Glucagon-like peptide 1 (GLP-1)

Abstract

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity.

Scope of review: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases.

Major conclusions: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders.

Keywords: Diabetes; GLP-1; Glucagon; Incretin; Insulin; Obesity.

Figure 1

Schematic on the tissue-selective processing of proglucagon. PCSK1: prohormone convertase 1/3; PCSK2: prohormone convertase 1/3; NTS: nucleus tractus solitarii; GRPP: glicentin-related polypeptide; IP-1 intervening peptide-1; IP-2: intervening peptide-2, MPGF: major proglucagon fragment; GLP-1: glucagon-like peptide-1; GLP-2: glucagon-like peptide-2. See text for further explanations.

Figure 2

Schematic on the tissue-selective processing of proglucagon in the pancreatic islets. Schematic on the transcriptional regulation of preproglucagon (PPG) in the pancreatic islets. Pax6: paired box 6; CDX2/3: caudal type homeobox 2/3; MafB: MAF bZIP transcription factor B; cMaf: c-Maf inducing protein; NKX2.1: NK2 homeobox 1; PDX1: pancreatic and duodenal homeobox 1; Pax4: paired box 4; CRE: cAMP response element; CREB: cAMP response element binding protein; PPG: preproglucagon; HNF3: hepatocyte nuclear factor 3; Isl1: ISL LIM homeobox 1; Preb: prolactin element binding. For further explanations, please see text.

Figure 3

Schematic on the nutrient-induced stimulation of GLP-1 secretion in the L-cell. CICR: calcium-induced calcium release; LCFA: long-chain fatty acids, GLUT2: glucose transporter 2; GLP-1: glucagon-like peptide-1; GLP-2: glucagon-like peptide-2; OXM: oxyntomodulin; Trpc3: transient receptor potential channel 3; VDCC: voltage-dependent calcium channel; SGLT1: sodium/glucose co-transporter 1. For further explanations, please see text.

Figure 4

Schematic on the GPCR Repertoire Involved in Control of Hormone Secretion from Gastric cells expressing either ghrelin or GLP-1. Green or red color background color indicates stimulation (green) or inhibition (red) of hormone secretion upon receptor activation. The colors of the receptors represent G protein signaling potential via G/s (green), G/q (orange) or G/i/o (red). The type of G protein responsible for the effect on hormone secretion has not been determined for all the receptors; for those where it has not been described, we have indicated the most likely coupling, based on data from other cell studies. 2-MAG, 2- monoacyl glycerol; BB2, bombesin receptor 2; Calcrl, calcitonin receptor-like receptor; CaSR, calcium sensing receptor; CGRP, calcitonin gene-related peptide; FACS, fluorescence-activated cell sorting; FFAR, free fatty acid receptor; GalR1, galanin receptor 1; GIP, glucose-dependent insulinotropic peptide; GIPR, GIP receptor; GPR, G protein receptor; MC$, melanocortin 4; MSH, melanocyte-stimulating hormone; NMC, neuromedin C; PYY, peptide YY; Ramp1, receptor activity modifying protein 1; SCTR, secretin receptor T; SSTR, somatostatin receptor; TGR5, bile acid receptor. Figure provided by the courtesy of Prof. T. W. Schwartz.

Figure 5

Schematic on GLP-1 mediated insulin secretion in the β-cell. GLUT1/2: glucose transporter 1/2; AC: adenylate cyclase; PKA: protein kinase A; Epac2: exchange protein activated by cAMP; Pdx-1: pancreatic and duodenal homeobox 1; CICR: calcium-induced calcium release. For further explanations, please see text.

Figure 6

Schematic on GLP-1 mediated exocytosis of the insulin granules in the β-cell. For further explanations, please see text.

Figure 7

Schematic on the metabolic effects of GLP-1. The shown effects include direct and indirect GLP-1 effects on metabolism. For further explanations, please see text.

Figure 8

Timeline of GLP-1R agonists approved by the FDA for the treatment of diabetes. Numbers in parenthesis reflect the half-life of the molecules. For further explanations, please see text.