin result in alterations in mitochondria function that impair the ability of beta cells to secrete insulin in response to glucose and increase the risk of beta cell death (259).

There are no controlled studies comparing different diabetes therapies in patients with Friedreich ataxia. Metformin and thiazolidinediones inhibit the mitochondrial respiratory chain and therefore they should probably be used with caution in patients with mitochondrial disease (259). Additionally, thiazolidinediones increase the risk of congestive heart failure and patients with Friedreich ataxia have a high risk of cardiomyopathies and therefore should be avoided. Insulin is often required to achieve glycemic control.

HUNTINGTON’S DISEASE

Huntington’s disease is an autosomal dominant disorder that begins in adulthood (usually 30-50 years of age) and has distinctive motor defects (chorea, dystonia, and dyskinesia), psychiatric symptoms (depression and anxiety), and cognitive decline (260). This disorder is due to an unstable expansion of CAG repeats in the first exon of the gene that encodes the protein huntingtin (260). The prevalence of this disorder is approximately 5-12 per 100,000 (260,261). While an early study reported that approximately 10% of patients with Huntington’s disease have diabetes a careful review of recent studies reached the conclusion that the prevalence of diabetes in patients with Huntington’s disease is not increased and might actually be decreased (261,262).

MYOTONIC DYSTROPHY

Myotonic dystrophy type 1 is an autosomal-dominantly inherited disease characterized by myotonia, distal muscular dystrophy, cataracts, hypogonadism, and frontal hair loss that occurs in middle age (263). The disease is due to a CTG triplet repeat expansion in the myotonic dystrophy protein kinase gene (263). Diabetes is not a characteristic finding in myotonic dystrophy type 1 but the prevalence is increased 2-4-fold in patients with this disorder compared to the general population (263-265). A large study in Korea with 387 patients with myotonic dystrophy type 1 found that 27% had diabetes (266). Patients with myotonic dystrophy type 1 and diabetes have elevated insulin levels suggesting insulin resistance (263,264). Pioglitazone alone and in combination with metformin has been reported to improve glycemic control in patients with myotonic dystrophy and diabetes (267,268).

Obesity Syndromes

BARDET-BIEDLE SYNDROME (BBS)

Bardet-Biedl syndrome (BBS), also earlier referred to as Laurence Moon Biedl syndrome, is a rare autosomal recessive disease with a prevalence of about 1/125,000 (269,270). BBS belongs to the group of ciliopathies characterized by obesity, retinal degeneration, finger anomalies, hypogonadism, renal abnormalities, and intellectual impairment (269,270). It can result from autosomal recessive mutations in at least 22 genes (BBS), which play a key role in structure and function of cilia (269,270). In a study of 152 patients with BBS it was reported that approximately 75% were obese and the average BMI was 35.7kg/m² (270). Twenty-five of these patients with BBS had diabetes (16.4%) with 24 having T2D and 1 having T1D (270). Of the 24 patients with T2D six patients were diet controlled, eight were taking metformin, and 10 were on insulin therapy. The mean A1c of subjects with T2D was 7.8 (270). In a smaller series of 46 patients, it was reported that 22 had T2D (46%) and the median age of onset of diabetes mellitus was 43 years (217). The risk of developing diabetes increases with age. In the BBS patients without diabetes fasting glucose, insulin levels, and HOMA-IR were significantly increased in the BBS group compared with an age and BMI matched control group (270). The metabolic syndrome was present in 54% of the patients with BBS (270).

PRADER WILLI SYNDROME (PWS)

PWS is a rare autosomal dominant disorder due to a mutation or deletion of several genes in an imprinting region on chromosome 15 (271). PWS in children is associated with excessive eating and morbid obesity, hypogonadism, low muscle tone, and short stature (271). The hyperphagia that occurs in PWS is believed to be due to a hypothalamic abnormality resulting in lack of satiety. This leads to excessive obesity in children, which is often associated with T2D due to severe insulin resistance (271). Approximately 20- 25% of adults with PWS have T2D with a mean age of onset of 20 years (271,272). Individuals with PWS who develop early diabetes have severe obesity, a high prevalence of psychiatric and metabolic disorders, and a family history of overweight and T2D (272). In recent years the earlier diagnosis and education of parents, use of growth hormone therapy, and the frequency of group homes specific for PWS have led to a reduction in the development of morbid obesity resulting in a decrease in the development of T2D among individuals with PWS (271). Metformin has been shown to be effective in the treatment of PWS patients with diabetes (273). Studies of GLP1 receptor agonists demonstrated lowering of A1c levels but effects on weight loss have been inconsistent (274).

ALSTROM SYNDROME

Alstrom syndrome is a rare autosomal recessive disorder with a prevalence of less than one per million characterized by retinal dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, T2D, hypertriglyceridemia, short stature in adulthood, cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction (275-277). Symptoms appear in infancy and multi-organ pathology leads to a decreased life expectancy (275,276). The syndrome is caused by mutations in ALMS1, which is a ciliary protein and hence many of the features of Alstrom syndrome resemble those seen in the Bardet-Biedl syndrome (275-277). Diagnosis is confirmed by finding biallelic pathogenic variants in ALMS1 gene.

Severe insulin resistance secondary to abnormalities in GLUT4 trafficking, hyperinsulinemia, and impaired glucose tolerance frequently present in early childhood and are often accompanied by acanthosis nigricans (275,277). T2D develops early in life with a mean age of onset at 16 years (275). In one study 82% of patients with Alstrom syndrome older than 16 years of age have T2D (278). Weight loss with diet, exercise, and medications is indicated (279). Therapy with oral agents, particularly insulin sensitizing agents, may be effective but insulin therapy may be required (275,279).

Miscellaneous

PORPHYRIA

Porphyria cutanea tarda has been associated with diabetes (280), but given that many patients with this disorder also have iron overload, genes for hemochromatosis, and HCV and HIV infection it is very difficult to tell if porphyria cutanea tarda per se is responsible for the association with diabetes (281,282).

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