The physiology and pharmacology of GLP-1 in man

The Glucagon-like peptides are formed by alternate tissue-specific cleavage of the proglucagon polypeptide; GLP- (7-37) and GLP-1(7-36)amide are potent insulinotropic peptides produced in the L cells of the intestines (and hind brain), which together with GIP constitute the nutrient-directed, gut-derived “incretin” activity. More recently, numerous other actions of GLP-1 have been identified, such as inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, stimulation of beta-cell proliferation and effects on cardiac function. My laboratory, in collaboration with J. Habener, has had a long-term interest in the physiology and pharmacology of the GLPs and more recently, exendin-4, in man. Our studies have defined the metabolic responses to the agents in short and longer term treatment, and demonstrated their efficacy in the improvement of glycemic control of type 2 diabetes. Of interest, our recent studies have shown that the improvement in glycemic control in elderly type 2 diabetics is accompanied by a restoration of pulsaltile insulin secretion. Ongoing studies examine their effects on insulin responsiveness in the type 2 diabetic, their utility in the type 1 diabetes, and their use in settings of myocardial dysfunction.

References

1. Mager DE, Abernethy DR, Egan JM, Elahi D. Exendin-4 Pharmacodynamics: Insights From the Hyperglycemic Clamp Technique. J Pharmacol Exp Ther. 2004 in press

2. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, Shannon RP. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-5.

3. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D. Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes. Diabetes Care. 2003;26:2835-41.

4. Meneilly GS, McIntosh CH, Pederson RA, Habener JF, Ehlers MR, Egan JM, Elahi D. Effect of glucagon-like peptide 1 (7-36 amide) on insulin-mediated glucose uptake in patients with type 1 diabetes. Diabetes Care. 2003;26:837-42.

5. Egan JM, Meneilly GS, Elahi D. Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes. Am J Physiol Endocrinol Metab. 2003;284:E1072-9

6. Egan JM, Meneilly GS, Habener JF, Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab. 2002;87:3768-73.

7. Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab. 2002;87:1282-90.

8. Meneilly GS, McIntosh CH, Pederson RA, Habener JF, Gingerich R, Egan JM, Elahi D. Glucagon-like peptide-1 (7-37) augments insulin-mediated glucose uptake in elderly patients with diabetes. J Gerontol A Biol Sci Med Sci. 2001;56:M681-5.

9. Meneilly GS, McIntosh CH, Pederson RA, Habener JF, Gingerich R, Egan JM, Finegood DT, Elahi D. Effect of glucagon-like peptide 1 on non-insulin-mediated glucose uptake in the elderly patient with diabetes. Diabetes Care. 2001;24:1951-6.

10). Korosi J, McIntosh CH, Pederson RA, Demuth HU, Habener JF, Gingerich R, Egan JM, Elahi D, Meneilly GS. Effect of aging and diabetes on the enteroinsular axis. J Gerontol A Biol Sci Med Sci. 2001;56:M575-9.

11. Clocquet AR, Egan JM, Stoffers DA, Muller DC, Wideman L, Chin GA, Clarke WL, Hanks JB, Habener JF, Elahi D. Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (insulin promoter factor 1 gene). Diabetes. 2000;49:1856-64.