vision restoration after form deprivation, plus lens wear). Pancreatic Islet cell carcinoma with capsule invasion. Violeta Stanojevic M.A., M.Phil, Joel F. Habener M.D., in Best Practice & Research Clinical Endocrinology & Metabolism, 2015. Recent studies in mice suggest that excessive glucagon signaling might be more diabetogenic than has heretofore been appreciated. These findings are consistent with increased glucose production observed in mice treated with OXM during a hyperinsulinemic-euglycemic clamp [49]. Pancreatic mixed acinar-islet cell neoplasms are much less common than typical islet cell or acinar cell neoplasms. In mammals, a single proglucagon precursor is differentially processed to yield multiple proglucagon-derived peptides, including glucagon in the islet alpha cell and glicentin, oxyntomodulin, GLP-1, GLP-2, and several spacer or intervening peptides in the gut enteroendocrine L cell. However, consistent with the known stimulatory effect of glucagon on hepatic glucose production, it was demonstrated that GLP1R-agonism exerts better glucose lowering than OXM at equimolar doses in a glucose challenge [45]. Although previous data have shown that the glucagon receptor is involved in the body weight and glucose lowering action of OXM in addition to GLP1R, OXM may activate additional receptors. It has been estimated that β cells survive for about 30 days in growing rats; after 30 days, they undergo apoptosis and are replaced by proliferation. For example, activation of the expression of the prohormone convertase PC1/3 so as to preferentially form GLP-1 by the cleavage of proglucagon thereby promoting beta cell regeneration. Unlike hyperplastic islets, cells containing glucagon or somatostatin are usually randomly distributed in the neoplasms. Nevertheless these data are not conclusive as in the same study cpd A alone in feed resulted in significant body-weight reduction thereby limiting the interpretation of each receptor's contribution to the body weight-lowering effect of OXM [46]. Recently, two publications [45,46] expanded the initial findings on the mechanism of action of OXM and demonstrated that OXM has glycogenolytic properties in perfused mice liver [46]. Further investigation is required on these data. form deprivation, minus lens wear) and increased by conditions inhibiting eye growth (i.e. It seems apparent that the side chain of position 9 is not directly involved in binding contacts but provides a major functional requirement for agonist activity. Clinical Trials, Triumphs, and Tribulations of Glucagon Receptor Antagonists Diabetes Care 2016;39:1075–1077 | DOI: 10.2337/dci15-0033 Since the discovery of glucagon’s opposing actions to insulin, drugs targeting the Glucagon excess represents one of the hallmark metabolic derangements that contribute to hyperglycemia in type 1 and type 2 diabetes.87 Conversely, increased glucagon secretion functions as the primary counterregulatory mechanism to restore normal levels of plasma glucose in the setting of hypoglycemia, and individuals who are prone to frequent episodes of hypoglycemia may use glucagon injections for emergency management of severe hypoglycemia. In humans, α cells appear to be more capable of proliferation than β cells in response to disease or injury of the islets. In contrast to the clearly opposite nature of glucagon towards insulin recalled above, the relationship between the two hormones inside their production site, the islets of Langerhans, are much more complex. In the case of glucagon, the conformation of the 10–14 and 15–18 residues may undergo a conformational transition during the second phase of the transduction process. Interestingly, glucagon is able to stimulate ERK even in the absence of added glucose during the experiment [42]. Alpha cells are now known to increase in numbers (alpha cell hyperplasia} and to produce GLP-1, in response to beta cell injuries. A major target for ERK is the transcription factor CREB (cyclic AMP response element binding protein) which controls expression of genes implicated in many cell functions. OXM inhibits food intake and stimulates energy expenditure in rodents and in human subjects [37–40]. Initial studies using semisynthetic [des-His1]glucagon, and later with a totally synthetic analog, as well as the presence of the negatively charged functional group of Asp9, led to speculations that an interaction of the negative Asp9 with positive His1 may constitute a part of the triggering mechanism at the molecular level (Unson et al., 1987). Rarely is there evidence of metastasis from spontaneous islet cell carcinomas in 2-year-old rats. These compounds potently counteract the hyperglycaemic response to a glucagon challenge with a concomitant rise in plasma lactate.25 Because of the overriding role of elevated glucagon on hepatic glucose production10, the acute suppression of hyperglycaemia is more likely to be due to inhibition of G6Pase than to the insulin-mimetic properties of the compounds. Of course, it also is possible to study the activity of the various enzymes in the cascade since they might be of interest to some specific downstream function one is examining. Results obtained from such sequence modifications suggest that the backbone conformation in the 9 to 12 region is crucial for the correct fit of the message sequence 1–5 to the active site of the receptor (Hruby et al., 1993a). Oxyntomodulin administered three times daily for 4 weeks reduced body weight in overweight and obese human subjects.104 Although distinct G protein–coupled receptors for glucagon, GLP-1, and GLP-2 have been characterized, separate receptors that mediate the actions of glicentin and oxyntomodulin have not been identified, and the anorectic action of oxyntomodulin requires a functional GLP-1 receptor.105 Oxyntomodulin simultaneously activates both glucagon and GLP-1 receptors, and oxyntomodulin mimetics resulted in enhanced weight loss in preclinical models compared with the actions of GLP-1 receptor agonists alone.106 Multiple co-agonists targeting the glucagon, GLP-1, or GIP receptors exhibit enhanced activity on appetite and weight loss and are being explored for the treatment of human subjects with diabetes and obesity.55, Victor J. Hruby, Dinesh Patel, in Peptides: Synthesis, Structures, and Applications, 1995. National Institutes of Health. In response to extreme injury of beta cells alpha cells can transform (transdifferentiate) into functioning beta cells. If these data translate to higher species, it is possible that central GCGR signaling may contribute to the improvement of glucose metabolism in animals treated with OXM. Compounds that increase prolactin secretion increase the incidence of pancreatic islet cell hyperplasia in rats. These methods have greatly aided studies of the early events of receptor transduction following glucagon agonist- and antagonist-glucagon receptor interactions. Another role of ERK in the β-cell is to phosphorylate proteins participating in insulin secretory granule exocytosis, favouring the secretory action of glucose [43]. Myopia Pharmacology: Etiologic Clues, Therapeutic Potential, ). The glucagon receptor antagonist RVT-1502, at the high dose 15 mg per day, lowered A1c by 1.0% without severe hypoglycemia. Accumulations of hemosiderin-laden macrophages may accompany the fibrosis. The loss of glucagon actions in genetically manipulated mice prevents the development of diabetes in the complete absence of pancreatic insulin, a convincing demonstration of the potent diabetogenic actions of glucagon. The regional distribution of cell types is retained in hyperplastic islets but the proportions are altered. Retinal or choroidal content of glucagon or its receptor mRNA levels also are altered in chicks under visual conditions modulating eye growth (Buck et al., 2004; Feldkaemper et al., 2004; Feldkaemper and Schaeffel, 2002). Several GLP-1 receptor agonists are suitable for once weekly administration (exenatide once weekly, albiglutide, dulaglutide); all of these agents are associated with weight loss or prevention of weight gain in randomized clinical trials of subjects with type 2 diabetes.94 The principal side effects associated with the use of GLP-1 receptor agonists are gastrointestinal, predominantly nausea. Central role of ERK in β-cell regulation by glucagon and insulin. have developed a pure, clean glucagon antagonist, [des-His1, des-Phe6, Glu9]glucagon (Azizeh et al., 1995; Van Tine et al., 1996), and subsequently other related analogues that are pure antagonists (Azizeh et al., 1997). Although, for the most part small, linear peptide hormones are extended, flexible molecules in aqueous solution, they are thought to adopt a specific conformation when interacting with the receptor. While glucagon can depress pancreatic exocrine secretions in normal animals and humans, it is still unclear how glucagon exerts this effect [59]. - Find MSDS or SDS, a COA, data sheets and more information. In addition, GLP-1 levels are increased, which have a beneficial effect on treating DM. The growth pattern is often more varied than that of adenomas. As a starting point, it is interesting to note that the hormone responsible for most if not all of glucagon's activity for interactions with hepatic glucagon receptors is the 29 amino acid structure shown in Figure 1, and we will concentrate all of our discussion of this product of the proglucagon gene. The physiologic importance of endogenous GLP-1 has been studied using the GLP-1 receptor antagonist exendin(9-39) and Glp1r−/− mice. The ERK pathway exists in the β-cell as shown by the effect of low glucose in the absence and in the presence of glucagon on ERK activation by double phosphorylation in the MIN6 β-cell line [42]. Because GLP-1 does not stimulate glucose absorption and an increase in hexose transport has been previously described for glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic peptide (GIP) [62,63], OXM could engage additional G-protein-coupled receptors (GPCR) of the secretin like (class B) family such as GLP-2 and GIP receptors [64,65]. In isolated hepatocytes, inhibitors of the T1 translocator inhibit both basal and glucagon-stimulated glucose production.26 In animal studies, acute administration of an inhibitor of the T1 translocator caused a rapid lowering of blood glucose that correlated with the accumulation of the compound in the liver. This fits well with the fact that α-cell is the first islet cell to appear during development [37] and thus precedes the β-cell. Policies. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Results Treatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. As GLP-1 increases the proliferation and cytoprotection of beta cells, intra-islet paracrine signaling between injured beta cells and alpha cells might be a process designed to repair and regenerate beta cells that are reduced in diabetes. The anorectic effects of central administrations of OXM are abolished by co-administration of the GLP1R antagonist, exendin(9–39), and are not observed in Glp1r−/− mice, suggesting that the acute central effect of OXM on food intake is mediated by the GLP1R [30,54,55].
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