Biologic actions and therapeutic potential of the proglucagon-derived peptides

Abstract

The actions of the structurally related proglucagon-derived peptides (PGDPs)—glucagon, glucagon-like peptide (GLP)-1 and GLP-2—are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores β-cell sensitivity to glucose, increases β-cell proliferation, and reduces apoptosis, leading to expansion of the β-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.

Key Points

  • The structurally related proglucagon-derived peptides are produced in the pancreas, gut and brain, and regulate complementary aspects of energy homeostasis

  • The glucagon-like peptide 1 receptor agonist exenatide has recently been approved for treatment of type 2 diabetes

  • Exenatide (exendin 4) and the amylin agonist pramlintide (another drug used to treat type 2 diabetes) also inhibit glucagon secretion

  • Dipeptidyl peptidase IV cleaves incretin hormones such as glucagon-like peptide 1, and drugs that inhibit this enzyme are in phase III trials for treatment of type 2 diabetes

  • Glucagon-like peptide 2 is currently in phase III clinical trials for treatment of short-bowel syndrome

  • Thus various strategies that modulate proglucagon-derived peptides show therapeutic potential in both diabetes and intestinal disease

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Figure 1: Structure of proglucagon and the proglucagon-derived peptides
Figure 2: Representation of normal glucagon action on the liver and pancreas
Figure 3: Actions of glucagon-like peptide 1 on multiple target tissues
Figure 4: The actions of glucagon-like peptide 2 in the gastrointestinal mucosa

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Acknowledgements

DJD is supported by a Canada Research Chair in Regulatory Peptides. Work on the glucagon-like peptides in DJD's laboratory is supported by operating grants from the Canadian Institutes for Health Research, the Juvenile Diabetes Research Foundation, and the Canadian Diabetes Association.

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Correspondence to Daniel J Drucker.

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D Drucker is a Consultant to Abbott Labs, Amylin Pharmaceuticals Inc, Bristol Myers Squibb, and Eli Lilly Inc, Glaxosmithkline, Merck & Co, Novartis, PPD, Syrrx, and Triad Pharmaceuticals Inc.

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Drucker, D. Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nat Rev Endocrinol 1, 22–31 (2005). https://doi.org/10.1038/ncpendmet0017

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