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The Extrapancreatic Effects of Glucagon-Like Peptide-1 and Related Peptides

Johns Hopkins University School of Medicine, Departments of Surgery (R.A.-H., A.R., D.K.A., D.E.) and Medicine (A.R., D.E.), Johns Hopkins Bayview Medical Center, Baltimore, Maryland 21224-2780; University of British Columbia (G.S.M.), Department of Medicine, Vancouver, British Columbia, Canada V5Z 1M9; and University of Pennsylvania School of Medicine (R.P.S.), Department of Medicine, Philadelphia, Pennsylvania 19104-2646

Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Departments of Surgery and Medicine, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, Maryland 21224-2780. E-mail: delahi1{at}jhmi.edu.

Context: Glucagon-like peptide-1 (GLP-1) 7-36 amide, an insulinotropic hormone released from the intestinal L cells in response to nutrient ingestion, has been extensively reviewed with respect to β-cell function. However GLP-1 receptors are abundant in many other tissues. Thus, the function of GLP-1 is not limited to the islet cells, and it has regulatory actions on many other organs.

Evidence Acquisition: A review of published, peer-reviewed medical literature (1987 to September 2008) on the extrapancreatic actions of GLP-1 was performed.

Evidence Synthesis: The extrapancreatic actions of GLP-1 include inhibition of gastric emptying and gastric acid secretion, thereby fulfilling the definition of GLP-1 as an enterogastrone. Other important extrapancreatic actions of GLP-1 include a regulatory role in hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. The primary metabolite of GLP-1, GLP-1 (9-36) amide, or GLP-1m, is the truncated product of degradation by dipeptidyl peptidase-4. GLP-1m has insulinomimetic effects on hepatic glucose production and cardiac function. Exendin-4 present in the salivary gland of the reptile, Gila monster (Heloderma suspectum), is a high-affinity agonist for the mammalian GLP-1 receptor. It is resistant to degradation by dipeptidyl peptidase-4, and therefore has a prolonged half-life.

Conclusion: GLP-1 and its metabolite have important extrapancreatic effects particularly with regard to the cardiovascular system and insulinomimetic effects with respect to glucose homeostasis. These effects may be particularly important in the obese state. GLP-1, GLP-1m, and exendin-4 therefore have potential therapeutic roles because of their diffuse extrapancreatic actions.