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Summary
The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), has been isolated and characterized because of its enterogastrone-type effects. It is also named glucose-dependent insulinotropic polypeptide and is actually considered to be the main incretin factor of the entero-insular axis. Besides these well-described effects on gastric secretion and pancreatic β cells, it also has direct metabolic effects on other tissues and organs, such as adipose tissue, liver, muscle, gastrointestinal tract and brain. In adipose tissue it is involved in the activation and regulation of lipoprotein lipase (LPL); it also inhibits glucagon-induced lipolysis and potentiates the effect of insulin on incorporation of fatty acids into triglycerides. It may play a role in the development of obesity because of the hypersensitivity of adipose tissue of obese animals to some of these actions. In the liver it does not modify insulin extraction, and its incretin effects are due only to the stimulation of insulin secretion and synthesis. It reduces hepatic glucose output and inhibits glucagon-stimulated glycogenolysis. It might increase glucose utilization in peripheral tissues such as muscle. GIP also has an effect on the volume and/or electrolyte composition of intestinal secretion and saliva. The functional importance of its effect on the hormones of the anterior pituitary lobe remains to be established, as it has never been detected in the brain.
Its links with insulin are very close and the presence of insulin is sometimes necessary for the greater efficiency of both hormones. GIP can be considered as a true metabolic hormone, with most of its functions tending to increase anabolism.
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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.
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Introduction Glucagon-like peptide 1 (GLP-1) is an intestinal incretin produced in L cells through proglucagon processing ( Holst 2007 , Drucker et al. 2017 ). The majority of circulating biologically active GLP-1 is found in the GLP-1
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
COMPARE University of Birmingham and University of Nottingham Midlands, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
COMPARE University of Birmingham and University of Nottingham Midlands, Birmingham, UK
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/ion channels. Perhaps the best characterised signals are derived from the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) released from the enteroendocrine L-cells and K-cells, respectively, following food
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/A-like cells expressed in the stomach increases food intake and body weight ( Nakazato et al. 2001 ); peptide YY (PYY) and the incretin glucagon-like peptide-1 (GLP-1) released from enteroendocrine L cells inhibit food intake and reduce body weight ( Davis
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Division of Medical Chemistry, Division of Diabetes and Endocrinology, Departamento de Bioquímica y Biología Molecular, Division of Cellular and Molecular Medicine, Department of Biophysics
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that can be used for the treatment of type 2 diabetes. These agents act by increasing the incretin hormone glucagon-like peptide-1 (GLP1), which stimulates insulin secretion ( Holst & Deacon 2004 ). In addition to this action, GLP1 and its analogs have
Human Gene and Cell Therapy Center, Division of Endocrinology and Metabolism, Division of Child Neurology, Department of Urology, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya 07058, Turkey
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Human Gene and Cell Therapy Center, Division of Endocrinology and Metabolism, Division of Child Neurology, Department of Urology, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya 07058, Turkey
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Human Gene and Cell Therapy Center, Division of Endocrinology and Metabolism, Division of Child Neurology, Department of Urology, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya 07058, Turkey
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( Peterson 2012 ). By comparison, incretin-based therapeutics have the potential to restore beta-cell function and reverse islet cell loss observed in T2D ( Aroda et al . 2012 , Vilsboll et al . 2012 ). As demonstrated in experimental animal models, GLP1
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, especially in old diabetic patients with high fracture risk ( Montagnani & Gonnelli 2013 ). It has been reported that the novel incretin-based drugs, such as glucagon-like peptide-1 (GLP1) receptor agonist exenatide, did not affect bone mineral density
Xiamen Diabetes Institute, Central Laboratory, Division of Gastroenterology, Division of Endocrinology and Diabetes, Beijing University of Chinese Medicine
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Xiamen Diabetes Institute, Central Laboratory, Division of Gastroenterology, Division of Endocrinology and Diabetes, Beijing University of Chinese Medicine
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Xiamen Diabetes Institute, Central Laboratory, Division of Gastroenterology, Division of Endocrinology and Diabetes, Beijing University of Chinese Medicine
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Xiamen Diabetes Institute, Central Laboratory, Division of Gastroenterology, Division of Endocrinology and Diabetes, Beijing University of Chinese Medicine
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potential regenerative influences of incretin therapy on preserving pancreatic β-cells are intriguing, the marked expansion of the exocrine and endocrine pancreatic compartments with the risk of carcinogenesis require more strict and convincing
Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
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Institut für Laboriatorumsmedizin IFLb, Berlin, Germany
Departments of Embryology and Nephrology, Basic Medical College, Jinan University, Guangzhou, China
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GLP-1 is an incretin which is secreted from intestinal L-cells in response to oral glucose load and can stimulate insulin secretion from pancreatic B cells and inhibit glucagon release. GLP-1 is secreted in active form, GLP-1 (7–36), and rapidly
