Cloning and Functional Expression of the Human Islet GLP-1 Receptor: Demonstration That Exendin-4 Is an Agonist and Exendin-(9–39) an Antagonist of the Receptor

Thorens, Bernard; Porret, Andrée; Bühler, Léo H.; Deng, Shaoping; Morel, Philippe; Widmann, Christian

doi:10.2337/diab.42.11.1678

Cited by 428 publications

(236 citation statements)

References 26 publications

(33 reference statements)

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“…The data summarized in Fig. 1 are similar to those previously reported for the cloned rat and human GLP-1 receptor in stably transfected fibroblasts [5,9] and for the endogenoes receptor expressed in insulinoma cell lines [4,9] but lower than those reported for transiently transfected COS-7 cells [10,11]. Fig.…”

Section: Glp-1 Receptor Binding and Camp Formationsupporting

confidence: 86%

“…We have previously demonstrated that in the mouse insulin-secreting cell line ffI'C3, GLP-l(7-36)amide produces a rise in [Ca2+]~ by promoting Ca2+-induced Ca2+-release (CICR) from intracellular stores [3]. The recent cloning of the GLP-1 receptor [4,5] has enabled a more detailed analysis of the cellular processes involved. Here we demonstrate for the first time that expression of the cloned GLP-I receptor in HEK 293 cells is associated with the induction of later steps in the sequence of events normally activated by GLP-1.…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of cloned human glucagon‐like peptide 1 receptor expressed in HEK 293 cells induces cAMP‐dependent activation of calcium‐induced calcium release

et al. 1995

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Section: Glp-1 Receptor Binding and Camp Formationsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Stimulation of cloned human glucagon‐like peptide 1 receptor expressed in HEK 293 cells induces cAMP‐dependent activation of calcium‐induced calcium release

et al. 1995

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“…It was first cloned from rat pancreatic islets (Thorens, 1992) and later from a human pancreatic insulinoma Thorens et al, 1993) and a gut tumor cell line (Graziano et al, 1993). The rat and human GLP-1Rs exhibit a 95% amino acid homology and are 90% identical (Thorens, 1992;Thorens et al, 1993), differing at 42 amino acid positions (Tibaduiza et al, 2001). The human GLP-1R gene is located on the long arm of chromosome 6p21 (Stoffel et al, 1993).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

“…The isolated N-terminus of the rat (Lopez de Maturana et al, 2003;Wilmen et al, 1996;Xiao et al, 2000) and human (Bazarsuren et al, 2002) GLP-1R associate with GLP-1, although with lower affinity than with the native receptor (Bazarsuren et al, 2002;Xiao et al, 2000). Similar to the glucagon receptor and other members of this subfamily, GLP-1R has six cysteine residues in the extracellular region that are highly conserved (Thorens et al, 1993). Disulphide bonds occur between cysteines 46 and 71, 62 and 104, 85 and 126 of human GLP-1R (Bazarsuren et al, 2002).…”

Section: Glp-1r In the Pancreasmentioning

confidence: 99%

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Doyle

Egan

2007

Pharmacology & Therapeutics

560

459

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Glucagon-like peptide-1 is a hormone that is encoded in the proglucagon gene. It is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. Its particular effects on insulin and glucagon secretion have generated a flurry of research activity over the past twenty years culminating in a naturally occurring GLP-1 receptor agonist, exendin-4, now being used to treat type 2 diabetes. GLP-1 engages a specific G-protein coupled receptor that is present in tissues other than the pancreas (brain, kidney, lung, heart, major blood vessels). The most widely studied cell activated by GLP-1 is the insulin-secreting beta cell where its defining action is augmentation of glucose-induced insulin secretion. Upon GLP-1 receptor activation, adenylyl cyclase is activated and cAMP generated, leading, in turn, to cAMP-dependent activation of second messenger pathways, such as the PKA and Epac pathways. As well as short-term effects of enhancing glucose-induced insulin secretion, continuous GLP-1 receptor activation also increases insulin synthesis, and beta cell proliferation and neogenesis. Although these latter effects cannot be currently monitored in humans, there are substantial improvements in glucose tolerance and increases in both first phase and plateau phase insulin secretory responses in type 2 diabetic patients treated with exendin-4. This review we will focus on the effects resulting from GLP-1 receptor activation in islets of Langerhans

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“…also binds [8], have been reported to be present in muscle [9,10], fat [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16].…”

mentioning

confidence: 99%

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

et al. 2003

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Aims/hypothesis. The aim of this study was to determine whether rapid conversion to inactive and potentially antagonistic peptides could alter the response to GLP-1. Methods. We evaluated the ability of exendin-4, a GLP-1 analogue resistant to degradation by dipeptidyl peptidase IV, to modulate insulin-induced stimulation of glucose uptake and suppression of glucose production in eight healthy subjects during infusion of GLP-1 (1.2 pmol·kg -1 ·min -1 ), exendin-4 (0.12 pmol·kg -1 · min -1 ), or saline. Glucose was clamped at 5.3 mmol/l and insulin was infused to progressively increase insulin concentrations to about 65, 190 and 700 pmol/l, respectively. Endogenous insulin secretion was inhibited with somatostatin to ensure comparable portal insulin concentrations while glucagon and growth hormone were maintained at basal concentrations. Results. Glucose, insulin, C-peptide, glucagon and growth hormone concentrations did not differ on the three occasions. In contrast, cortisol concentrations were greater during both exendin-4 (25.1±4.4 mmol/l per 7 h; p<0.01) and GLP-1, (17.0±2.0 mmol/l 7 h; p<0.05) than saline (13.5±1.5 mmol/l per 7 h). While insulin-induced stimulation of glucose disappearance at the highest insulin concentrations tended to be greater and insulin-induced suppression of glucose production lower in the presence of exendin-4 or GLP-1 than saline, the differences were not significant. Conclusion/interpretation. Exendin-4 and GLP-1 increase cortisol secretion in human subjects. However, neither alters insulin action in non-diabetic human subjects. These data also suggest that the lack of an effect of GLP-1 on insulin action is not likely to be explained by rapid degradation to inactive or antagonistic peptides. [Diabetologia (2002[Diabetologia ( ) 45:1410[Diabetologia ( -1415 Keywords GLP-1, exendin-4, insulin action, glucose production, cortisol secretion. [11,12] and the liver [13]. GLP-1 (7-36) can increase glucose uptake in each of these tissues with its effects being additive to those of insulin [12,14,15,16]. In contrast, results from in vivo studies have been less consistent. GLP-1 (7-36) has been reported to increase glucose uptake during hyperglycaemia and hyperinsulinaemia in diabetic rats [17], pancreatectomized dogs [18] and in Type I (insulin-dependent) diabetic patients [19,20]. In contrast, GLP-1 (7-36) has been reported to have no effect on the insulin action in non-diabetic human subjects [21] GLP-1 (7-36) is actively being evaluated as a therapy for diabetes mellitus. GLP-1 (7-36) increases insulin secretion, decreases glucagon secretion and delays gastric emptying [1,2,3,4,5,6,7]. In vitro data suggest it might also enhance insulin action. Although controversial, GLP-1 receptors, to which Exendin-4

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Cloning and Functional Expression of the Human Islet GLP-1 Receptor: Demonstration That Exendin-4 Is an Agonist and Exendin-(9–39) an Antagonist of the Receptor

Cited by 428 publications

References 26 publications

Stimulation of cloned human glucagon‐like peptide 1 receptor expressed in HEK 293 cells induces cAMP‐dependent activation of calcium‐induced calcium release

Stimulation of cloned human glucagon‐like peptide 1 receptor expressed in HEK 293 cells induces cAMP‐dependent activation of calcium‐induced calcium release

Mechanisms of action of glucagon-like peptide 1 in the pancreas

Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans

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