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Insulin Secretion Is Increased in Pancreatic Islets of Neuropeptide Y-Deficient Mice

Department of Medicine (Y.I., H.R.P., E.J.H., R.S.A.), Division of Endocrinology, Diabetes, and Metabolism, and Department of Biochemistry and Biophysics (N.M.D., F.M.M.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Yumi Imai, M.D., Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104. E-mail: imai{at}mail.med.upenn.edu.

Neuropeptide Y (NPY), whose role in appetite regulation is well known, is also expressed in pancreatic islets. Although previous studies indicated that application of NPY to pancreatic islets inhibits insulin secretion, its physiological role in the regulation of insulin secretion is not fully understood. We hypothesized that NPY in islets tonically suppresses insulin secretion and the reduction of islet NPY increases insulin secretion. To address the hypothesis, islet function of NPY-deficient mice was analyzed. Although there was little change in glucose homeostasis in vivo, pancreatic islets from NPY-deficient mice had higher basal insulin secretion (1.5 times), glucose-stimulated insulin secretion (1.5 times), and islet mass (1.7 times), compared with wild-type mouse. Next we sought to determine whether the expression of NPY and Y₁ receptor in islets was altered in hyperinsulinemia associated with obesity. Islets from C57BL/6J mice on a high-fat diet had 1.9 times higher basal insulin secretion and 2.4 times higher glucose-stimulated insulin secretion than control mice, indicating islet adaptation to obesity. Expression of NPY and Y₁ receptor mRNA levels was decreased by 70 and 64%, respectively, in high-fat diet islets, compared with controls. NPY and Y₁ receptor in islets were also reduced by 91 and 80%, respectively, in leptin-deficient ob/ob mice that showed marked hyperinsulinemia. Together these results suggest that endogenous NPY tonically inhibits insulin secretion from islets and a reduction of islet NPY may serve as one of the mechanisms to increase insulin secretion when islets compensate for insulin resistance associated with obesity.

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				Y. Imai, H. R. Patel, N. M. Doliba, F. M. Matschinsky, J. W. Tobias, and R. S. Ahima Analysis of gene expression in pancreatic islets from diet-induced obese mice Physiol Genomics, December 12, 2008; 36(1): 43 - 51. [Abstract] [Full Text] [PDF]