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Exendin-4 Normalized Postcibal Glycemic Excursions in Type 1 Diabetes

Department of Medicine, University of Western Ontario and London Health Sciences, London, Ontario N6A 5A5, Canada

Address all correspondence and requests for reprints to: John Dupré, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, N6A 5K8 Canada. E-mail: john.dupre{at}lhsc.on.ca.

Exendin-4 is a reptilian peptide that activates the mammalian receptor for truncated glucagon-like peptide 1 (tGLP-1) with relatively prolonged actions. Exendin-4 and tGLP-1 can reduce blood glucose levels by stimulating insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying. We tested a range of doses of exendin-4 on postcibal glycemic excursions in nine volunteers with type 1 diabetes, all with negligible endogenous insulin secretion, in paired comparisons with vehicle in at least six volunteers with each of six doses. We established a side effect-free dose and an appropriate antecibal time for sc administration of exendin-4. Subsequently, exendin-4 was administered 15 min before breakfast, with usual insulin, to eight of the volunteers. Acetaminophen was ingested with the meal as an indicator of gastric emptying. The mean plasma glucose excursion was reduced by 90%, falling into the normal range, after breakfast, whereas plasma pancreatic polypeptide, glucagon, and acetaminophen levels were reduced, and insulin levels were not affected. Thus, normalization of postcibal glycemia was associated with delayed gastric emptying and suppression of glucagon secretion, without increased secretion or blood levels of insulin. We suggest that tGLP-1 agonists have therapeutic potential as congeners with insulin in C-peptide-negative type 1 diabetes.

J.D. holds a patent entitled "Treatment of Diabetes," assignee London Health Sciences Centre with pending applications in the United States, 08/737,446; Canada, 2,190,112; and Europe, 076 289 0B1.

Part of this work was presented in abstract form at the 61st Scientific Sessions of the American Diabetes Association, Philadelphia, Pennsylvania, 2001, and at the 62nd Scientific Sessions of the American Diabetes Association, San Francisco, California, 2002.

Abbreviations: AUC, Area under the curve; BMI, body mass index; HPP, pancreatic polypeptide; PC, postcibal; T1D, type 1 diabetes; tGLP-1, truncated glucagon-like peptide 1 (7–36 amide).

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