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Expression of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 in Pancreatic β-Cells and Its Role in Promotion of Insulin Secretion and Protection against Diabetes

Laboratory of Biosignal Sciences (M.K., H.Oh., H.Ok., Y.M., Y.H., H.K., T.M.) and Metabolic Signal Research Center (T.K.), Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan

Address all correspondence and requests for reprints to: Takashi Matozaki or Hiroshi Ohnishi, Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan. E-mail: matozaki{at}showa.gunma-u.ac.jp or ohnishih{at}showa.gunma-u.ac.jp.

Insulin secretion by β-cells of pancreatic islets is regulated by various soluble factors including glucose and hormones. The importance of direct cell-cell communication among β-cells or between β-cells and other cell types for such regulation has remained unclear, however. Transmembrane proteins Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) and its ligand CD47 interact through their extracellular regions and contribute to intercellular communication. We now show that both SHPS-1 and CD47 are prominently expressed in β-cells of the pancreas. The plasma insulin level in the randomly fed state was markedly reduced in mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region compared with that in wild-type (WT) mice, although the blood glucose concentrations of the two types of mice were similar. This reduction in the plasma insulin level of SHPS-1 mutant mice was even more pronounced in animals maintained on a high-fat diet. Glucose tolerance was also markedly impaired in SHPS-1 mutant mice on a high-fat diet, whereas both peripheral insulin sensitivity and the insulin content of the pancreas in the mutant animals were similar to those of WT mice. Glucose-stimulated insulin secretion was similar for islets isolated from WT or SHPS-1 mutant mice. The impaired glucose tolerance of SHPS-1 mutant mice was ameliorated by treatment with the 2-adrenergic antagonist yohimbine. These results suggest that SHPS-1 promotes insulin secretion from β-cells and thereby protects against diabetes. Preventing of 2-adrenergic receptor-mediated inhibition of insulin secretion may partly participate in such a function of SHPS-1.