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BackgroundThe Src-homology 2 domain-containing adaptor protein Shb was recently cloned as a serum-inducible gene in the insulin-producing β-TC1 cell line. Subsequent studies have revealed an involvement of Shb for apoptosis in NIH3T3 fibroblasts and differentiation in the neuronal PC 12 cells. To assess a role of Shb for β-cell function, transgenic mice utilizing the rat insulin promoter to drive expression of Shb were generated.Materials and MethodsA gene construct allowing the Shb cDNA to be expressed from the rat insulin 2 promoter was microinjected into fertilized mouse oocytes and implanted into pseudopregnant mice. Mice containing a low copy number of this transgene were bred and used for further experimentation. Shb expression was determined by Western blot analysis. The insulin-positive area of whole pancreas, insulin secretion of isolated islets and islet cell apoptosis, glucose tolerance tests, and in vivo sensitivity to multiple injections of the β-cell toxin streptozotocin were determined in control CBA and Shb-transgenic mice.ResultsWestern blot analysis revealed elevated islet content of the Shb protein. Shb-transgenic mice displayed enhanced glucose-disappearance rates in response to an intravenous glucose injection. The relative pancreatic β-cell area neonatally and at 6 months of age were increased in the Shb-transgenic mice. Islets isolated from Shb-transgenic mice showed enhanced insulin secretion in response to glucose and increased insulin and DNA content. Apoptosis was increased in islets isolated from Shb-transgenic mice compared with control islets both under basal conditions and after incubation with IL-1β + IFN-γ. Rat insulinoma RINm5F cells overexpressing Shb displayed decreased viability during culture in 0.1 % serum and after exposure to a cytotoxic dose of nicotinamide. Shb-transgenic mice injected with multiple doses of streptozotocin showed increased blood glucose values compared with the corresponding controls, suggesting increased in vivo susceptibility to this toxin.ConclusionThe results suggest that Shb has dual effects on β-cell growth: whereas Shb increases β-cell formation during late embryonal stages, Shb also enhances β-cell death under certain stressful conditions and may thus contribute to β-cell destruction in type 1 diabetes.

Transgenic Mice Expressing Shb Adaptor Protein under the Control of Rat Insulin Promoter Exhibit Altered Viability of Pancreatic Islet Cells