Expression of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 in pancreatic beta-Cells and its role in promotion of insulin secretion and protection against diabetes.
Insulin secretion by beta-cells of pancreatic islets is regulated by various soluble factors including glucose and hormones. The importance of direct cell-cell communication among beta-cells or between beta-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 beta-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 alpha2-adrenergic antagonist yohimbine. These results suggest that SHPS-1 promotes insulin secretion from beta-cells and thereby protects against diabetes. Preventing of alpha2-adrenergic receptor-mediated inhibition of insulin secretion may partly participate in such a function of SHPS-1.
Kobayashi
Masaki
M
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan.
Ohnishi
Hiroshi
H
Okazawa
Hideki
H
Murata
Yoji
Y
Hayashi
Yuriko
Y
Kobayashi
Hisae
H
Kitamura
Tadahiro
T
Matozaki
Takashi
T
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D051928:CD47 Antigen / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004036:Diet, Atherogenic; D005247:Feeding Behavior / Q000502:physiology; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D007328:Insulin; D050505:Mutant Proteins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D015016:Yohimbine