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Neurogenin 3-Specific Dipeptidyl Peptidase-2 Deficiency Causes Impaired Glucose Tolerance, Insulin Resistance, and Visceral Obesity

Department of Pathology (O.V.D., A.K.T., D.A.M., B.T.H.), Tufts University School of Medicine, Molecular Cardiology Research Institute (M.B.), Molecular Pharmacology Research Center, and Tupper Research Institute and Department of Medicine (P.S.S., R.M.L.), Division of Endocrinology, Diabetes, and Metabolism, Tufts Medical Center, and Department of Obesity and Metabolism (A.S.G., J.W.P., J.D.), Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111; and Department of Medicine (A.B.L.), University of Massachusetts Medical School, Worcester, Massachusetts 01605

Address all correspondence and requests for reprints to: Brigitte T. Huber, 150 Harrison Avenue, Jaharis 901D, Boston Massachusetts 02111. E-mail: brigitte.huber{at}tufts.edu.

The control of glucose metabolism is a complex process, and dysregulation at any level can cause impaired glucose tolerance and insulin resistance. These two defects are well-known characteristics associated with obesity and onset of type 2 diabetes. Here we introduce the N-terminal dipeptidase, DPP2, as a novel regulator of the glucose metabolism. We generated mice with a neurogenin 3 (NGN3)-specific DPP2 knockdown (kd) to explore a possible role of DPP2 in maintaining metabolic homeostasis. These mice spontaneously developed hyperinsulinemia, glucose intolerance, and insulin resistance by 4 months of age. In addition, we observed an increase in food intake in DPP2 kd mice, which was associated with a significant increase in adipose tissue mass and enhanced liver steatosis but no difference in body weight. In accordance with these findings, the mutant mice had a higher rate of respiratory exchange than the control littermates. This phenotype was exacerbated with age and when challenged with a high-fat diet. We report, for the first time, that DPP2 enzyme activity is essential for preventing hyperinsulinemia and maintaining glucose homeostasis. Interestingly, the phenotype of NGN3-DPP2 kd mice is opposite that of DPP4 knockout mice with regard to glucose metabolism, namely the former have normal glucagon-like peptide 1 levels but present with glucose intolerance, whereas the latter have increased glucagon-like peptide 1, which is accompanied by augmented glucose tolerance.