The production of a diabetic mouse using constructs encoding porcine insulin promoter-driven mutant human hepatocyte nuclear factor-1 alpha .

摘要

A diabetic mouse model was produced using a mutant human hepatocyte nuclear factor-1 alpha gene (HNF1 alpha P291fsinsC) regulated by the porcine insulin promoter. The functionality of 2 different constructs containing HNF1 alpha P291fsinsC, termed PD1 and PD2 (cytomegalovirus enhancer minus and plus), was examined in transgenic mice. The blood glucose levels and body weights of the PD1 transgenic mice did not differ from their non-transgenic littermates over the period of 3-8 weeks of age. The PD2 transgenic mice exhibited hyperglycaemia and decreased body weight. Western blot analysis demonstrated that mutant HNF-1 alpha protein (HNF1 alpha P291), derived from the PD2 transgene, was expressed in the PD2 mice. Morphometric studies of the pancreas of a PD2 mouse revealed that the number of pancreatic islets present was less than that in the non-transgenic mice, indicating disturbed islet neogenesis. These results suggested that impaired insulin secretion in disrupted islets caused hyperglycaemia. Moreover, the phenotype of PD2 transgenic mice was similar to that of the HNF-1 alpha gene-deficient mouse, which displayed growth retardation and impaired viability. These results indicated that HNF1 alpha P291 expression driven by the porcine insulin promoter, together with the cytomegalovirus enhancer, induced a diabetic phenotype in transgenic mice..