Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse

Aims/hypothesis. The Nagoya-Shibata-Yasuda (NSY) mouse closely mimics human Type II (non-insulin-dependent) diabetes mellitus in that the onset is age -dependent, the animals are not severely obese, and both insulin resistance and impaired insulin response to glucose contribute to disease development . The aim of this study was to clarify the influence of age on the pathogen esis of diabetes and to analyse a candidate gene for Type II diabetes in th is strain. Methods. Several phenotypic characteristics related to diabetes mellitus we re monitored longitudinally in male NSY and control C3H/He mice. The nucleo tide sequence of Glut4, a candidate gene for Nidd1nsy (a susceptibility gen e for Type II diabetes) on Chromosome 11, encoding insulin-sensitive glucos e transporter, was determined in NSY and C3H mice. Results. Glucose intolerance worsened with age, and fasting blood glucose a nd fasting plasma insulin concentration increased with age in NSY mice. Pan creatic insulin content increased until 24 weeks of age but then decreased at 48 weeks of age ill NSY mice. The hypoglycaemic response to insulin was statistically significantly smaller in NSY than in C3H/He mice. The nucleot ide sequence of GLUT4 cDNA was identical in NSY and C3H/He mice, but both w ere different from the sequence reported previously. Conclusion/interpretation. Insulin secretion and insulin resistance, as wel l as ageing possibly play an important part in the disease development in N SY mice. A decline of pancreatic insulin content in older age might cause t he relative insulin deficiency in this strain. Nucleotide sequencing sugges ts that Glut4 is unlikely to be a candidate gene for Nidd1nsy.