Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse.
OBJECTIVE
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 pathogenesis of diabetes and to analyse a candidate gene for Type II diabetes in this strain.


METHODS
Several phenotypic characteristics related to diabetes mellitus were monitored longitudinally in male NSY and control C3H/He mice. The nucleotide sequence of Glut4, a candidate gene for Nidd1nsy (a susceptibility gene for Type II diabetes) on Chromosome 11, encoding insulin-sensitive glucose transporter, was determined in NSY and C3H mice.


RESULTS
Glucose intolerance worsened with age, and fasting blood glucose and fasting plasma insulin concentration increased with age in NSY mice. Pancreatic insulin content increased until 24 weeks of age but then decreased at 48 weeks of age in NSY mice. The hypoglycaemic response to insulin was statistically significantly smaller in NSY than in C3H/He mice. The nucleotide sequence of GLUT4 cDNA was identical in NSY and C3H/He mice, but both were different from the sequence reported previously.


CONCLUSIONS
Insulin secretion and insulin resistance, as well as ageing possibly play an important part in the disease development in NSY mice. A decline of pancreatic insulin content in older age might cause the relative insulin deficiency in this strain. Nucleotide sequencing suggests that Glut4 is unlikely to be a candidate gene for Nidd1nsy.
Ueda
H
H
Department of Geriatric Medicine, Osaka University Medical School, Suita, Japan.
Ikegami
H
H
Kawaguchi
Y
Y
Fujisawa
T
T
Nojima
K
K
Babaya
N
N
Yamada
K
K
Shibata
M
M
Yamato
E
E
Ogihara
T
T
D016475:3T3 Cells; D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018149:Glucose Intolerance / Q000235:genetics* / Q000503:physiopathology; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000494:pharmacology; D007515:Islets of Langerhans / Q000737:chemistry; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009124:Muscle Proteins; D010641:Phenotype; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse