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Glucagon is a 29 amino acid polypeptide, secreted predominantly by α-cells in the islets of Langerhans in response to diverse stimuli, including hypoglycemia, starvation, exercise, circulating amino acids and fatty acids, certain...
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Glucagon is a 29 amino acid polypeptide, secreted predominantly by α-cells in the islets of Langerhans in response to diverse stimuli, including hypoglycemia, starvation, exercise, circulating amino acids and fatty acids, certain regulatory peptides, and increased adrenergic activity. It was discovered as a hyperglycemic element of pancreatic extract in 1923, purified and sequenced in 1957, and used subsequently to treat severe hypoglycemia in type 1 diabetes. In the last four decades, glucagon excess has been documented as contributing to the etiology of hyperglycemia in various forms of diabetes, which has stimulated the pursuit of novel approaches to mitigating glucagon action in order to improve glycemic control.
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Introduction: Glucagon receptor antagonists (GCGRAs) have been an area of ongoing research in the pharmaceutical industry for more than two decades. Blocking the action of the glucagon peptide leads to repression of hepatic glucos...
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Introduction: Glucagon receptor antagonists (GCGRAs) have been an area of ongoing research in the pharmaceutical industry for more than two decades. Blocking the action of the glucagon peptide leads to repression of hepatic glucose production and reduced blood glucose. Small molecule GCGRAs continue to be pursued as a potential new treatment for diabetes.
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Introduction: The ever increasing prevalence of type 2 diabetes mellitus (T2DM) in the developed and developing nations calls for the introduction of new and more effective treatments. Glucagon receptor (GCGR) antagonists are high...
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Introduction: The ever increasing prevalence of type 2 diabetes mellitus (T2DM) in the developed and developing nations calls for the introduction of new and more effective treatments. Glucagon receptor (GCGR) antagonists are highly validated in preclinical models of T2DM and thus have the potential to be developed as a new therapy. Small molecule GCGR antagonists have been an active area of research since the 1990s. As evidenced from the number of patents and laboratories involved, these efforts have accelerated during the last decade. Areas covered: During the period 2006 - 2010, there were numerous patent publications from several laboratories claiming the discovery of novel small molecule GCGR antagonists. Herein, we present our interpretation of these new patent publications as well as follow-up disclosures appearing in the peer-reviewed literature. This paper provides an up-to-date overview of the field of small molecule GCGR antagonism as a potential treatment for T2DM. Attempts were made wherever possible to identify preferred or representative compounds from the patent applications reviewed. In vitro and in vivo data are also discussed where they were disclosed. Expert opinion: The novel small molecule GCGR antagonists reviewed here represent many diverse structural motifs. Some molecules are very potent antagonists of the GCGR in in vitro assays with acceptable selectivity. Some have intriguing in vivo activity in models of T2DM in a variety of preclinical species. It is to be hoped that clinical developments following these preclinical discoveries might result in a long-awaited new treatment for T2DM.
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The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been asso...
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The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored. Here, we use a recently-developed reverse tetracyline transactivator promoter-regulated ZnT8 transgene to drive the over-expression of human ZnT8 selectively in the α cell in adult mice. Glucose homeostasis and glucagon secretion were subsequently assessed both in vivo during hypoglycemic clamps and from isolated islets in vitro. Doxyclin-dependent human ZnT8 mRNA expression was apparent in both isolated islets and in fluorescence-activated cell sorting- (FACS) purified α cells. Examined at 12?weeks of age, intraperitoneal glucose (1?g/kg) tolerance was unchanged in transgenic mice versus wild-type littermates (n?=?8-10 mice/genotype, p?>?0.05) and sensitivity to intraperitoneal insulin (0.75U/kg) was similarly unaltered in transgenic animals. In contrast, under hyperinsulinemic-hypoglycemic clamp, a ~45?% (p 0.05). Over-expression of ZnT8 in glucagonoma-derived αTC1-9 cells increased granule free Zn2+ concentrations consistent with a role for Zn2+ in this compartment in the action of ZnT8 on glucagon secretion. Increased ZnT8 expression, and a likely increase in intragranular free Zn2+ concentration, is deleterious in pancreatic α cells for stimulated glucagon release. These data provide further evidence that type 2 diabetes-associated polymorphisms in the SLC30A8/ZnT8 gene may act in part via alterations in glucagon release and suggest that ZnT8 activation may restrict glucagon release in some settings.
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Peptidal glucagon receptor antagonists and antiglucagon monoclonal antibodies lower glucose levels in diabetic rodent models, suggesting a potential to treat hyperglycaemia in Type 2 diabetics through the inhibition of glucagon fu...
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Peptidal glucagon receptor antagonists and antiglucagon monoclonal antibodies lower glucose levels in diabetic rodent models, suggesting a potential to treat hyperglycaemia in Type 2 diabetics through the inhibition of glucagon function. Several research groups have discovered small molecule glucagon antagonists from multiple chemical series and at least one has been clinically evaluated. Although multiple compounds have blocked the rise in blood glucose levels in response to a glucagon challenge, no preclinical or clinical efficacy data from chronic studies have been reported. In general, drug candidate potency, pharmacokinetics, physical properties and cross-species potency have hindered progress and preclinical efficacy assessment. Recently, antisense oligonucleotides against the glucagon receptor have been described, providing a guiding post for the type of activity a small molecule glucagon antagonist may possess, as well as offering a potential therapeutic strategy.
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Abstract Objective Despite increasing evidence that pharmacologic concentrations of biotin modify glucose metabolism, to our knowledge there have not been any studies addressing the effects of biotin supplementation on glucagon pr...
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Abstract Objective Despite increasing evidence that pharmacologic concentrations of biotin modify glucose metabolism, to our knowledge there have not been any studies addressing the effects of biotin supplementation on glucagon production and secretion, considering glucagon is one of the major hormones in maintaining glucose homeostasis. The aim of this study was to investigate the effects of dietary biotin supplementation on glucagon expression, secretion, and action. Methods Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (1.76 or 97.7?mg biotin/kg diet) for 8?wk postweaning. Glucagon gene mRNA expression was measured by the real-time polymerase chain reaction. Glucagon secretion was assessed in isolated islets and by glucagon concentration in plasma. Glucagon action was evaluated by glucagon tolerance tests, phosphoenolpyruvate carboxykinase ( Pck1 ) mRNA expression, and glycogen degradation. Results Compared with the control group, glucagon mRNA and secretion were increased from the islets of the biotin-supplemented group. Fasting plasma glucagon levels were higher, but no differences between the groups were observed in nonfasting glucagon levels. Despite the elevated fasting glucagon levels, no differences were found in fasting blood glucose concentrations, fasting/fasting–refeeding glucagon tolerance tests, glycogen content and degradation, or mRNA expression of the hepatic gluconeogenic rate-limiting enzyme, Pck1 . Conclusions These results demonstrated that dietary biotin supplementation increased glucagon?expression and secretion without affecting fasting blood glucose concentrations or glucagon tolerance and provided new insights into the effect of biotin supplementation on glucagon production and action. Highlights ? Biotin increases fasting plasma glucagon without modifying glucose concentration. ? Biotin supplementation increases glucagon secretion and Gcg mRNA expression. ? Biotin supplementation does not affect hepatic glucagon sensitivity. ? Biotin supplementation does not modify glycogen content or degradation. ? Biotin supplementation does not modify mRNA expression of gluconeogenic enzyme Pck .
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Objective: To review the safety, efficacy, and administration of intranasal (IN) glucagon for the management of hypoglycemia. Data Source: A literature search of PubMed/MEDLINE (1995 to November 2019) using the terms intranasal gl...
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Objective: To review the safety, efficacy, and administration of intranasal (IN) glucagon for the management of hypoglycemia. Data Source: A literature search of PubMed/MEDLINE (1995 to November 2019) using the terms intranasal glucagon, nasal glucagon, glucagon, hypoglycemia treatment, and hypoglycemia management was completed. Study Selection and Data Extraction: English-language studies evaluating IN glucagon were evaluated. Data Synthesis: IN glucagon is a newly approved product for the treatment of hypoglycemia in patients with diabetes, 4 years and older. Administered as a 3-mg dose, it was shown to be noninferior to intramuscular (IM) glucagon. In comparison trials, more than 98% of hypoglycemic events were treated successfully with IN glucagon in both pediatric and adult patients. In simulated and real-world studies, IN glucagon was administered in less than a minute for the majority of scenarios. IM glucagon took longer to administer, ranging from 1 to 4 minutes, and often, patients did not receive the intended full dose. Nausea and vomiting, known adverse events for glucagon, as well as local adverse events were most commonly reported with IN glucagon. Relevance to Patient Care and Clinical Practice: IN glucagon is safe, effective, easy to use, and does not require reconstitution prior to use, which can lead to faster delivery in a severe hypoglycemic event. It does not require age- or weight-based dosing. This delivery method offers an option for someone who fears needles or is uncomfortable with injections. Conclusion: IN glucagon is a safe, effective, easy to use, needle-free treatment option for severe hypoglycemia.
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Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide hormone released from the intestinal endocrine cells following nutrient ingestion. GLP-2 exerts trophic effects on the small and large bowel epithelium via stimulation of ...
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Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide hormone released from the intestinal endocrine cells following nutrient ingestion. GLP-2 exerts trophic effects on the small and large bowel epithelium via stimulation of cell proliferation and inhibition of apoptosis. GLP-2 also upregulates intestinal glucose transporter activity, and reduces gastric emptying and gastric acid secretion. The activity of GLP-2 is regulated in part via renal clearance and cleavage by the aminopeptidase dipeptidyl peptidase IV. In experimental models of intestinal disease, GLP-2 reversed parenteral nutrition-induced mucosal atrophy and accelerated the process of endogenous intestinal adaptation in rats following major small bowel resection. GLP-2 also markedly attenuated intestinal injury and weight loss in mice with chemically-induced colitis, and significantly reduced mortality, bacterial infection and intestinal mucosal damage in mice with indomethacin-induced enteritis. The actions of GLP-2 are transduced by a recently cloned glucagon-like peptide-2 receptor (GLP-2R) that represents a new member of the G protein-coupled receptor superfamily. The GLP-2R is expressed in a highly tissue-specific manner predominantly in the gastrointestinal tract and GLP-2R activation is coupled to increased adenylate cyclase activity. The available evidence suggests that the biological properties of GLP-2 merit careful therapeutic assessment in selected human diseases characterized by injury and defective repair of the gastrointestinal epithelium.
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The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates ...
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The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.
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Purpose: People with diabetes taking insulin are at risk of severe hypoglycemia, an unpredictable, life-threatening event that requires assistance from others. Outside the clinical setting, glucagon is indicated for the treatment ...
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Purpose: People with diabetes taking insulin are at risk of severe hypoglycemia, an unpredictable, life-threatening event that requires assistance from others. Outside the clinical setting, glucagon is indicated for the treatment of hypoglycemia. However, there is significant unmet medical need to improve successful administration of glucagon by caregivers and acquaintances. This study assesses perceptions about glucagon delivery and potential effects of 2 glucagon delivery devices for severe hypoglycemia.
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