Chapter 5a - MANAGEMENT OF TYPE-1 AND TYPE-2 DIABETES Berrin Ergun-Longmire, MD:Assistant Professor of Pediatrics, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Akron Children’s Hospital, Akron, OH 44308 Debra Margulies,MD:Lenox Hill Hospital andBioseek Endocrinology 200 West 57thSt. Ste 610 New York, NY 10019 Svetlana Ten, MD:Associate Professor of Pediatrics, SUNY Downstate, Director of Pediatric Endocrine Fellowship Program and Pediatric Endocrine Divisions of Infants and Children’s Hospital of Brooklyn at Maimonides and SUNY Downstate, Brooklyn, NY 11219 Noel Maclaren, MD:Professor of Pediatrics, Weill Cornell Medical College, New York, NY 10021, Bioseek Endocrinology, New York, NY 10019 Last Updated: March 8, 2010 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE	Index Contributors Search

INTRODUCTION

The term diabetes mellitus comprises a large number of diseases resulting in hyperglycemia. They can be broadly sub-divided by etiology into diabetes resulting from insulin deficiency (type-1 diabetes or T1DM), resistance to insulin action (type-2 diabetes or T2DM) or combinations of the two (Figure 1). In the US as elsewhere, the incidence of these diseases continues to climb in parallel to the rising rates of obesity. Insulin resistance can arise as a consequence of obesity while obesity in others may result as a complication of insulin resistance which is often genetic. Whereas T2DM appears in patients who can no longer maintain a degree of hyper-insulinemia sufficient to overcome their insulin resistance, with time T2DM patients become increasingly insulin deficient as well, as mediated by glucosamine and lipid toxicities to the pancreatic β cells, often to the point of needing insulin replacement. Furthermore, the age of onset of T2DM continues to fall as infants and children have become heavier than in former years which results in increased insulin requirements. Since the age of onset of T1DM is roughly equal in children versus adults, and T2DM once thought to be relatively rare in children has been increasingly indentified in them, these diseases are often confused as their ages at diagnosis in either type is so variable.

Population studies have defined cut-off levels of glycemia that are eventually associated with increased micro-vascular disease, such as retinopathy. Two replicate fasting levels that exceed 126 mg/dl (>7 mmol/L) are diagnostic of diabetes in the absence of symptoms. The 2003 ADA’s definition of the cut-point for normal fasting blood glucose levels was dropped from 110 mg/dl to 100 mg/dl, meaning that a value of 100 mg/dl or above would lead to a diagnosis of impaired fasting glucose (IFG). Persons with IFG levels (FPG= 100-125 mg/dl (5.66.9 mmol/l) and/or with impaired glucose tolerance test (IGT) (2 hour post-load glucose 140-199 mg/dl (78.8 mmol/L-11.1 mmol/L) are at risk of diabetes and should be observed periodically to detect hyperglycemic progression. Replicate, two-hour glycemic responses >200 mg/dl (>11.1 mmol/L) after a standard oral glucose tolerance test also indicates diabetes. However, this stage is often reached before the fasting glucose levels rise in T2DM. Indeed post-prandial hyperglycemia may precede fasting hyperglycemia by months to years. Thus, the reliance on only fasting glucose levels as recommended by the ADA expert committee is generally useful for identification of impending T1DM but not for T2DM. More recently, the ADA has acknowledged the utility of glycated hemoglobulin (HbA1c) measurements for the diagnosis of diabetes (Table 1).

This chapter is to update from the previous edition.

TYPE-I DIABETES

Insulin treatment

The immune mediated form of T1DM accounts about 10-15% of all patients with diabetes. The incidence of T1DM has wide ranges worldwide with the highest rates seen in Finland (>40/100,000) and Sardinia (37.8/100,000), and the lowest rates in Venezuela (0.1/100,000) and China (0.1-4.5/100,000) (186). It is common among Caucasian races and is rare in pure blood African-Americans, albeit the latter frequently develop an atypical form of maturity onset diabetes of youth or MODY. The SEARCH for Diabetes in Youth Study recently described the incidence of T1DM before 20 years of age among the five major race and ethnic groups in the US (187)). Overall the incidence rate of T1DM was the highest among 10 to 14 year old children in all ethnic groups, probably reflecting their puberty - associated increases in muscle mass and thereby an increased need for insulin, as muscle is the principle target for insulin effects.

T1DM most often results from the autoimmune destruction of the β-cells of the pancreas which leads to absolute insulin deficiency. It can be diagnosed in patients with diabetes in the presence of auto-antibodies to islet cells, islet protein enzymes and/or to insulin (Fig.2).

However, an insulin deficient type of diabetes in the presence of the high-risk HLA phenotypes may be taken as presumptive, but not absolute, evidence. Adult onset T1DM is characterized by a more gradual decline in insulin secretion compared to children, a situation readily confused with T2DM unless auto-antibodies to islet cell cytoplasm (ICA) and/or to glutamic acid decarboxylase (GAD₆₅) and/or to the tyrosine phosphatases named insulinoma associated antigens (IA-2 and IA-2ß) can be detected. The term latent autoimmune diabetes of adults or LADA is used by some to describe this entity. Whereas most instances of T1DM have the hallmarks of anautoimmune disease, a minority of patients lack such hallmarks. One such entity described amongst Japanese is a form of fulminate diabetes which some believe is virally mediated. Type one diabetes can occur from genetic disorders affecting insulin secretion, a topic which is described elsewhere.

Figure 2.Different phases of natural history of immune mediated T1DM and possible treatments.

Glycemic Control

Glycemic control which is of sufficient degree to prevent diabetes related complications without unnecessarily restricting life style choices is the goal of treatment. Glycemic control should be assessed by periodic measurement of HbA1c levels. The target levels for blood glucose excursions should be individualized, especially in younger children, to avoid frequent hypoglycemia (Table 2) (188). Optimum glycemic control can be achieved by monitoring blood glucose levels frequently and adjust their treatment accordingly. When the child is old enough, he/she should be encouraged for self-monitoring of blood glucose (SMBG). Today, diabetes is recognized as a primarily self-managed disease (189). The authors herein are strongly biased to the use of insulin pumps for infants and young children with T1DM for both safety and ease of management reasons.

* HbA1C <7% is a reasonable goal for this age group without excessive hypoglycemia.

The Effect of Treatment on the Honeymoon Period in T1DM

Various studies have demonstrated the beneficial effect of intensive insulin therapy to protect pancreatic β-cell function through the induction of β-cell "rest" in newly diagnosed T1DM patients (2, 3). Numerous studies including the Diabetes Control and Complications Trial (DCCT) have shown that preservation of β-cell function in patients with T1DM diabetes results in better glycemic control and fewer end-organ complications (158-161). Use of exogenous insulin in T1DM may provide "rest" for the β-cells and preserve endogenous insulin secretion. Two studies by Kobayashi et al. (2, 4) of adult patients with T1DM have shown that CSII (continuous subcutaneous insulin infusion) therapy preserves cell function over time compared with sulfonylurea therapy in ICA positive patients. It has also been reported that diazoxide, a K+-channel opener which inhibits the release of insulin, can preserve endogenous insulin in diabetic animal models and in insulin treated ICA positive patients. This supports the ß-cell "rest" theory (5-11); however, the recently concluded DPT-1 trial in which insulin was given to autoantibody positive relatives of patients with T1DM showed no protection against progression to diabetes. Arguably, this trial may not have provided sufficient dosages of insulin to induce effective ß-cell rest; however, the results were not encouraging that higher doses would be effective.

Pancreatic ß-cell "rest" or suppression of β cell function at the time of diagnosis of T1DM may render insulin-producing cells less susceptible to immunological destruction because of their lowered expressions of T1DM autoantigens, such as insulin, GAD₆₅and IA-2, and IA-2ß on resting ß cells. This would have the effect of making the β cells immunologically "invisible" to the immune system, which had been reacting against them (12). Schnell et al. (13) demonstrated that high dose IV insulin infusions and intensive insulin therapy, as initial treatment for newly diagnosed patients with T1DM, were equally effective in preserving insulin secretary capacity after a one year follow up period. Protection of the pancreatic ß-cells against complete destruction allows for some endogenous insulin secretion (appropriate to physiological signals), which is important to the reduction of acute metabolic disturbances e.g., hypoglycemia, the maintenance of metabolic control and the prevention of diabetic microangiopathy.

In addition to intensive insulin treatment, and immunomodulators, the antigens involved in the autoimmune process against β cells themselves have been used during early phase of disease to preserve β cell function. Multiple studies were conducted using systemic immunomodulators (non-Fc binding anti-CD3 and DiaPep277) or antigen-specific therapies (GAD65 and altered peptide ligand derived from the insulin B chain, B9-23) (190-193).

Among these studies, the promising results have been reportedwith anti-CD3, Diapep277, oral insulin and GAD65 treatments. Clinical trials with these immunomodulatars have shown the possibility of preservation of β cell function with the evidence of high residual C-peptide secretion in individuals who received the one of these immunomodulators within the first months of the diagnosis of diabetes. Whether any of these approaches will result in a practical therapy remains to be shown.

Preventing complications: intensive treatment

The DCCT trial (14) and a prospective Swedish study (15) and a meta-analysis of 16 other randomized trials of intensified therapy in T1DM (16) documented that tight diabetes control can reduce complications (Fig. 3). After the DCCT, the Epidemiology of Diabetes Interventions and Complications Study (EDIC) continues to follow the 1441 DCCT participants. After 30 years, EDIC demonstrated intensive treatment lowers cumulative incidences of retinopathy, nephropathy, and cardiovascular disease (21%, 9%, and 9%, respectively), compared to conventional treatment (50%, 25% and 14%, respectively) (194).

However, there were different opinions reached from the Accord study which found that tight glycemic control amongst largely elderly patients actually reduced their life spans. We are unable to know at this point, whether these controversial findings are relevant to diabetes care in children and urge practitioners to continue to achieve the best degrees of glycemic excursions without excessive intrusions into the life styles of diabetic children. Different regimens are not equal in their abilities to preserve ß-cell function. Diabetes control is important to achieve from the time of diagnosis, even in children. Whereas a balanced lifestyle is important to childhood development and self esteem, we argue that this is best achieved by normalizing glycemia as much as possible without undue hypoglycemia or an unreasonable number of insulin injections. In our experience, this is best accomplished by continuous subcutaneous insulin infusion (CSII) (17). The same opinion was supported by several other studies (18, 19).

Though there are several ways to achieve tight glycemic control, our experience differs from that of Tsui et al. (20) and Reeves et al. (21), who concluded that different regimens of insulin treatment are similar in their improvement of overall blood glucose control, reduction in HbA1c, frequency of hypoglycemic events, and impact on the quality of life. However, our experience with newly diagnosed patients with T1DM treated by CSII versus multiple daily injections (MDI) indicates better diabetes control with CSII at lower doses of insulin to keep the same level of HbA1c with less hypoglycemia, and for more convenient management (17).

Principles of insulin therapy: the different types of insulin and treatment schedules

Patients with T1DM lack sufficient pancreatic insulin to maintain normoglycemia. Thus, management of T1DM primarily focuses on adequate insulin replacement matched with food intake, as modified by exercise. Insulin dose in practice are only matched in units per gram of carbohydrate consumed, albeit some protein sources may have a significant glycemic index. Basal insulin, even in the short-term absence of food, is required throughout the whole day to prevent the development of a starvation state. Both short- and rapid-acting insulin as well as long-acting insulin preparations are needed to mimic the pattern of insulin delivery that normally controls blood glucose levels in non-diabetic individuals (22, 23). Throughout the day, short acting insulin is given to normalize blood glucose levels and to cover carbohydrates consumed during meals. Currently, we use CSII with lispro (Humalog), glulisine (Apidra), aspartate (Novolog), or once or twice daily glargine (Lantus) or detemir (Levemir) insulin to mimic basal insulin secretion, in addition to intermittent lispro/aspartate injections, based upon glycemic corrections and carbohydrate food boluses throughout the day. In the stimulated phase after meals, insulin levels increase within minutes and peak at 15-30 minutes. Levels fall of to basal values within 2 hours (Figs.4 and 5).

Since the common daily diet includes three meals per day, short acting insulins should be given at least three times daily to prevent excessive hyperglycemic excursions. The dose depends upon the level of glycemia before the meal (SEE EXAMPLE BELOW). The difference between the measured blood glucose and the target of 120 mg/dl is used to calculate the correction bolus dose. This may range from 1-10 units for 100 mg/dl blood glucose, depending upon the age and body size of the patient. The starting correction dose begins with an estimation of the total average daily dose as divided into 1,500 or 1800 depend on the type of insulin used and the age of the patient. The accuracy of this calculation is then modified by serial blood glucose level experiences. Meal boluses are calculated from an estimation of the carbohydrate content in grams and an individual factor relating insulin dosage to the amount of carbohydrate to be consumed. The range is from 1-5 units to cover 50 grams of carbohydrate. The starting carbohydrate bolus can be estimated by 500 divided by the total daily dose of insulin, but will need to be modified based on individual post-prandial glycemic responses. For infants, the intermittent, short acting insulin may be given after the meal when food consumption is unpredictable. In addition to the three main meals, additional amounts of short acting insulin may be taken at any and all times to cover snacks, and to reduce blood glucoses as necessary at bedtime. Correction boluses should not be given more often than at 3.5-4.0 hour intervals.

Most newly diagnosed patients with T1DM can be started on 0.25 to 0.5 units of insulin per kilogram of body weight with about half of this given as long acting glargine. Adolescents often need relatively more, but the dose can be adjusted every few days based on symptoms and blood glucose measurements. There are several ways to calculate basal and bolus doses (24, 25). The total daily dose (TDD) of insulin when a patient is making the switch to CSII can be reduced to 80% if the patient on MDI is in good control with a HbA1c < 7.5% but for HbA1c > 7.5% it is usually better to start with 100% of TDD.

Example: How to Estimate an Insulin-to-Carbohydrate Ratio for 50 kg patient with a total daily dose 1 unit/kg/day.

1. Total daily dose of insulin for such patient will be 50 unit/day (1 unit/kg/day for 50 kg patient)

2. Insulin-to-Carbohydrate Ratio

500/50 =10 (therefore give 1 unit per every 10 grams carbohydrate eaten)

How to estimate correction factor for 50 kg patient with a total daily dose 1 unit/kg/day.

1500 =30 (therefore 1 unit of short acting insulin given will decrease blood
50 glucose by 30 mg/dl )

3. Target blood glucose-- we use 150 mg/dl in the beginning while training and later 120 mg/dl during daytimes after patient is comfortable with the insulin schedule.
Example: In case of blood glucose 300 mg/dl and target blood glucose 150 mg/dl:
Correction factor = 300 -150/30 = 5 unit of short acting insulin ( therefore 5 unit of short acting insulin will decrease blood glucose to 150 mg/dl).We confirm the accuracy of these ratios by frequent blood glucose testing. The insulin sensitivity factor (ISF) or correction factor however, should be individualized before administration, depending on other factors such as puberty, sports, and presence of insulin resistance. Insulin injections are usually given subcutaneously because injections into the peri-umbilical area have the most rapid and consistent absorption kinetics (26-28).The goal of treatment is to achieve a fasting blood glucose (FPG) concentration between 80 and 110 mg/dL, postprandial glucose between 100 and 140 mg/dL, and glycosylated hemoglobin (HbA1C) below 6.5 % (29-31). Several insulin preparations are available: rapid-acting insulin (lispro or Humalog), glulisine (Apidra), (aspart or Novolog), short-acting preparations (regular insulin), long-acting insulins (neutral protamine Hagedorn [NPH], Lente insulins) and ultra-long-acting insulins (Ultralente, Glargine [Aventis Pharmaceuticals, Parsipanny, NJ]) insulins (Table 2).

In addition to insulin preparations presented in Table 2, there are pre-mixed (short and long acting) insulin preparations e.g. 70% NPH/30% regular (Humulin 70/30; Novolin 70/30), 75% lispro-protamine (NPL)/25% lispro (Humalog Mix 75/25) and 70% aspart-protamine/30% aspart (Novolog 70/30). Premixed insulins are convenient for some patients, especially the elderly. However, the ratio of insulin cannot be changed and this may lead to inadequate glycemic control or unexpected hypoglycemia episodes. Thus in our practice, we seldom use pre-mixed insulin except in some elderly patients and adolescents who are significantly non-compliant with their MDI regimen to reduce the number of the injections.

Continuous subcutaneous insulin infusion (SCII)

One of the primary focuses of long-term management of diabetes is to develop an artificial pancreas or a system that delivers insulin based on real-time glucose information. Since its’ introduction in the late 1970s, CSII (insulin pump) has become an increasingly popular option for diabetes management. Because CSII is the most appropriate physiological regimen of insulin replacement, we prefer to use CSII in all possible patients with T1DM in our practices. Today, the yearly increase rate of patients-treated with CSII is about 40% in USA. There are multiple models available and their operations continue to change with advancing technology. They contain multiple programs including basal and temporary basal rates, correction and carb boluses. They can be programmed according an individual’s life style. Pre-programmed CSII automatically gives basal insulin (unit/hour) according to that individual’s requirements and in addition temporary basal rates can be programmed for exercise or for inter-current infections. Again bolus doses can be automatically calculated by modern insulin pumps to help reduce calculation errors. Insulin pumps are as small as a pager (Figure 6) and can hold 2-3 day supply of rapid acting insulin (Humalog, Apidra or Novolog). All insulin pumps except OmniPod (Insulet Corp, Bedford, MA) deliver insulin via a catheter to the sub-cutaneous tissues (Figure 6). The Omnipod system has created a system using disposable pumps which utilize a remote control. In CSII, the infusion site is best changed every 2-3 days to avoid skin infections and clogging up of the catheters. Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is available in Europe more than 20 years (195).Insulin is delivered through the intraperitoneal (IP) route rather than subcutaneous tissue. It requires a minor surgical procedure. IP insulin delivery is more physiological (absorbed by the portal system) than either subcutaneous or intravenous infusion. CIPII provides better synchronization of the insulin peak with postprandial hyperglycemia and a more rapid onset of insulin action than subcutaneous injections of regular or rapid/long-acting insulin (196). The devise has been likened to a hockey puck in terms of its’ size and shape. Such devices have not been approved for use in the US by the FDA. In the diabetic rats, IP insulin improves glucagon secretion and hepatic glucose production in response to hypoglycemia by alleviating peripheral hyperinsulinemia (197).

The advantages of CSII are that insulin is taken only when needed, and not in an anticipatory fashion as with long acting insulins, insulin boluses are taken to cover all carbohydrate food intake whenever this is, no special diets as required, hypoglycemic episodes are minimal and the system is convenient and portable (38, 39). This increased flexibility has the greatest impact on the patients’ quality of life (170). Another advantage is that basal rates can be lowered overnight when insulin requirements are at the lowest, and raised before waking time to prevent the glycemic rise when growth hormone and cortisol levels go up inducing the “dawn phenomenon”. Such an over-night insulin excursion cannot be mimicked by long acting insulins.

Whereas CSII has traditionally been reserved for adolescents and adults, it is gaining more widespread acceptance in children especially in infants and toddlers (162-164). Although parental supervision is maximum in this age group to monitor BG levels and to give multiple insulin injections, it is usually difficult to achieve near-normal metabolic control in this population by MDI because of the extremely small insulin doses required due to marked insulin sensitivity, erratic dietary habits with unpredictable food intake, the varied activity level during the day and day to day, and frequent infections in this age group. As a result, infants face hypoglycemia and hyperglycemia episodes more often than older children. Therefore, we find that CSII is the ideal treatment option for this age group. In the past, there were concerns about safety and suitability of CSII in these young patients. Any parent will quickly identify the inaccuracy inherent in giving small doses or insulin by syringes and greatly appreciate CSII when they discover that they can deliver insulin doses as small as a 1/40th unit with precision. To date, multiple clinical trials and our experience demonstrated that CSII is a safe and effective treatment for optimizing glycemic control which minimizes hypoglycemia episodes (165-169). Furthermore, CSII achieves a 0.8% greater reduction in HbA1c levels to that achievable with multiple insulin injections. Most modern pumps have a child lock feature.

We find that CSII may even help with compliance where this has been a management problem and not the converse.

The one down side of CSII is that since only short acting insulin (Humalog effects are mostly gone within 4 hours) are taken, any blockage (a kinked or damaged catheter) or pump failure or forgetting to put the pump back on after showers or swimming etc can lead to rapid onset of hyperglycemia and/or ketoacidosis, with a rapid loss of control of diabetes and/or dehydration. Adolescents, especially girls who use pumps, complain that the treatment is uncomfortable, embarrassing, or unpleasant, particularly when bathing or having sexual intercourse (40). The disadvantages of CSII although few, need to be explained before this form of therapy is begun. If the patient is not a candidate for aggressive insulin management (and a few are not), we modify their MDI regimen accordingly to the life style of the patient.

Continuous Glucose Monitoring System (CGMS)

Current approach to monitor blood glucose is limited with premeal and bedtime glucose measurements achieved four to five times daily. This approach, however, will not assess postprandial state and overnight blood glucose levels particularly nocturnal hypoglycemia. CGMS gives more detailed information on glycemic control with respect to the time of meals, impact of insulin dosages, exercise and overnight glucose profile. It measures subcutaneous interstitial glucose every 5 minutes of the entire day continuously for 3-7 day periods and the information can be downloaded for analysis (Figure 7). Today, CGMS has been used in patients with high variability of glucose values, or for assessment of glycemic control at postprandial and overnight to optimize insulin therapy and metabolic control in patients with CSII (171, 172). With the newest devices, it is possible to trace the direction and rate of change of glucose concentrations and therefore to make appropriate adjustments to the diabetes management. Some of the devices are also equipped with adjustable alarm for impending or actual hypoglycemia and hyperglycemia so that an immediate action can be taken (198). Furthermore, patients can adjust their insulin requirements throughout the day according to their lifestyle and set tight glucose targets without having hypoglycemia episodes. Multiple clinical trials have shown a significant reduction in HbA1c level in patients using CGMS (199). Another widely used CGMS is DEXCOM, which has been approved by the FDA for 7 days of usage per sensor. Currently, DEXCOM is working closely with both Animas and OMNI-POD to develop composite units.

Multiple Daily Injections (MDI)

The next best regimen is intensive insulin treatment with long acting insulin substituting for basal insulin by CSII and short acting MDI before meals and as necessary with additional short-acting insulins at bedtime. While the choice of regimen is an individual matter of patient and physician preferences, we exclusively use glargine with short acting lispro, glulisine or aspart in our practice. We prefer glargine (Lantus) insulin to all other available long-acting insulins to provide our basal insulin requirements because it provides day-long basal insulin without significant peaks of action (32, 33) (Fig.7), such as confound NPH or insulin mixtures. We also prefer glulisine in young infants with low basal insulin flow rates, as there are less episodes of occlusion and its’ relatively faster action makes it more suitable to cover carb boluses after the child has eaten, since appetites at young ages are often spurious.

However glargine does have a shallow peak of action, while in about a third of our patients especially in infants and young children, the single dose does not cover a 24-hour period (34), (35). We usually give glargine at a convenient and the same time each day after dinner, to achieve a BS before breakfast near 100, and may add a second and smaller dose of glargine before breakfast if the BSs before lunch and dinner remain consistently above target.

Glargine cannot be mixed in the same syringe with another form of insulin in a single syringe due to pH incompatibilities, and must be given in a syringe by itself. The burden of many injections of short acting insulin each day can be reduced by use of an insulin "pen", which is a convenient way of carrying multiple doses in a single dispenser. Both Humalog, Apidra and Novolog pens are in wide use. Pen forms are also available for both glargine and detemir insulin as well.

Monomeric insulins, such as lispro (Humalog), glulisine (Apidra) and aspart (Novolog), have fewer episodes of hypoglycemia as compared with regular insulin. They are effective in normalizing post-prandial blood glucose levels (36). A meta-analysis of 8 large multi-center trials representing over 1,400 patient-years of insulin treatment revealed that severe hypoglycemia occurred in 3.1 percent of patients during lispro treatment compared with 4.4 percent while taking regular insulin (37).

The twice-daily injection regimen, consisting of regular or Humalog/Novolog insulin and intermediate-acting insulin (NPH or Lente) as basal insulin, used to be the standard of care. The downside of this is that the morning dose of intermediate-acting insulin usually is often not sufficient to prevent a post-lunch rise in blood glucose. Moreover, the intermediate-acting insulin administered before the evening meal may not be sufficient to induce normoglycemia the next morning unless a larger dose is given, which increases the risk of hypoglycemia during the night (Fig.8). Unfortunately, this happened more often than we and our patients were aware of in the past. We do not use premixed insulin preparations because of variability in their actions (41). Ultra-lente has irregular absorption properties and so we seldom use this insulin either in our practices.

Non-invasive insulin treatment in the future

Insulin therapy is central to the treatment of people with T1DM. Intensive insulin therapy, in particular, is associated with better long-term clinical outcomes. Originally, insulin was administered intramuscularly. It soon became clear that subcutaneous injections were just as effective but considerably less traumatic. Over the years, researchers have suggested transdermal, oral, buccal, nasal, and pulmonary routes of administration as alternatives (146-149). High permeability and large surface area of the lungs (75m²) makes pulmonary insulin a viable alternative to injections. Very rapid absorption of insulin after inhalation mimics the time activity profile of fast acting insulin, and thus it is appropriate for pre-meal administration. It appears comparable to subcutaneous insulin on glycemic parameters for both T1DM and T2DM patients (179-181). Several pulmonary insulin delivery systems are in various stages of development. The first inhaled insulin, Exubera, was approved by FDA in 2006. However, Exubera was withdrawn from the market shortly after its release by its company because of its expense, and concerns about possible association between Exubera and lung toxicity and lung cancer (150, 151). A rapid acting, inhalation powder, technosphere insulin, was developed thereafter. Technosphere insulin delivers insulin with an ultra rapid pharmacokinetic profile similar to natural insulin release. In-vitro studies in human lung cell models do not as yet indicate cytotoxicity with technosphere insulin (200). Technosphere insulin was recently submitted for FDA approval. Intranasal insulin is delivered significantly smaller area compared to inhaled insulin. Although absorption of insulin intranasally appears faster than subcutaneous insulin (201), many factors affect its absorption including composition and character of nasal mucus (202, 203). Nasal and oral insulins have been used in trials attempting to prevent T1DM in high risk persons. One of the trials, however, showed that, in children with HLA-conferred susceptibility to diabetes, administration of nasal insulin started soon after detection of autoantibodies, did not prevent or delay T1DM (204). In another large multi-center trial of oral insulin conducted by the National Institutes of Health in individuals found to be at high risk for T1DM because of their islet cell antibody profiles, the outcome was promising and a second trial is currently underway. Inaddition to diabetes prevention trials, new oral insulin formulas appear to maintain their biological activity after delivery, suggesting a potential role for this product in management of diabetes (205). In children, the subcutaneous route is the only one recommended at present. There is a long history of attempts to develop novel routes of insulin delivery that are both clinically effective and tolerable.

Insulin analogues and the risk of cancer

Multiple epidemiologic studies indicate the possible association between hyperinsulinemia and increased cancer risk in individuals with obesity and T2DM (206, 207). Although the underlying mechanism remains unclear, hyperinsulinemia appears to be of importance since insulin is a growth factor with mitogenic activities (208). Insulin like growth factor one or IGF-1, has over 50% homology with insulin. Furthermore, insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. In-vitro studies have shown that downregulation of IR inhibits cancer cell proliferation, angiogenesis, lymphangiogenesis and metastasis (209). It appears that there is a certain degree of cross-talk between insulin, IGF-1 and their receptors (210). There is a concern about the potential safety of long-term use of newly developed insulin analogues after findings of increased affinity of binding to IGF1R and potential mitogenic activities that were found in in-vitro studies. When breast, colorectal and prostate cancer cell lines were treated with pharmacologic doses of glargine, detemir and lispro insulin they showed increased proliferative and anti-apoptotic activity not found with regular insulin (211). However, glargine and detemir insulin , like IGF-1, do not cause DNA damage or activate oncogenes in otherwise healthy cells (212). Furthermore, in animal models, there was no difference in the rate of developing mammalian tumor in rats treated with insulin glargine and NPH insulin or control solutions (213). A large observational study from Germany showed an increase risk of developing certain cancers in patients treated with glargine compared to human insulin, while glargine appeared to prevent other cancers (214). The following population based studies from Scotland and Sweden, however, were inconclusive. In both studies, however, there was an increased incidence of breast cancer in women using insulin glargine as compared with women using other types of insulin (215, 216). In both studies, authors indicated the possibility of allocation bias for their results and therefore, no definitive conclusions were made regarding possible association between insulin glargine and the occurrence of tumors. Furthermore, Rosenstack et al., showed no difference neither in the progression of diabetic retinopathy or the development of malignancy in patients treated with insulin glargine compared with NPH insulin (217, 218).

Future Directions

With the technological advancements, a wide variety of insulin preparations and delivery systems will not only facilitate improvement of blood glucose control but also provide an easy, less painful administration of insulin and give improving lifestyle flexibility for patients. Improvements in glucose monitoring and in insulin delivery will continue to reduce the risks of long term complications in T1DM. In addition to prevention of diabetes, the major goal for diabetes treatment is to provide life-long insulin independence. In addition to β cell preservation trials with immunomodulators, β cell regeneration and/or transplantation has become an important target in the field of diabetes research. Although there is a significant improvement in islet cell and pancreas transplant graft survival (219), pancreas transplantation is an invasive procedure which involves the continued administration of heavy duty immunosuppressants needs to prevent graft rejection and retard recurrence of the autoimmune process that led to T1DM in the first place. Shapiro et al. introduced successful human islet transplantation in seven adult patients with T1DM by using non-invasive Edmonton protocol (220). Patients were able to attain insulin independence quickly and sustain normoglycemia more than one year. Currently, multiple centers established clinical trials to replicate the results of the Edmonton Protocol (221). However, both pancreas and islet cells for transplantation have limited availability. In order to overcome this problem, the development of insulin producing β cells which respond glucose is under investigation (222). Regeneration of β cell mass from pancreatic tissue both in-vivo and in-vitrohave promising results although the cells appear to lose insulin secretion and degenerate after a period of time (223). In addition, administration of embryonic and adult stem cells and the transdifferentiation of adult somatic cells (224) have been explored as an alternative source for generating β cells or for regenerating β cell mass for diabetes treatment (225). Currently, there are multiple clinical trials of islet regeneration and stem cell transplantation (226).

Treatment of associated auto-immunities

The clinical associations between T1DM itself and other autoimmune diseases are well established, and have been extensively covered elsewhere in the chapter on Autoimmune Polyglandular Syndromes. The presence of other organ-specific auto-antibodies suggests that patients with T1DM have a generalized tendency toward autoimmunity involving multiple endocrine glands and specific organs. All patients with T1DM should be optimally be screened for the presence of adrenal, celiac disease related, gastric parietal, and thyroid relevant autoantibodies at the time of their diagnoses, which itself should be confirmed as the immunological form of T1DM by ICA, GAD₆₅A, IA-2A, and IAA testing when clinical presentations are not classical for T1DM (Table 3).

Immune mediated T1DM, GAD, glutamic acid decarboxylase; H+, K+-ATPase, the parietal cell protein pump; IAA, insulin autoantibody; ICA, islet cell antigen; TSH, thyroid-stimulating hormone; 21-OH, P450 steroidogenic enzyme 21-hydroxylase; 17-OH, 17a-hydroxylase; P450scc, P450 side-chain cleavage enzyme; IA-2, members of protein tyrosine phosphatase; AADC, aromatic L-amino acid decarboxylase, ANA-antinuclear antibodies, SMA-smooth muscle antibodies, LKM-antibodies against liver/kidney microsomes, SLA - anti-soluble liver protein antibodies.

Family members of a proband with T1DM should also undergo these autoantibody studies, especially when the proband is found positive. Positive autantibodies should be followed for the relevant hormonal evaluations and treatments. Positive thyroid autoantibodies should be followed by thyroid function tests and coexisting hyper-or hypothyroidism treated. Fully 25% of females with T1DM will have co-existant thyroid autoimmunities. Similarly, the finding of positive 21-hydroxylase autoantibodies should be followed by the screening of serum electrolytes, recumbent renin and PM ACTH levels (Fig. 8). However it is outside of the scope of this article to cover all of these associated disorders.

TYPE-2 DIABETES

Treatment

T2DM is a metabolic disease that characterized by both impaired insulin secretion and insulin resistance. Today, better understanding the pathophysiology of the disease leads to develop more effective treatment options and therefore prevent microvascular and macrovascular complications. At present, at least six different major forms of therapy are available for T2DM: lifestyle modifications of diet and exercise, insulin replacement therapy, insulin secretagogues, biguanides, meglinitides, a-glucosidase inhibitors, and PPAR-γ agonists. The newer therapeutic agents, glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitors, both incretins, have been recently introduced to control postprandial glucose excursions. Patients with T2DM have delayed and decreased insulin secretion in response to meals (227). As a result, endogenous glucose production is not adequately suppressed and clearance of ingested carbohydrates are prolonged, resulting with postprandial hyperglycemia. Incretins stimulate 50-60% of insulin release after meals (228).

To achieve good glucose control and prevent complications of diabetes, patients are usually provided multiple drug combinations. These combinations, however, may cause side-effects which can limit the efficacy of treatment. However, it is impossible to know which combinations produce the best long-term outcomes for individual patients, and it more clinical trial data is needed to address this issue.

The goals of treatment are to achieve physiologic control of blood glucose (HbA1c near 6.5%), pre-prandial blood glucose 110 mg/dl and post-prandial blood glucose 140 mg/dl) and to prevent/reduce complications and mortality (140). We believe that insulin sensitizers are the most optimal initial pharmacological agents with respect to safety and efficacy. We use metformin, but up to, 40% of patients may have transient G-I upsets. Thus we urge patients initially to take it immediately after food and to use 1 tablet daily for a few days before building up the day. While PPAR- agonists can lead to fluid retention and weight gains. For that reason, we usually avoid them, especially as older patients have been shown to have an increased risk of heart attacks and congestive heart failure. We may add a second agent like Januvia to older teenagers and young adults as a second line agent. Other alternatives include the sulfonylureas. Exactly which additional agents to add once a patient fails to be controlled by this regimen remains unclear.

Conventional therapy for T2DM has taken a stepwise approach. First we prescribe lifestyle modification, then oral agents as monotherapy, and then combinations of oral agents. Sulfonylureas add to glycemic control, although at a risk of provoking hypoglycemia, since insulin secretion is promoted whether food is taken or not. This is an increasing problem in the aged as well as in incapacitated children such as those with cerebral palsy. Another possible problem arises from the concern that such agents may shorten the period whereby appreciable amounts of insulin are capable of being secreted, as was the case in the UPD trial. Another approach is to add an -glucosidase inhibitor such as acarbose. These agents are poorly tolerated and lead to flatulence. Thus the dosage needs to be carefully built up to improve compliance. When oral therapy fails, exogenous insulin is often prescribed as the last resort, an approach that we believe is flawed since at the time of initial presentation of T2DM, 50% of patients already have significant macro-vascular complications. We therefore advocate early consideration of insulin therapy to better control hyperglycemia and retain insulin secretory capacity.

Such an approach is supported by recent advances in understanding of the progressive nature of T2DM, gained from UKPDS, Kumomota and other studies. These studies proved the possibility of prevention of complications when the HbA1c is less than 6.5%.

Insulin

It remains unclear when to initiate insulin replacement in T2DM. In the face of progressive impairment in insulin secretion with ongoing ß-cell dysfunction leading to a progressive insulinopenic phase, a large percentage of patients with T2DM will eventually fail to achieve adequate glycemic control and will require insulin therapy. Insulin therapy can also be started as an initial therapy when diet/exercise alone fails, especially when the initial HbA1c level is high. It was stated by a recent American Diabetes Association (ADA) consensus that "if glycemia goals are not achieved with combination therapy, then treatment with insulin is indicated". We hold that the benefits of good glycemic control which ultimately can only be achieved with insulin therapy in T2DM patients, albeit there is reluctance from both patients and physicians to initiate insulin therapy (78, 152). Previous studies showed better glycemic control when insulin is added to the oral anti-diabetic regimen and there are multiple studies that have shown better glycemic control can be achieved with insulin combination therapy than with insulin alone (153). Combination therapies allow use of reduced daily insulin replacements.

Several studies, have documented that intensive insulin therapy for up to 4 weeks improves insulin sensitivity in T2DM and in insulin resistant subjects, as measured by the glucose-insulin clamp method (86). In obese, non-insulin dependent diabetics, control of hyperglycemia for 1 month, led to improvements in both insulin secretion and action that persisted for at least 2 weeks after cessation of therapy (6-11, 81, 87, 88). Insulin therapy decreased hepatic glucose production and improved endogenous insulin secretion. The mechanism for this improvement in insulin sensitivity is presumably reduced glucose/glucosamine or lipid mediated pancreatic cell toxicities from improved glucose control.

In T2DM glargine insulin has been shown to produce less hypoglycemia than NPH insulin with less weight gains (79, 80). However such patients have a primary problem with excessive post-meal glycemia that long acting insulins do not often solve. Most require MDI form the outset of insulin replacement therapy. The studies of CSII in adults with T2DM revealed significant improvement in endogenous insulin and C-peptide secretion, reduction in hepatic glucose output, improved insulin sensitivity, and significant improvement in HbA1c comparing to twice-daily injections of regular and NPH (81, 82). Ryan et al. demonstrated that in newly diagnosed T2DM with elevated fasting glucose levels, a 2- to 3-week course of intensive insulin therapy by MDI can successfully lay a foundation for prolonged good glycemic control (78a). Studies with CSII treatment have shown that transient CSII can also induce long term glycemic control in newly diagnosed T2DM patients. These results could be due to improvement of b cell function, especially the restoration of first phase insulin secretion, could be the responsible for the remissions seen (155, 156). Li et al. demonstrated that short-term (2 weeks) CSII treatment in newly diagnosed T2DM patients with severe hyperglycemia induced adequate glycemic control and the patients stayed euglycemic without requiring anti-diabetic agents which is similar to the honeymoon period in T1DM (157).

Our own preferred approach is to add insulin therapy after diet, exercise and combination of insulin sensitizers have failed to keep normoglycemia and Hb1Ac levels to near 6.5%. We use the same principles of insulin therapy as discussed above in T1DM, giving preferences to intensive multiple short acting insulin injections (Humalog, Apidra or Novolog) plus glargine (Lantus) insulin or by CSII. Many patients find that CSII is more convenient than MDI when it has been established that they need multiple doses of insulin each day to control their blood glucose levels.

As mentioned earlier, the issue of when to initiate insulin treatment in T2DM is controversial. However, above observations clearly indicate that early insulin treatment in T2DM patients may preserve endogenous insulin secretion by improving β cell function. In some, the improved endogenous insulin secretion coupled to lowered insulin requirements may permit them to come off insulin therapy after some time, albeit relapses are eventually common.

Preventing complications: intensive insulin treatment

The principal aim of treatment of T2DM is to prevent complications. The large study United Kingdom Prospective Diabetes Study (UKPDS) (83) revealed that diabetes is a progressive disease with complications that are directly proportional to the level of glycemic control. Concomitant with the inexorable decline in endogenous insulin secretion in the UKPDS was a progressive increase in hyperglycemia, and HbA1_Clevels regardless of the mode of treatment given. Thus, over the course of 15 years of T2DM, the proportion of patients able to use oral agents alone significantly declines, with most (some 90%) requiring exogenous insulin treatment (84, 85). With over 10 years of follow-up, intensive therapy resulted in an absolute 1% reduction in HbA1_Cvalue over conventional therapy (Fig. 10). The 11% difference in HbA1_Cwas associated with a 12% lower risk in aggregate diabetes outcomes, with most of the reduction based on a 25% reduction in micro-vascular disease such as in retinopathy and nephropathy (Fig. 11). Increased atherosclerotic disease in T2DM may depend more on concomitant dyslipidemia and hypertension than on glycemic control.

To delay or prevent T2DM by improving insulin sensitivity

The relationship between insulin sensitivity and insulin secretion predicts that the disposition index (DI), a measure of β cell compensation for insulin resistance, is the best measure of effective β cell function. As persons develop worsening insulin sensitivity, those who develop diabetes fail to show sufficient compensatory increase in insulin secretion to overcome heir insulin resistance. Both short-term and long-term changes in insulin sensitivity and in glycemia may affect the risk of developing diabetes. Therefore, it is possible to produce β cell rest by improving insulin sensitivity; the β cell "rest" hypothesis. The Troglitazone in Prevention of Diabetes (TRIPOD) study, which delayed or prevented onset of T2DM in high-risk Hispanic women (89), appeared to confirm this. The diabetes rate decreased in the troglitazone-treated group to 5.5%, as compared to 12.5% in the placebo group (Fig.12).

The theory of β-cell rest was invoked from studies on children and adolescents. Several studies revealed that metformin and diet may act synergistically to limit weight gain and improve glucose tolerance (90-92). The recently completed Diabetes Prevention Program (93) showed that metformin could delay or prevent the onset of T2DM. The 3-yr cumulative incidence of diabetes in the group overall was 28.9% in the placebo group, 21.7% in the metformin-treated group, and 14.4% in the intensive lifestyle group. However the intensive lifestyle intervention was more effective than metformin. We argue that as a result of these studies, and given the natural history of progression of IGT to diabetes, that the earlier use of insulin sensitizers and insulin replacement therapy will likely preserve endogenous insulin reserves (Fig.13). Ultimately, it should reduce long-term diabetes-associated complications.

Medications

INSULIN SENSITIZERS

Metformin: Metformin is approved for the treatment of T2DM in children as in adults, but is the drug of choice for the treatment of insulin resistance in the absence of diabetes too. Some have suggested that it is the gastrointestinal side effects of the drug that accounts for much of its action. However the drug is effective in T2DM without weight loss, being found to reduce hepatic glucose output and increase insulin sensitivity in muscles amongst other actions. Metformin has various mechanisms of action in insulin resistance. For detailed explanations, the reader should refer to the following references: (82-99). Metformin is safe in cases of treatment of insulin resistance in pediatric patients (90-92, 94, 95) and in pregnant woman to decrease extreme hyper-androgenemia and improve pregnancy outcomes (96, 97). Furthermore, obese patients in the UKPDS who were assigned initially to receive metformin rather than sulfonylurea or insulin therapy had a decreased risk of any diabetes-related endpoint and mortalities from all causes (83).

Our experience in treating obese children and adolescents with metformin is likewise very positive. We begin with 500mg or 850mg once daily with the evening meal and as tolerated, add a second dose with breakfast and than a third with lunch to an eventual dose of 850 mg TID in adolescents or adults. Extended release metformin is available making it unnecessary to take a midday dose. In children, the size of the metformin pill causes compliance problems and the use of a metformin suspension as in Riomet can be very useful. The much touted lactic acidosis from metformin use appears to have largely evaporated in recent years. We still do not give the agent to patients with chronic renal or congestive heart failure because of this possible side effect. We also do not routinely continue metformin throughout pregnancy out of prudence, and give MDI or CSII as needed often after the end of the first trimester until delivery.

Thiazolidinediones (TZDs) [The peroxisome proliferator activated receptor γ-agonists (PPAR-γs): They are a group of ligand-activated transcription factors that govern numerous biological processes, including energy metabolism, cellular proliferation, and inflammation (98). PPAR-γ agonists are effective as insulin sensitization but are less useful in patients who are trying to lose weight. The PPAR-γ isotype is mainly expressed in adipose tissue where it stimulates adipogenesis and lipogenesis. It is the target of a group of anti-diabetic drugs called thiazolidinediones. These PPAR-γ agonists have been shown to inhibit FFA release from adipocytes, increase FFA uptake and storage in adipocytes, increase adipocyte triglyceride synthesis and storage by induction of adipocyte glycerol kinase, decrease inflammatory proteins and adhesion molecules, decrease cytokine production, improve lipid oxidation, decrease 11β HSD type-1, reduce intra-myocellular lipids, reduce muscle insulin resistance (99-101), decrease PAI-1 expression in endothelial cells (102) and decrease testosterone levels in insulin resistance females (103).

There is no clinical experience with the use of thiazolidinediones (TZDs) in the prevention or treatment of T2DM in obese children. One reservation with their use has been with the instances of fatal hepato-toxicity seen with the prototype agent troglitazone, resulting in the FDA withdrawing the agent. This side effect has not been implicated with later agents of this class such as pioglitazone or rosiglitazone, albeit it should be monitored for. Thiazolidinediones as mentioned above commonly cause weight gains, although this appears to result from the accumulation of subcutaneous, rather than visceral fat (104). Rosiglitazone can cause edema and have been implicated in cardiac complications among adults. Other medications indicated for treatment of T2DM, such as a-glucosidase inhibitor acarbose (105), lipase inhibitors (106), meglitinides are not often used in our pediatric practice as they are relatively ineffective and have significant side effects.

INSULIN SECRETAGOGUES

Sulfonylureas: We believe that the use of sulfonylureas in children with T2DM should be minimal. A typical initial sulfonylurea regimen consists of 2.5-5 mg of glipizide or glyburide taken 30 minutes before breakfast with another before dinner. Amaryl is a 24-hour sulfonylurea that can be given once daily at 2-8 mgs dosing and thus is the one that is used preferentially in our clinic. Sulfonylureas directly stimulate the KATP channel subunit containing the cytoplasmic binding sites for both sulfonylureas and ATP and result in the closure of the KATP channel and insulin secretion. However, as mentioned, hypoglycemia induced by a long-acting sulfonylurea may be severe and is a frequent problem (107) especially in the elderly. Our additional concern is that, such agents might actually enhance progression to β cell failure.

Glucagon-like peptide-1 (GLP-1) receptor agonists and Dipeptidyl peptidase-4 (DPP-4) inhibitors: GLP-1 is one of the intestinal pro-glucagon-derived peptides synthesized from pro-glucagon in the lower gut, mainly distal ileum and colon (141). It is an incretin hormone secreted in response to food intake rich in fat and carbohydrate (142). GLP-1 stimulates insulin secretion, inhibits glucagon secretion, improves β-cell sensitivity to glucose, increase postprandial insulin responses, regulates food intake by delaying gastric emptying and induces satiety. Subsequently, enhances the transition from the fasting to posprandial state by inhibiting endogenous hepatic glucose production and limits the postprandial hyperglycemia (229). In addition, it stimulates islet cell proliferation and differentiation while inhibiting apoptosis (142, 143). It is a promising drug for the future in the management of T2DM. However, GLP-1 is rapidly metabolized by the dipeptidyl peptidase-4 (DPP-4) enzyme. To overcome this, GLP-1 receptor agonists and DPP-4 inhibitors have been developed. Studies with GLP-1 receptor agonist exenatide and liraglutide have shown significant decrease in BG levels resulting in a reduction of HbA1c with minimum side effects (nausea, mild hypoglycemia) (144, 145). In addition there was a marked weight loss in subjects treated with GLP-1 receptor agonists. One relative problem with the agent is that it must be taken by injection before meals. DPP-4 inhibitors, sitagliptin (Januvia) and saxagliptin were introduced in 2006 and can be used alone or in combination with other oral anti-diabetics as mentioned above.

MEGLITINIDES

Meglitinides are structurally different than sulfonylureas, but act similarly by regulating ATP-dependent potassium channels in pancreatic b cells, thereby increasing insulin secretion. Repaglinide (PRANDIN) is a short-acting glucose-lowering drug with similar efficacy to the sulphonylureas. Repaglinide appears to act via different receptors than sulfonylureas. It is less effective than glyburide at higher blood glucose concentrations (108). Hypoglycemia is the most common adverse effect. However it can be given pre-prandially to reduce the hyperglycemic excursions following food ingestion.

Nateglinide (Starlix) is a meglitinide analogue and a derivative of d-phenylalanine (173). Nateglinide mimics physiologic insulin secretion dynamics seen in healthy individuals by increasing early phase insulin secretion into the portal vein and in that way increases hepatic glucose uptake as well as hepatic glucose suppression (174). In contrast to sulfonylureas and repaglinide, nateglinide is a more potent agent to restore early phase insulin release with less hypoglycemia episodes (175). When administered before meals, nateglinide rapidly acts at the same pancreatic ß- cell K+ATPase channel as sulfonylureas and repaglinide but dissociates from the receptor within seconds (176). Therefore, delayed hyperinsulinemia and an increased risk of hypoglycemia are unlikely with nateglinide. Clinical trials have demonstrated that nateglinide can reduce postprandial hyperglycemia and thereby improve glycemic control (176-178).

alpha-GLUCOSIDASE INHIBITORS

Acarbose and miglitol are members of the a-glucosidase inhibitors. They inhibit the upper gastrointestinal enzymes (alpha-glucosidases) that convert carbohydrates into monosaccharides leading to slow absorption of glucose. The slower rise in post-prandial blood glucose concentrations improve glycemic control without increasing the risk for weight gain or hypoglycemia. Acarbose as well decrease LDL cholesterol and increase HDL cholesterol (109). Miglitol has similar efficacy (110). The main side effects of these drugs are flatulence and diarrhea. Slow increases in dosage minimize these adverse effects (111). Hepatic injuries have been reported with acarbose as well (112).

LIPASE INHIBITORS (ORLISTAT)

Orlistat (Xenical) inhibits pancreatic and gastric lipases, blocking absorption of approximately 30 percent of ingested fat (113). The agent is sometimes given as part of a regimen to induce weight loss and will contribute to correcting triglyceride elevations from the dyslipidemia associated with insulin resistance and T2DM.

Currently available oral antidiabetic agents are summarized in Table 4.

ANTI-OBESITY DRUGS

Obesity not only in adults but also in children has become an epidemic disease and a major public health problem worldwide. Obesity is associated with serious medical complications including T2DM, dyslipidemia, and hypertension. Especially, there is a strong correlation between obesity and the early onset of T2DM in the children. T2DM was known as an adult type of diabetes. However, over the past decade, there is an alarming increase in T2DM as a new diagnosis of diabetes in particularly adolescents. Prevention of obesity is a logical first step for the prevention of developing diabetes. The usual approach is to start with lifestyle modification (diet and age appropriate exercise programs). When lifestyle intervention fails, the last resource is pharmacotherapeutic agents for prevention of weight gain. However, because of their serious side effects many anti-obesity and appetite suppressant drugs have been abandoned. Today, sibutramine and orlistat are the only anti-obesity drugs approved for children ³ 16 year and ³ 12 year respectively. Both sibutramine and orlistat found to be effective in decreasing BMI, HbA1c, improving dyslipidemia, fasting and postprandial BG levels (182-184). Sibutramine inhibits serotonin re-uptake and induces premeal hypophagia. The common side effects are mild elevation of blood pressure (182, 183). It may induce depression, anxiety and insomnia. Orlistat inhibits gastric and pancreatic lipase and thereby reduces triglyceride and cholesterol absorption. Orlistat side effects are mainly gastrointestinal problems (184). Fat soluble vitamin deficiency (A, D, and E) may be seen with orlistat.

Metformin is also effective in significant weight loss in obese adolescents (185).

Prevention and treatment of diabetic complications

Besides insulin replacement therapy for T1DM and T2DM, co-existing hypertension and dyslipidemia should be aggressively treated.

ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS

Angiotensin converting enzyme (ACE) inhibitors are widely used for treatment of hypertension and microalbuminuria, and protection of the kidney against diabetes provoked damage (114-116). In animal studies, induced aldosterone blockade prevented myocardial remodeling and reduced myocardial and renal damage (117-119). Diabetes and hypertension promote development of atherosclerosis and renal impairment (120, 121). This understanding was reflected by recent guidelines published by the American Diabetes Association and National Kidney Foundation specifying that in patients with diabetes, BP should be lowered to <130/80 mm Hg in an attempt to prevent cardio-vascular events and preserve renal function (122). Two recent studies - Irbesartan Diabetes Nephropathy Trial (IDNT) (123) and Reduction of Endpoints in Non-insulin diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) (124) - demonstrated that blockade of the renin-aldosterone system protects the kidney from damage. The combination of ACE inhibitors and angiotensin II type-1 receptor blocker (ARB) has been proven beneficial for urinary albumin excretion (125-128). We use enalopril (Vasotec) at 5-20 mgs daily depending upon the age of the patient.

Poorly controlled diabetes induces rise in hepatic VLDL output and triglyceride levels. There is also a rise in total cholesterol, since 20% of VLDL is cholesterol. Whereas there may be a modest rise in LDL-cholesterol, a low level of the protective HDL-cholesterol is fairly constant with this atherogenic lipid profile. With severe (>500mgs/dl) and/or chronic hypertriglyceridemia, pancreatitis may result. This is a serious problem with a mortality of some 20% with an acute attack. Diet reduced in animal fat and administration of fibrates (eg gemfibrozil) should be given to combat established hypertriglyceridemia (129).

Fibrates lower triglycerides as mediated through the PPAR- transcription factor, mainly in liver where it has an important role in FA oxidation, gluconeogenesis, and amino acid metabolism. Pretreatment of endothleial cells with a PPAR- agonist (fenofibrate) reduced markers of inflammation such as vascular cell adhesion molecule-1 (VCAM-1) expression, CRP, fibrinogen, PAI-1 and IL-6 (130-132). The American Diabetes Association recommends use of the agents in children for elevated triglyceride level =150 mg/dl, to enhance efforts to maximize blood glucose control and achieve desirable weight. If triglycerides are =500 mg/dl, a significantly increased risk of pancreatitis is present, and treatment with a fibric acid medication should be given (129).

Statins inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway through which cells synthesize cholesterol. To compensate for decreased synthesis and to maintain cholesterol homeostasis, cells, particularly hepatocytes, increase the expression of LDL receptors, which increases the uptake of plasma LDL, the main carrier of extra-cellular cholesterol, resulting in lower plasma LDL concentrations. Decreased plasma LDL levels reduce the progression of atherosclerosis and may even lead to the regression of preexisting atherosclerotic lesions. Statins have important immunomodulatory effects as well, and are able to decrease the recruitment of monocytes and T cells into the arterial wall and inhibit T cell activation and proliferation in vitro (133, 134). If after 6 months of optimized blood glucose control and dietary intervention there is no significant improvement in lipid parameters, intervention based on LDL is proposed by American Diabetes Association in children (129):

• LDL 100-129 mg/dl: maximize non-pharmacologic treatment.

• LDL 130-159 mg/dl: "consider" medication, basing the treatment decision on the child's complete CVD risk profile, including assessment of blood pressure, family history, and smoking status.

• LDL =160 mg/dl: begin medication.

Low doses of aspirin inactivate the enzyme cyclo-oxygenase, which catalyzes the conversion of arachidonic acid to prostaglandins G₂and H₂. These prostaglandins are precursors of thromboxane, a potent platelet pro-aggregant and vasoconstrictor. Low doses of aspirin (81 mg/day) are preferred. Aspirin should be used in diabetic individuals over the age of 30 years who are at high risk for cardiovascular events (78).

We will not discuss in this review benefits of various combinations of oral agents and oral agents and insulin, albeit most of them have additive beneficial effect. Our own approach is to start with low carbohydrate low animal fat diet, daily anerobic exercise plus metformin to tolerance. If normoglycemia is not achieved, we often add a small dose of Avandia (4mg) to our patients who are unable to take full doses of metformin or are unable to be controlled by metformin alone. In the cases where combination of insulin sensitizes fail to keep normoglycemia and a Hb1Ac less than 6.5%, we add insulin (glargine plus intermittent Humalog/Apidra or CSII) early to provide intensive insulin management.

T1DM WITH UNDERLYING INSULIN RESISTANCE

T1DM with underlying insulin resistance and obesity is a clinically confusing entity that is often misunderstood. Too often, a child or adolescent presenting with symptoms of insulinopenia in the presence of obesity and acanthosis nigricans will be given the diagnosis of T2DM even when they develop DKA. However, positive islet cell autoantibodies will delineate a distinct group of T1DM developing in obese children who happen to have coincidental insulin resistance syndrome. It may be that the latter condition dictates an earlier onset of T1DM than would otherwise be the case. Currently four classic autoantibodies are available for confirmation of immune nature of the disease: islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GAD₆₅A), insulin antibodies (IAA), and tyrosine phosphatase antibodies (IA-2) (135, 136). Hathout et al (137) measured islet cell autoantibodies in phenotypic T2DM patients and found 8.1 % to be ICA positive, of which 30.3 % were GAD₆₅A positive and 34.8 % were IAA positive. The epidemic of obesity has become as pronounced in childhood as in adulthood where it leads to the development of insulin resistance much earlier. The combination phenotype should not mislead physician. We advocate that assay of islet cell autoantibodies in any patient who presents with insulinopenic symptoms of diabetes since it creates a management problem in the face of insulin resistance, since the diabetes is more severe with rapid deterioration to absolute insulinopenia and larger than normal requirements for daily insulin replacement (138, 139).

A possible explanation may be that increased insulin secretion as a compensation for the degree of insulin resistance may induce an increase in the quantitative expression of certain antigenic determinants in ß-cells and them more susceptible to immune mediated destruction. Insulin resistance will also increase insulin requirements and lead to an earlier age of onset.

Many physicians select a therapy according to the clinical phenotype of the patient. However, it is necessary to determine islet cell auto-antibodies in every patient with diabetes, and when found to prompt the initiation of intensive insulin therapy much earlier than would otherwise be the case. The routine recommendation of diet and exercise and early use of insulin sensitizers are clearly indicated as well to such subgroup of patients, according the same principles we have already discussed (Fig. 13).

CONCLUSION

The prognosis of T1DM continues to improve with advances in home blood monitoring, in long acting insulins with modest peaks of action, in fast acting insulins suitable for meal boluses and insulin delivery systems exemplified by insulin pumps. Great advances have been made with subcutaneous glucose sensing, and the first closed loop systems are anticipated by the mid 2010 decade. Continued progress in these directions will continue to resolve the management of T1DM. To our minds, T2DM has emerged as the more serious form of childhood diabetes, while prevention of it through attention to the predisposing factors are looming increasingly important to our public health. The US obesity epidemic continues unabated, with ever increasing numbers of the nation's obese children becoming irreversibly obese adults, replete with the insulin resistance in all of its' burgeoning complications, notably of progressive atherosclerotic disease, hypertension, increased frequencies of common cancers and T2DM. The only rational long term solution must lie in the realization that the epidemic has its' genesis in childhood and thus it must be that the interventional focus should be placed in early life. Long term therapeutic trials that can show the long-term benefits of aggressive prevention and intervention, initially targeting highly prone ethnicities, are urgently needed. One interesting potential research development, has been the creation of oral agents that lower the renal threshold for glucose. Thus blood glucose levels exceeding 120-130 mg/dl (instead of the normal 185 mg/dl) would be filtered off into urine. Such a property should be useful at least in obese patients with T2DM. However such drugs are unlikely to become available within two years at the time of writing.

ACKNOWLEDGMENT

We remain grateful to our patients who ultimately teach us most of what we may know.