1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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40 4. Incretin mimetics and enhancers Incretin hormones are peptides released by the gastrointestinal tract in response to nutrient ingestion that enhance insulin secretion and aid in the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion and control of body weight (157). The two major incretins are Glucagon-like peptide –1(GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are small peptides, 30 and 42 amino acids, released by the enteroendocrine L cells located in the distal ileum and colon and by the K cells in the duodenum, respectively. Both rapidly stimulate the release of insulin only when blood glucose levels are elevated, thereby enhancing the glucose-sensing and insulin secretory capacity of the endocrine pancreas during postprandial hyperglycemia (157). While GLP-1 controls blood glucose via other actions besides stimulating glucose-dependent insulin release by inhibiting glucagon secretion and suppression of hepatic glucose output as well as decreasing the rate of gastric emptying, GIP decreases gastric emptying to a much lesser degree and does not inhibit glucagon secretion (157, 158). GLP-1 also activates regions in the central nervous system important for control of satiety (159). However, GLP-1 and GIP have also been shown in preclinical studies to exert significant cytoprotective and proliferative effects on the islets of Langerhans (160, 157, 161). The incretin hormones elicit their actions through direct activation of distinct G-protein-coupled receptors expressed on islet beta-cells (161, 162). Native GLP-1 and GIP are rapidly inactivated by the ubiquitously expressed proteolytic enzyme dipeptidyl peptidase (DPP)-IV, which cleaves 2 N – terminal amino acids from both peptides to produce inactive metabolites (163). Regarding GLP-1, DPP-IV activation results in the inactivation of GLP-1(7-36)amide and the generation of the metabolite GLP-1(9-36) amide, which did not activate the GLP-1 receptor thus not enhancing the insulin secretion and not blocking GLP-1(7-36) amide-enhancement of insulin secretion during an intravenous glucose tolerance in healthy subjects (164). Recently, the suppression of hepatic glucose production by GLP-1 (9-36) amide not
41 mediated by inhibition of glucagon secretion nor through interaction with the known GLP- 1 receptor has been shown in subjects with normal oral glucose tolerance tests (165). Thus, GLP-1(9-36) amide may reduce postprandial glucose levels independent of insulin. The short circulating half-life of bioactive intact GLP-1 and GIP initially limited enthusiasm for the potential use of incretin hormones in the treatment of diabetes. However, incretin analogs have been developed with significantly increased half-lives due to modification of the DPP-IV cleavage site and/or conjugation to large circulating proteins, such as albumin (i.e., liraglutide). Furthermore, other GLP-1 receptor agonists are being tested in the treatment of type 2 diabetes, presently available synthetic exendin-4 structurally identical to native exendin-4, originally isolated from the venom of a lizard, Heloderma suspectum (Exenatide by Amylin Pharmaceuticals, Inc and Eli Lilly and Co.) (166-168) Although both GLP-1 and GIP act as incretin hormones in normal subjects, only GLP-1 can be used to treat DM 2 because diabetes is often associated with a blunted or absent response to GIP. It has been shown that while GLP-1 levels are significantly decreased in DM2, GIP values are normal, suggesting that DM 2 are resistant to the biological effects of GIP rendering it relatively ineffective (169). The mechanisms underlying the diminished GIP responsiveness in experimental and clinical diabetes are not fully understood (170) but may involve downregulation of GIP receptor expression (171) or receptor desensitization (172). Recent data has suggested that desensitization is not a major contributor to defective GIP action in diabetic patients (173). A possible explanation for the decreased GLP-1 secretion in DM2 may be a decrease gastric emptying rate, which hypothetically might increase the absorption in the proximal intestine resulting in less food reaching the distal intestine where Lcells are more numerous (169). Indeed, the opposite situation, increased exposure of carbohydrates to the distal intestinal mucosa by α-glucosidase inhibitors or accelerated gastric emptying increases GLP-1 secretion (174,175). However, the gastric emptying rate does not seem to exhibit consistent changes in DM2 and obesity, but is more oftern reported as delayed (ref. cit in 169). In the study reported by Toft-Nielsen et al. (169), the decreased GLP-1 secretion in DM2 was considered most likely a consequence of the disease.
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