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ROLE OF GLUCAGON IN FUEL HOMEOSTASIS Although adipocytes have glucagon receptors and there is evidence that alterations in plasma glucagon can affect lipolysis (58), the main target organ of glucagon is the liver. At concentrations that approximate those found in the portal vein in vivo, glucagon is a potent stimulator of hepatic glycogenolysis, gluconeogenesis, and ketogenesis in vitro (59). These actions of glucagon and the increases in plasma glucagon observed during hypoglycemia (60), exercise (61), trauma (62), infection (63), and other stress (64) provide considerable evidence that glucagon is important in the maintenance of euglycemia in the postabsorptive state and at times when there are increased demands for fuels and when the organism must rely on mobilization of endogenous substrate. Under these conditions, when ß-cell function is normal, the major action of glucagon would be to counteract the actions of insulin on storage of glucose and other fuels. Conversely, when ß-cell function is deficient, glucagon could accentuate the metabolic consequences of insulin deficiency and be an important determinant of the magnitude of hyperglycemia and hyperketonemia found in diabetes. Substantial evidence for the role of glucagon in glucose homeostasis has been provided from studies employing somatostatin; a potent inhibitor of glucagon and insulin secretion which does not itself directly affect substrate metabolism at doses used in vivo. Infusion of somatostatin in normal man results in an acute decrease in the glucose production rate, which is accompanied by a decrease in plasma glucose; this occurs despite a concomitant decrease in plasma insulin and can be prevented by replacement infusion of glucagon. These observations suggest that in the postabsorptive state, glucagon action on the liver balances insulin action on the liver to maintain an appropriate output of glucose to match glucose utilization and, therefore, maintain stable euglycemia. With prolongation of the glucagon deficiency during infusion of somatostatin, glucose production does not exceed normal rates. These changes reflect the effects of the concomitant insulin deficiency and the unopposed actions of other counterregulatory factors. When insulin deficiency is avoided by infusion of replacement amounts of insulin along with somatostatin, which results in an isolated deficiency of glucagon, plasma glucose decreases more than that observed during infusion of somatostatin alone, and both it and the glucose production rate remain suppressed below normal. In addition to a role for glucagon in the maintenance of euglycemia by antagonizing the effects of postabsorptive (i.e. low) plasma insulin concentrations, there is considerable evidence that glucagon acts in the defense against hypoglycemia by antagonizing the effects of excess plasma insulin (65,66). When hypoglycemia is produced in humans by injection of insulin, release of glucagon is stimulated along with that of other counterregulatory hormones when the plasma glucose decreases below 3.8 mM (~68 mg/dl) (Figure 11). Restoration of euglycemia is due to a compensatory increase in hepatic glucose production. Although secretion of catecholamines, growth hormone, and cortisol are stimulated along with that of glucagon, only the increases in plasma glucagon and catecholamines coincide with or precede the compensatory increase in the glucose production rate (66,67). That glucagon is the major acute glucose counterregulatory hormone is suggested by the fact that inhibition of the plasma glucagon responses by somatostatin markedly attenuates the compensatory increase in the glucose production rate and impairs restoration of euglycemia following insulin administration (Figure 12). Prevention of cortisol secretion (68), adrenergic blockade (66), adrenalectomy (65), or acute growth hormone deficiency (66) does not appreciably affect immediate glucose counterregulation. The effects of glucagon during restoration of euglycemia involves both glycogenolysis and gluconeogenesis, predominantly the former (69).
There is also evidence for the role of glucagon in disposal of ingested carbohydrate (70-76). The liver is the main organ responsible for clearance of glucose appearing in the portal vein after ingestion of carbohydrate and presumably also that derived from a meal (77,78). The increases in the portal venous insulin and glucose concentrations act to promote formation of glycogen from the ingested glucose. Suppression of glucagon secretion is probably also important in the decrease in endogenous glucose output and in the formation of glycogen from the ingested glucose. In insulin-dependent diabetics incapable of insulin secretion, suppression of increases in plasma glucagon following ingestion of a mixed meal or glucose load improves postprandial glucose tolerance (79). Moreover, the effectiveness of exogenous insulin in preventing postprandial hyperglycemia and improving diabetic control is markedly augmented when glucagon secretion is suppressed by somatostatin (79). Circulating levels of ketone bodies (e.g. acetone, acetoacetic acid, and ß-hydroxybutyrate) are determined by the net balance between rates of ketone body production and removal. The plasma ketone body concentration and insulin seem to be the major factors affecting removal of ketone bodies by tissues (80). While there is no evidence to suggest that glucagon influences this process, there are considerable data, mainly from animal studies, that indicate that glucagon may play a key role in the formation of ketone bodies. Ketone body formation results from ß-oxidation of free fatty acids derived from intra- and extrahepatic sources. Two key factors are necessary for ketone body formation: sufficient substrate in the form of free fatty acids and a shift in the hepatic handling of free fatty acids from triglyceride synthesis (i.e. esterification) to oxidation. Glucagon directly acts on the liver in vitro to augment ketogenesis (81). This is thought to involve the promotion of transport of free fatty acids across the mitochondrial membrane by acylcarnitine transferase, an important rate-limiting step for free fatty acid oxidation. Glucagon apparently does not directly affect this enzyme but indirectly causes its activation by lowering intrahepatic levels of malonylcoenzyme A (CoA), an inhibitor of acylcarnitine transferase (82). It has been postulated that glucagon is essential for switching the liver to a ketogenic mode (i.e. from an organ primarily esterifying free fatty acids to one oxidizing them) to permit maximal rates of ketogenesis to occur (82). Pharmacologic doses of glucagon given as a bolus have been reported to increase both plasma free fatty acid and ketone body concentrations in normal subjects despite concomitant increases in plasma insulin (83). Following acute withdrawal from insulin in insulin-dependent diabetics, the expected hyperketonemia can be markedly attenuated by suppression of glucagon secretion with somatostatin (3). Under such conditions (e.g. insulin withdrawal and somatostatin administration), infusion of physiologic amounts of glucagon, producing circulating glucagon concentrations less than those reported in ketoacidosis, results in a marked degree of hyperketonemia. There are thus two prerequisites for glucagon to stimulate ketogenesis: adequate substrate (e.g. free fatty acids) and insulin deficiency or the inability to increase plasma insulin concentrations. It is well established that the actions of glucagon on glycogenolysis, gluconeogenesis, and ketogenesis are mediated mainly by cAMP (84) (Figure 13). Binding of glucagon with its receptor activates the catalytic subunit of the membrane bound enzyme adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cAMP which in turn leads to activation of intracellular kinase. For glycogenolysis, this results in phosphorylation of phosphorylase, which activates the enzyme and desphosphorylation of glycogen synthase which inactivates the enzyme. Thus, glycogen formation is inhibited and glycogen breakdown stimulated.
The actions of glucagon on gluconeogenesis is more complex and involves several steps (85). Glucagon increases hepatic uptake of amino acids, but its main effect is intrahepatic. Glucagon stimulates gluconeogenesis mainly by increasing the rate of phosphoenolpyruvate production and decreasing the rate of its disposal by pyruvate kinase. Stimulation of ketogenesis by glucagon is linked to some of the biochemical steps involved in its stimulation of gluconeogenesis (86), namely, an inhibition of glycolysis. The rate-limiting step of ketogenesis is the transport of fatty acid CoA esters across the mitochondrial membrane where they undergo ß-oxidation. The enzyme catalyzing this transfer is fatty acid carnitine acyl transferase II. This enzyme is inhibited by malonyl-CoA. The inhibition of glycolysis by glucagon lowers intracellular levels of malonyl-CoA and results in activation of the fatty acid CoA acyl transferase. GLUCAGON SECRETION IN DIABETES MELLITUS In human diabetes, plasma glucagon concentrations are either increased in an absolute sense or are "normal" but inappropriate for the prevailing plasma glucose concentration (87); they are markedly increased in diabetic ketoacidosis (88). In contrast to the normal situation, carbohydrate ingestion does not appropriately suppress plasma glucagon in people with impaired glucose tolerance and diabetes (89) (Figure 14). This failure to suppress glucagon secretion leads to excessive appearance in plasma of glucose released from the liver which has been correlated with plasma insulin: glucagon molar ratios (Figure 15). Excessive increases in plasma glucagon are observed with protein meals (90), mixed meals (91), and infusion of amino acids (92). Some of these abnormalities, such as the fasting hyperglucagonemia and excessive responses to infusion of arginine, protein, or mixed-meal ingestion, can be improved or corrected by administration of physiologic quantities of insulin, suggesting that they were, in part, the result of insulin deficiency.
In contrast to the above, acute administration of physiologic or even pharmacologic amounts of insulin have not been able to correct abnormal A-cell responses to glucose in human diabetes (91). These observations suggest that abnormal A-cell responses to glucose may not be solely due to insulin deficiency. Evidence for a selective defect in A-cell glucose recognition independent of insulin deficiency is provided by the findings that plasma glucagon can be suppressed normally in human diabetes by elevation of circulating free fatty acid levels but not by hyperglycemia (93), and that the diabetic A cell fails to respond appropriately to hypoglycemia or to hyperglycemia (94). METABOLIC CONSEQUENCES OF A-CELL DYSFUNCTION IN DIABETES MELLITUS PATIENTS At the present time, the preponderance of evidence suggests that the full-blown manifestations of diabetes cannot be explained solely on the basis of insulin deficiency, and that abnormal A-cell function is an important determinant of the magnitude of hyperglycemia and hyperketonemia found in diabetes. The evidence for this can be summarized as follows. Fasting hyperglycemia and insulin requirements are lower in pancreatectomized patients lacking glucagon (95). Moreover, in such individuals (95) and in insulin-dependent diabetics whose glucagon secretion is suppressed with somatostatin (96), hyperglycemia and hyperketonemia following acute withdrawal of insulin are markedly diminished. The failure to suppress glucagon secretion appropriately after meal ingestion increases postprandial hyperglycemia in people with impaired glucose tolerance and diabetes. In insulin-dependent diabetics, acute suppression of glucagon secretion decreases plasma glucose to concentrations only slightly above normal, and chronic suppression markedly improves diabetic control (97). Finally, the failure of hypoglycemia to stimulate glucagon secretion in people with type 1 diabetes and in those with type 2 diabetes and marked beta cell dysfunction increases the risk for severe hypoglycemia in these individuals (98). Thus abnormalities in alpha cell function play an important role not only in the pathophysiology of metabolic abnormalities in diabetes mellitus but also in its management. |
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