Physiology and Pathophysiology of GLP-1

Göke, Burkhard; Göke, Rüdiger; Fehmann, Hans-Christoph; Bode, Hans-Peter

doi:10.1007/978-3-642-61150-6_17

Cited by 17 publications

(30 citation statements)

References 193 publications

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“…A naturally occurring DPP IV resistant GLP-1 analog with potent blood glucose lowering properties was originally identified in extracts of Gila monster lizard (Heloderma suspectum) salivary glands, and it is known as Exendin-4 because it was demonstrated to interact with receptors located on exocrine (EXendin) and endocrine (ex-END-in) tissues of the pancreas [152,153]. The specific interactions of Exendin-4 (an agonist form) and Exendin-(9-39) (an antagonist form) with the GLP-1 receptor was demonstrated [154], and more recently it has become appreciated that Exendin-4 recapitulates many if not all of the biological actions of GLP-1 [155]. These GLP-1-like actions of Exendin-4 are understandable because it retains within its primary sequence amino acid residues at positions His7, Gly10, Phe12, Thr13, Ser14, Asp15, Phe28, and Ile29 that are critical to receptor binding and receptor stimulation [72,156].…”

Section: Exendin-4: a Naturally Occurring Glp-1 Analogmentioning

confidence: 99%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

123

105

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Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing b-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate b-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted. Keywords GLP-1; diabetes mellitus; insulin secretion A. INTRODUCTIONGlucagon-like peptide-1-(7-36)-amide (GLP-1, also known as t-GLP-1 or GLIP) is an intestinally-derived insulinotropic hormone that has attracted considerable attention by virtue of its proven ability to act as a blood glucose lowering agent. The efficacy with which GLP-1 lowers concentrations of blood glucose in type 2 diabetic subjects (adult onset diabetes mellitus) has prompted clinical investigations whereby the therapeutic value of GLP-1 as an antidiabetogenic agent has been substantiated. Earlier studies revealed that © 2003 Bentham Science Publishers Ltd. * Address correspondence to this author at the Department of Physiology and Neuroscience, MSB 442, New York University School of Medicine, 550 First Avenue, NY 10016, New York, USA; Tel: 212-263-5434; Fax: 212-689-9060; holzg01@popmail.med.nyu.edu. NIH Public Access Author ManuscriptCurr Med Chem. Author manuscript; available in PMC 2010 July 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGLP-1 is an ...

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Section: Exendin-4: a Naturally Occurring Glp-1 Analogmentioning

confidence: 99%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

123

105

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“…We here report an example of a nonpeptidic, orally available GLP-1R agonist with potentially beneficial effects on food intake, body weight, glucose tolerance, and HbA1c in db/db mice, a useful model of type 2 diabetes mellitus (11). Effects appear to be receptor-mediated and are blocked with the selective GLP-1R antagonist exendin(9-39) (12).…”

mentioning

confidence: 99%

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db / db mice

Chen

Liao

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

155

143

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“…Postprandial release of incretins from the intestine, including gastric inhibitory polypeptide (GIP) and glucagon-like-peptide-1(7±36) amide (truncated GLP-1, tGLP-1), stimulates insulin secretion through the enteroinsular axis [2]. This pathway has been estimated to contribute up to 50 % of the insulin released after ingestion of glucose [2].The incretin, tGLP-1, is a product of the preproglucagon gene [proglucagon (78±107)amide] and is secreted by L-cells in the intestine after ingestion of carbohydrate, fat or protein [3,4]. It is an extremely potent stimulator of insulin secretion as well as somatostatin release but is an inhibitor of glucagon secretion [4,5].…”

mentioning

confidence: 99%

“…The incretin, tGLP-1, is a product of the preproglucagon gene [proglucagon (78±107)amide] and is secreted by L-cells in the intestine after ingestion of carbohydrate, fat or protein [3,4]. It is an extremely potent stimulator of insulin secretion as well as somatostatin release but is an inhibitor of glucagon secretion [4,5].…”

mentioning

confidence: 99%

Glycation of glucagon-like peptide-1(7-36)amide: characterization and impaired action on rat insulin secreting cells

et al. 1998

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It has long been recognised that gut hormones have an important role in the regulation of endocrine pancreatic function [1]. Postprandial release of incretins from the intestine, including gastric inhibitory polypeptide (GIP) and glucagon-like-peptide-1(7±36) amide (truncated GLP-1, tGLP-1), stimulates insulin secretion through the enteroinsular axis [2]. This pathway has been estimated to contribute up to 50 % of the insulin released after ingestion of glucose [2].The incretin, tGLP-1, is a product of the preproglucagon gene [proglucagon (78±107)amide] and is secreted by L-cells in the intestine after ingestion of carbohydrate, fat or protein [3,4]. It is an extremely potent stimulator of insulin secretion as well as somatostatin release but is an inhibitor of glucagon secretion [4,5]. In humans, insulin secretion was considerably increased after intravenous infusion of tGLP-1 with glucose [4] and increased twofold when tGLP-1 was given alone [3]. Glucose clearance was also strongly increased by tGLP-1, suggesting that this peptide has an important impact on glucose turnover in humans [6]. Other studies have suggested that part of this action is attributable to direct effects of Diabetologia (1998) Summary Glucagon-likepeptide-1(7±36)amide(truncated GLP-1, tGLP-1) is a potent insulin releasing hormone of the enteroinsular axis. This study has examined glycation of tGLP-1 and effects of such structural modification on insulin secretion. Monoglycated tGLP-1 (M r 3463.8, determined by plasma desorption mass spectrometry) was prepared by incubation with glucose under reducing conditions and purified by reversed-phase high performance liquid chromatography. Automated Edman degradation indicated that tGLP-1 was specifically glycated at the amino terminal His 7 site. In extracts from mouse small intestine, glycated tGLP-1 represented approximately 14 % of the total tGLP-1 content. Effects of glycated and non-glycated tGLP-1 on insulin secretion were examined using glucose-responsive clonal BRIN-BD11 cells. In acute (20 min) incubations, 10 ±9 mol/l tGLP-1 enhanced insulin release by 2.2-fold and 1.5-fold at 5.6 and 11.1 mmol/l glucose, respectively. In contrast, 10 ±9 mol/l glycated tGLP-1 failed to stimulate secretion and insulin output was decreased by 34±73 % following glycation. At 5.6 mmol/l glucose, non-glycated tGLP-1 (3´10 ±10 mol/l±10 ±8 mol/l) exerted a 2.3-fold to 3.2-fold increase in insulin secretion compared with controls. The effect of glycated tGLP-1 at 10 ±9 mol/l and 3´10 ±9 mol/l was reduced by 51±55 % compared with non-glycated peptide, and its insulinotropic action was effectively abolished. These data indicate that when tGLP-1 is glycated at the amino terminal His

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Physiology and Pathophysiology of GLP-1

Cited by 17 publications

References 193 publications

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db / db mice

Glycation of glucagon-like peptide-1(7-36)amide: characterization and impaired action on rat insulin secreting cells

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