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information about dietary nutrients entering the bloodstream. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) play a particularly important role in glucose metabolism and regulation of food intake
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with diabetes has remained elusive, but since their discovery, WNT/β-catenin signaling has been shown to increase the expression of incretin hormones ( Garcia-Martinez et al . 2009 ) that are global regulators of metabolism and are required for normal
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Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden
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Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Gothenburg, Sweden
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already in the gastrointestinal tract ( Lu et al. 2021 ). Nutrients, like carbohydrates and fat, can stimulate hormone secretion from enteroendocrine cells (EECs) residing in the epithelial layer of the gut. Incretins are hormones secreted from EECs in
State Key Laboratory of Pharmaceutical Biotechnology, First Affiliated Hospital of Nanjing Medical University, School of Biological Sciences, Jiangsu Diabetes Center, Nanjing University, Nanjing, Jiangsu 210093, People's Republic of China
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Introduction It is widely recognized that oral ingestion of glucose triggers more insulin release than intravenous delivery of glucose, which results in a similar plasma glucose profile – a phenomenon known as the ‘incretin effect’ ( Elrick et al
Department of Geriatric Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Department of Bile Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Department of Occupational and Environmental Health, School of Public Health, Nantong University, Nantong, China
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resistance, it may also impact glucose metabolism through effects on insulin secretion. Glucagon-like peptide-1 (GLP-1) is one of the primary incretins that is primarily produced by intestinal enteroendocrine L-cells ( Drucker 2018 ). It may enhance insulin
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hypoglycemia under normal plasma glucose concentration conditions ( Baggio & Drucker 2002 , Nauck et al . 2002 ). In addition to its incretin activity, GLP1 stimulates proliferation and differentiation of pancreatic β-cells ( Xu et al . 1999 , Drucker 2003
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(GIPr; NM_012714) was approximately twofold lower in GK low glucose when compared with GK high glucose. This suggests a tonic reduction of incretin signaling in GK islets, potentially a major contributor to the islet defect in this diabetes model. Since
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Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada
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Department of Physiology, University of Toronto, Medical Sciences Building, Toronto, Ontario, Canada
McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada
Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada
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collectively confirmed the existence of the TCF7L2–ISL1 transcriptional network in rodent islets. More importantly, our investigations have expanded this novel network study into the function of the incretin hormone GLP-1, on which a series of diabetes drugs
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-like peptide 1 (GLP-1), an incretin which also activates Rac1 ( Kalwat & Thurmond 2013 ), we show that Kalirin more specifically integrates glucose signaling and granule age-related secretory decisions. Materials and methods Materials Monoclonal
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Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.
