Discovery, characterization, and clinical development of the glucagon-like peptides

Abstract

The discovery, characterization, and clinical development of glucagon-like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.

Keywords: Diabetes; Endocrinology; Gastroenterology; Islet cells.

Figure 1. Historical timeline depicting seminal events in the discovery and development of glucagon-like peptide therapeutics.

Figure 2. Structure and processing of anglerfish and human proglucagon.

Representation of the structures of proglucagon cDNAs from Anglerfish (A) and Human (B), with tissue-specific liberation of individual proglucagon-derived peptides in pancreas or intestine. PC1, prohormone convertase 1; PC2, prohormone convertase 2; MPGF, major proglucagon fragment. Arrows in A represent sites of cleave by prohormone convertase enzymes.

Figure 3. Processing of proglucagon and glucagon-like peptides in the pancreas and intestine.

Detection of immunoreactive forms of GLP-1 in extracts from rat pancreas (A) and intestine (B) as adapted from ref. . Characterization of proglucagon-derived peptide immunoreactivity secreted from perfused pig pancreas and intestine (C) using peptide-specific antisera reveal tissue-specific posttranslational processing of the PGDPs, as outlined in ref. .

Figure 4. GLP-1 directly stimulates signal transduction and glucose-dependent insulin secretion in islet cells.

GLP-1(7-37) directly stimulates cyclic AMP accumulation (A), insulin gene expression (B), and glucose-dependent insulin secretion (C) in a rat insulinoma cell line, as adapted from ref. .

Figure 5. Truncated forms of GLP-1 stimulate glucose-dependent insulin secretion.

GLP-1(7-37) (A) but not GLP-1(1-37) (B) stimulates insulin secretion from the perfused rat pancreas as adapted from ref. . Sequences of GLP-1(1-37), GLP-1(7-37), and GLP-1(7-36_amide). (C) Intraluminal glucose stimulates enteroglucagon, GLP-1, and GLP-2 secretion from the perfused pig ileum (D), as adapted from ref. . Demonstration that GLP-1(7-36)_amide stimulates insulin secretion from the perfused pig pancreas (E), as adapted from ref. .

Figure 6. The pleiotropic local and systemic actions of GLP-1 and GLP-2 secreted in response to nutrients, bacterial metabolites, or inflammatory toxins and cytokines, from enteroendocrine L cells of the small and large intestine.