Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1.

Abstract

Glucagon-like peptide 1 (GLP-1) is a hormone derived from the preproglucagon molecule and is secreted by intestinal L cells. It is the most potent stimulator of glucose-induced insulin secretion and also suppresses in vivo acid secretion by gastric glands. A cDNA for the GLP-1 receptor was isolated by transient expression ofa rat pancreatic islet cDNA library into COS cells; this was followed by binding of radiolabeled GLP-1 and screening by photographic emulsion autoradiography. The receptor transfected into COS cells binds GLP-1 with high affinity and is coupled to activation of adenylate cyclase. The receptor binds specifically GLP-1 and does not bind peptides ofrelated structure and similar function, such as glucagon, gastric inhibitory peptide, vasoactive intestinal peptide, or secretin. The receptor is 463 amino acids long and contains seven transmembrane domains. Sequence homology is found only with the receptors for secretin, calcitonin, and parathyroid hormone, which form a newly characterized family of G-coupled receptors.Glucose-induced insulin secretion is modulated by a number of hormones and neurotransmitters. In particular, two gut hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP), potentiate the effect of glucose on insulin secretion and are thus called gluco-incretins (1, 2). GLP-1 is a gluco-incretin in rat and in man (1-3). It is part of the preproglucagon molecule (4) that is proteolytically processed in intestinal L cells to GLP-1-(1-37) and GLP-1-(7-36) amide or GLP-1-(7-37) (5, 6). Only the truncated forms of GLP-1 are biologically active and both have identical effects on insulin secretion in ,. cells (7, 8). They are the most potent gluco-incretins so far described and are active at concentrations as low as 1-10 pM. The stimulatory effect of these gluco-incretin hormones requires the presence of glucose at or above the normal physiological concentration of about 5 mM and is mediated by activation of adenylate cyclase and a rise in the intracellular concentration of cAMP (9, 10). GLP-1 has also a stimulatory effect on insulin gene transcription (9). In rat, non-insulin-dependent diabetes mellitus (NIDDM) is associated with a reduced stimulatory effect of GLP-1 on glucose-induced insulin secretion (11). In man, in one study, GLP-1 levels were elevated in NIDDM patients in the basal state and after glucose ingestion; however, following a glucose load there was only a very small rise in plasma insulin concentration (12). This suggests that diabetic 3 cells, in addition to being glucose-unresponsive, may also have a decreased sensitivity to the incretin effect of GLP-1. However, a recent study (13) showed that GLP-1 infusion could ameliorate postprandial insulin secretion and glucose disposal in NIDDM patients, and this hormone, or derivatives thereof, has been proposed as a new therapeutic agent to stimulate insulin secretion by P cells of type II diabetic patients. Thus, as a further step in understanding the complex modulation ofinsulin secretion by gut...

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

“…These data suggest that AMPK activation by liraglutide might be responsible for inhibition of cytokineinduced NF-κB activation. GLP-1 is widely believed to exert its actions through a distinct heptahelical G protein-coupled receptor (GLP-1 receptor), which is functionally associated with adenylate cyclase through the stimulatory Gs [11,12]. GLP-1 may increase intracellular cyclic AMP (cAMP) and activate PKA, thereby increasing insulin secretion in beta cells.…”

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

“…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).…”

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity

“…A concentration of 10 nmol/l GLP-1 was used throughout this study. It corresponds to a maximal effective concentration that is broadly used in the literature and to plasma concentration of the incretin following a high-carbohydrate meal [23,30,45,46]. Figure 1a shows the percentages of apoptotic cells as determined by HOECHST staining in dispersed human islet cells.…”