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Clinical Gems

Our clinical gems come from the top selling medical books, and text books because knowledge is everything when it comes to diabetes.

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #48: Biosynthesis, secretion, and action of glucagon Part 2 of 4

Physiologic effects of glucagon: Glucagon acts through binding to specific receptors located at the target cell plasma membrane. The major common effect of glucagon is to activate adenylate cyclase and to increase the intracellular production of cAMP. There is considerable evidence that binding of glucagon to its receptor activates an intermediate transduction process that involves the participation of guanosine triphosphate (GTP), divalent cations, and adenosine (or other similar natural substances).

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #47: Biosynthesis, secretion, and action of glucagon Part 1 of 4

Glucagon, discovered in 1923 as a contaminant of early insulin preparations, has long been a neglected hormone. Glucagon was among the very first polypeptide hormones to be isolated, purified, sequenced, and synthesized. Thanks to the pioneering work of Unger, it was the first polypeptide hormone to become measurable by radioimmunoassay, almost one year before insulin. It has served two Nobel Prize winners as a unique tool, which permitted Sutherland and his associates to discover cyclic AMP (cAMP), and Rodbell and his coworkers to discover the role of G-proteins in cell-membrane receptors.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #46: Neuropeptides and Islet Hormone Secretion Part 5 of 5

Summary of present-day knowledge: We know today that the pancreatic islets are innervated by parasympathetic, sympathetic, and sensory nerves. The parasympathetic nerves stimulate insulin and glucagon secretion whereas sympathetic nerves inhibit insulin secretion and stimulate glucagon secretion; the net influence of the sensory nerves is not yet clearly established.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #45: Neuropeptides and Islet Hormone Secretion Part 4 of 5

Sympathetic effects and mediation: Sympathetic nerves inhibit insulin and stimulate glucagon secretion. Their activation may help mediate stress-induced changes in islet hormone secretion including the glucagon counterregulatory response to hypoglycemia.These effects may be mediated by the combination of the classical neurotransmitter noradrenaline and the sympathetic neuropeptides (galanin and NPY). All three neurotransmitters can inhibit insulin and stimulate glucagon secretion, thus mimicking the effects of sympathetic activation on islet hormone secretion. In addition, galanin and NPY meet several other of the criteria needed to be classified as a physiologic neurotransmitter.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #44: Neuropeptides and Islet Hormone Secretion Part 3 of 5

Islet sympathetic nerves: Islets are densely innervated by sympathetic nerves, as demonstrated by fluorescence microscopy, electron microscopy, and immunocytochemistry. The islet sympathetic nerves are postganglionic nerve fibers with most nerve cell bodies located in the celiac ganglion and some in the paravertebral sympathetic ganglia. Electrical activation of the sympathetic nerves inhibits insulin secretion and stimulates glucagon secretion.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #43: Neuropeptides and Islet Hormone Secretion Part 2 of 5

Vasoactive intestinal polypeptide (VIP): VIP was originally isolated from the porcine small intestine in the early 1970s and found to consist of 28 amino acid residues, with a C-terminal α-amidation showing structural similarities to other members of the glucagon superfamily of peptides [18]. VIP is formed by processing of 149-amino acid proVIP and is highly conserved as illustrated by human, porcine, and rat VIP increased glucose tolerance with a reduction of circulating glucose.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #42: Neuropeptides and Islet Hormone Secretion Part 1 of 5

The traditional view is that islet hormone secretion is mainly regulated by circulating nutrients (glucose, amino acids, free fatty acids) as well as the gut incretin hormones (glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)). However, in certain circumstances regulation of insulin and glucagon secretion is also dependent on the autonomic nerves which innervate the islets. These nerves belong to the parasympathetic, sympathetic, and sensory branches of the autonomic nervous system.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #41: Normal Beta-cell Function Part 6 of 6

Beta-Cell function and glucose homeostasis: Insulin secretion, together with the sensitivity to insulin of glucose-utilizing tissues, is a key player in glucose homeostasis. What is relevant for glucose homeostasis is not the absolute insulin secretion levels but insulin secretion relative to glucose, as typically assessed by the beta-cell dose-response during the physiologic condition of oral glucose ingestion. Thus, beta-cell glucose sensitivity is strongly inversely associated to mean glucose levels during a standard OGTT and explains, together with insulin sensitivity, a substantial proportion of the variability in glucose levels.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #40: Normal Beta-cell Function Part 5 of 6

Beta-cell mass and function: beta-cell mass can be accurately evaluated only through autopsy studies. Complex in vivo tests aiming at measuring maximal secretory capacity combining different stimuli have been proposed as an alternative. However, their ability to discriminate between defects in function and mass, as well as their feasibility, is a matter of debate. As thoroughly reviewed by Robertson, the acute response to an i.v. glucose bolus in normoglycemic subjects and the acute response to an i.v. arginine bolus in hyperglycemic subjects do correlate with beta-cell mass.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #39: Normal Beta-cell Function Part 4 of 6

Beta-Cell response to hormones and the nervous system: As already mentioned insulin is the only hormone with a blood glucose lowering effect, while many other hormones (glucagon, cortisol, adrenaline) exert a hyperglycemic action. The changes in glucose levels elicited by these hormones obviously will be detected by the beta cell, which will respond by enhancing insulin secretion. Yet, all these hormones, as well as others and the nervous system exert a coordinated direct effect on the beta cell resulting in an integrated and sophisticated control network.

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