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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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of amidated and glycine-extended glucagon-like peptide I in humans . Diabetes 43 535 – 539 . ( doi:10.2337/diab.43.4.535 ) Parker HE Habib AM Rogers GJ Gribble FM Reimann F 2009 Nutrient-dependent secretion of glucose-dependent
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Glucagon-like peptide 1 (GLP-1) is a potent insulinotropic hormone currently under study as a therapeutic agent for type 2 diabetes. Since an understanding of the molecular mechanisms leading to high-affinity receptor (R) binding and activation may facilitate the development of more potent GLP-1R agonists, we have localized specific regions of GLP-1R required for binding. The purified N-terminal fragment (hereafter referred to as NT) of the GLP-1R produced in either insect (Sf9) or mammalian (COS-7) cells was shown to bind GLP-1. The physical interaction of NT with GLP-1 was first demonstrated by cross-linking ((125)I-GLP-1/NT complex band at approximately 28 kDa) and secondly by attachment to Ni(2+)-NTA beads. The GLP-1R NT protein attached to beads bound GLP-1, but with lower affinity (inhibitory concentration (IC(50)): 4.5 x 10(-7) M) than wild-type (WT) GLP-1R (IC(50): 5.2 x 10(-9)M). The low affinity of GLP-1R NT suggested that other receptor domains may contribute to GLP-1 binding. This was supported by studies using chimeric glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptors. GIP(1-151)/GLP-1R, but not GIP(1-222)/GLP-1R, exhibited specific GLP-1 binding and GLP-1-induced cAMP production, suggesting that the region encompassing transmembrane (TM) domain 1 through to TM3 was required for binding. Since it was hypothesized that certain charged or polar amino acids in this region might be involved in binding, these residues (TM2-TM3) were analyzed by substitution mutagenesis. Five mutants (K197A, D198A, K202A, D215A, R227A) displayed remarkably reduced binding affinity. These studies indicate that the NT domain of the GLP-1R is able to bind GLP-1, but charged residues concentrated at the distal TM2/extracellular loop-1 (EC1) interface (K197, D198, K202) and in EC1 (D215 and R227) probably contribute to the binding determinants of the GLP-1R.
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µmol/L, stimulated the rate of insulin release from BRIN-BD11 cells ( McClenaghan et al. 1996 ) in the presence of 1.1 and 5.6 mmol/L glucose and the effect was maintained at high (16.7 mmol/L) glucose. The insulinotropic effect of the peptide was
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–activity studies of glucagon-like peptide-1 . Journal of Biological Chemistry 269 6275 – 6278 . Alana I Malthouse JP O'Harte FP Hewage CM 2007 The bioactive conformation of glucose-dependent insulinotropic polypeptide by NMR and CD spectroscopy
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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patients with T2D ( Dejager & Schweizer 2012 ). GLP1 is naturally released from the gut into circulation after a meal. Because natural peptide forms of GLP1 and glucose-dependent insulinotropic peptide (GIP; incretins) are quickly destroyed by dipeptidyl
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subsequent KCl effect. The insulinotropic effect of KCl was not significantly different when preceding or following the glucose stimulation ( Fig. 1A ). Figure 1 Insulinotropic effect of successive stimulation with 40 mM KCl and 30 mM glucose at 37°C
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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. 1964 , McIntyre et al . 1965 , Perley & Kipnis 1967 ). This is mainly attributed to two hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) ( McIntyre et al . 1964 , Thorens 1995 ). GLP1 is a product of
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insights concerning the glucose-dependent insulin secretagogue action of glucagon-like peptide-1 in pancreatic β-cells . Hormone and Metabolic Research 36 787 – 794 . Hui H Nourparvar A Zhao X Perfetti R 2003 Glucagon-like peptide-1 inhibits
Laboratory of Molecular, Division of Endocrinology, Cellular Endocrinology and Metabolism
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. In addition, the existence of common receptor(s) for the three peptides has been suggested. In the case of Ob-induced cAMP elevation, the cAMP-dependent enzyme PKA phosphorylates and activates the transcription factor CREB. The effect of AG and UAG on
