Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #50: Biosynthesis, secretion, and action of glucagon Part 4 of 4

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #50: Biosynthesis, secretion, and action of glucagon Part 4 of 4

Nov 15, 2016

Glucagon and diabetes

Plasma levels of glucagon have been found to be increased in all experimental and clinical forms of diabetes mellitus. This disturbance undoubtedly contributes to the hyperglycemia of the disease and excessive ketogenesis of diabetic coma. Numerous studies have shown that failure of glucagon suppression contributes to postprandial hyperglycemia in type 1 [67] and type 2 [68,69] diabetes. Impaired glucagon suppression contributes with impaired insulin release to the excessive blood glucose levels in early type 1 diabetes [70], in subjects with impaired glucose tolerance [71,72], and in patients with ketosis-prone atypical diabetes [73,74]. Morphologic studies have established that the main abnormality in the islet cell population of diabetes is a decrease in the β cells with a relative expansion of the α-cell mass [75].

The proposal of Unger and Orci to consider diabetes as a “paracrinopathy” of the islets of Langerhans [3] is based on the concept that the very high concentrations of insulin normally reached inside the stimulated islet exerts, directly or by proxy, a major inhibitory effect on glucagon secretion from the neighboring α cells. Conversely, a reduction in intra-islet insulin concentrations would permit glucagon release from the α cells. Disruption of this mechanism is proposed as a key factor in the pathophysiology of diabetes [76]. This concept is supported by recent data on the micro-anatomy of the islets of Langerhans [74,77]. In type 1 diabetes, α cells lack constant action of high insulin levels from juxtaposed β cells. Replacement with exogenous insulin subcutaneously injected does not approach the paracrine levels of insulin, except with high doses that “overinsulinize” the peripheral insulin targets, thereby promoting glycemic volatility [3]. In type 2 diabetes, the α-cell dysfunction may result from the failure of the juxtaposed β cells to secrete the first phase of insulin or from the loss of the intra-islet pulsatile secretion of insulin. Observations made in experimental diabetes in minipigs [78] and recently confirmed in human type 2 diabetes [79] are in support of the second mechanism.

Inhibition of glucagon secretion markedly improves experimental diabetes in rodents [80] and knockout of the glucagon receptor makes rodent models of insulin-dependent type 1 diabetes thrive without insulin [29]. The critical role of glucagon action in the liver in diabetes has been demonstrated by expressing glucagon receptors in livers of glucagon receptor-null (GcgR-/-) mice before and after β cell destruction by high doses of streptozotocin [81]. Wild-type mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR-/- mice remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB) and phosphoenol-pyruvate carboxykinase, markers of glucagon action rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 days later, P-CREB declined and hyperglycemia disappeared. In this experimental setting, the metabolic manifestations of diabetes cannot occur without glucagon action, and once present, disappear promptly when glucagon action is abolished.

These observations strongly suggest that targeting the α cell and glucagon are innovative approaches in diabetes management. Compounds such as pramlintide and GLP-1 agonists reduce glucagon release and this is considered an important component of their antidiabetic action (see Chapter 48). On the other hand, numerous glucagon antagonists, either peptidic or nonpeptidic, have been identified and some have entered clinical trials. However, marked inhibition of glucagon signaling may result in α-cell hyperplasia, increased mass of the pancreas, increased susceptibility to hepatosteatosis and hepatocellular injury, and an increased risk of hypoglycemia [82]. Further studies in normal and diabetic subjects should identify the extent to which reduction of glucagon signaling produces a compelling therapeutic benefit without incurring a risk of adverse events.

The glucagonoma syndrome

The glucagonoma syndrome is a rare disorder associating necrolytic migratory erythema, cheilosis, usually mild diabetes mellitus, anemia, weight loss, venous thrombosis, and, frequently, neuropsychiatric symptoms [83].

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