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Elevated Glucagon-Like Peptide-1-(7–36)-Amide, but Not Glucose, Associated with Hyperinsulinemic Compensation for Fat Feeding

Department of Physiology and Biophysics (G.W.V.C., M.K., S.P.K., S.D.M., M.K.D., R.N.B.), Keck School of Medicine, University of Southern California, Los Angeles, California 90089-9142; and Department of Physiology (P.L.B.), University of Toronto, Toronto, Ontario, M5S 1A8 Canada

Address all correspondence and requests for reprints to: Richard N. Bergman, Ph.D., Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, 1333 San Pablo Street, MMR 626, Los Angeles, California 90089-9142. E-mail: rbergman{at}usc.edu.

Abstract

We previously developed a canine model of central obesity and insulin resistance by supplementing the normal chow diet with 2 g cooked bacon grease/kg body weight. Dogs fed this fatty diet maintained glucose tolerance with compensatory hyperinsulinemia. The signal(s) responsible for this up-regulation of plasma insulin is unknown. We hypothesized that meal-derived factors such as glucose, fatty acids, or incretin hormones may signal ß-cell compensation in the fat-fed dog. We fed the same fat-supplemented diet for 12 wk to six dogs and compared metabolic responses with seven control dogs fed a normal diet. Fasting and stimulated fatty acid and glucose-dependent insulinotropic peptide concentrations were not increased by fat feeding, whereas glucose was paradoxically decreased, ruling out those three factors as signals for compensatory hyperinsulinemia. Fasting plasma glucagon-like peptide-1 (GLP-1) concentration was 2.5-fold higher in the fat-fed animals, compared with controls, and 3.4-fold higher after a mixed meal. Additionally, expression of the GLP-1 receptor in whole pancreas was increased 2.3-fold in the fat-fed dogs. The increase in both circulating GLP-1 and its target receptor may have increased ß-cell responsiveness to lower glucose. Glucose is not the primary cause of hyperinsulinemia in the fat-fed dog. Corequisite meal-related signals may be permissive for development of hyperinsulinemia.

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