Insulin-Mediated and Non-Insulin-Mediated Metabolic Effects of Gastroenteropancreatic Peptides in Type I and Type II Diabetes
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The recognition of secretion as a physiological regulator of the exocrine secretions of the pancreas in 1902 led to generalization of the concept of hormonal control of digestive sections,1 and excited interest in such mechanisms as possible mediators of the functions of the pancreas in control of glycemia.2 According to the “incretin” hypothesis, hormones released from the gastrointestinal tract in response to ingestion of nutrients serve to activate the glucoregulatory function of the pancreas.3 With the later identification of insulin as a hormonal effector of these functions, the hypothesis was adapted by suggesting that incretin stimulates insulin secretion. A variety of experiments with crude extracts of gastrointestinal tissues yielded conflicting results4, and following the recognition of direct effects of glucose on the release of insulin interest in incretin waned. However in the early 1960’s it was recognized that the glycemic stimulus to insulin secretion cannot account for differences in blood insulin levels after enteral and parenteral administration of glucose, which are also accompanied by apparent differences in glucose disposa1.5,6 These observations revived the hormonal hypothesis for stimulation of the beta cells by gastrointestinal factors, and a renewed search for candidate peptides that might fill this role was undertaken. Studies of these phenomena have yielded evidence related to the pathophysiology of disorders of intermediary metabolism in diabetes, with indications of differences between Type I and Type II diabetes in this context. However, before discussing the identification of incretins it is necessary to consider the question whether the hypothetical enteroinsular axis is necessary or sufficient to account for differences in glucose homeostasis observed with enteral and parenteral administration of the sugar, and whether mechanisms other than those simply dependent on portal perfusion of the liver and/or the recognized effects of insulin must be invoked.
KeywordsInsulin Secretion Beta Cell Glucose Disposal Continuous Subcutaneous Insulin Infusion Gastric Inhibitory Polypeptide
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