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Diabetes 51:2677-2683, 2002
© 2002 by the American Diabetes Association, Inc.

Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat

A Euglycemic-Hyperinsulinemic Clamp Study

John A. Pospisilik1, Sara G. Stafford1, Hans-Ulrich Demuth2, Christopher H.S. McIntosh1, and Raymond A. Pederson1

1 Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada
2 Probiodrug AG, Halle (Saale), Germany

Upon release into circulation, the potent insulin secretagogues glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are rapidly cleaved and inactivated by the enzyme dipeptidyl peptidase IV (DP IV). Long-term administration of specific DP IV inhibitors, so as to enhance circulating active GIP and GLP-1 levels, has been shown to improve glucose tolerance and ß-cell glucose responsiveness and to reduce hyperinsulinemia in the Vancouver diabetic fatty (VDF) rat model of type 2 diabetes. Using the VDF model, the current study was undertaken to examine the effects of long-term DP IV inhibitor treatment on insulin sensitivity. Euglycemic-hyperinsulinemic clamps were performed on two sets of conscious VDF rats treated with or without the DP IV inhibitor P32/98 (20 mg · kg-1 · day-1 for 12 weeks). The protocol consisted of three sequential 90-min periods with insulin infusion rates of 0, 5, and 15 mU · kg-1 · min-1 and included a constant infusion of [ 3H]glucose for measure of hepatic and peripheral insulin sensitivity. Relative to untreated littermates, the treated animals showed a left shift in the sensitivity of hepatic glucose output to insulin (average reduction ~6 µmol · kg-1 · min-1) and a marked gain in peripheral responsiveness to insulin, with glucose disposal rates increasing 105 and 216% in response to the two insulin steps (versus 2 and 46% in controls). These results provide the first demonstration of improved hepatic and peripheral insulin sensitivity after DP IV inhibitor therapy, and coupled with apparent improvements in ß-cell function, they offer strong support for the utility of these compounds in the treatment of diabetes.


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