Glucagon-like peptide-1 is synthesized in intestinal endocrine cells in 2 principal major molecular forms, as GLP-1(7-36)amide and GLP-1(7-37). The peptide was first identified following the cloning of cDNAs and genes for proglucagon in the early 1980s, and is one of the two principal incretin hormones.
Initial studies of GLP-1 biological activity in the mid 1980s utilized the full length N-terminal extended forms of GLP-1 (1-37 and 1-36amide). These larger GLP-1 molecules were generally devoid of biological activity. In 1987, 3 independent research groups demonstrated that removal of the first 6 amino acids resulted in a shorter version of the GLP-1 molecule with substantially enhanced biological activity, measured asstimulation of insulin secretion.
The majority of circulating biologically active GLP-1 is found in the GLP-1(7-36)amide form), with lesser amounts of the bioactive GLP-1(7-37) form also detectable. See Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes. 1994 Apr;43(4):535-9 for the human data. Both peptides appear equipotent in all biological paradigms studied to date Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes. 1993 May;42(5):658-61. GLP-1 is secreted from gut endocrine cells in response to nutrient ingestion and plays multiple roles in metabolic homeostasis following nutrient absorption.
An important locus for regulation of GLP-1 biological activity is the N-terminal degradation of the peptide by Dipeptidyl Peptidase-4 (DPP-4)-mediated cleavage at the position 2 alanine. For an overview, see DPP-4.
The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. GLP-1 appears to have a number of additional effects in the GI tract and central nervous system, as reviewed in Diabetes 1998 47(2):159-69, Minireview: the glucagon-like peptides. Endocrinology. 2001 Feb;142(2):521-7, Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes. Curr Pharm Des. 2001 Sep;7(14):1399-412. Review and Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002 Feb;122(2):531-44, Pharmacology, physiology, and mechanisms of incretin hormone action Cell Metab. 2013 Jun 4;17(6):819-37 and Deciphering metabolic messages from the gut drives therapeutic innovation: the 2014 Banting Lecture Diabetes. 2015 Feb;64(2):317-26.
The finding that GLP-1 lowers blood glucose in patients with diabetes, taken together with suggestions that GLP-1 may restore β-cell sensitivity to exogenous secretagogues, suggests that augmenting GLP-1 signaling is a useful strategy for treatment of diabetic patients. There are a number of different GLP-1 targets or loci that may be exploited to enhance GLP-1 action in diabetic subjects.
Mounting evidence demonstrates that GLP-1R signaling regulates islet proliferation and islet neogenesis. For a review of the data to date, see GLP-1 and islet proliferation.
GLP-1 and the CNS. There is considerable interest in understanding the role (s) of GLP-1 in the control of satiety and food intake. A large body of evidence demonstrates that ICV GLP-1 can reduce food intake in both acute and chronic studies. Conversely, ICV administration of the GLP-1 antagonist exendin (9-39) can acutely increase food intake and promote weight gain in chronic rodent studies. These satiety-related effects have also been observed in human studies with peripheral administration of GLP-1 or Exenatide or Liraglutide to both normal and diabetic subjects. Nevertheless, there remains some controversy as to whether the satiety-related effects of GLP-1 are specific, or perhaps indicative of GLP-1 effects on brain regulatory networks that respond to stress or aversive conditions. For an overview of different aspects of GLP-1 biology, see: