Mouse Genome Informatics
involves: 129P2/OlaHsd * C57BL/6
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
• homozygotes develop into adulthood without apparent growth defects but exhibit a mild but significant fasting hyperglycemia, which is more pronounced during fed states
• homozygotes develop inadequate compensatory hyperinsulinemia
• in response to oral glucose load, 2-mo-old homozygotes display a mild glucose intolerance, with increased blood glucose levels at all time points measured
• in response to i.p. administration of insulin, homozygotes display significantly elevated blood glucose levels relative to wild-type mice at all time points measured (at 60 min; 70.8 7.9 mg/dl vs 22.3 1.1 mg/dl, respectively)
• in euglycemic-hyperinsulinemic clamp expts, homozygotes exhibit peripheral insulin resistance along with complete failure of insulin to suppress hepatic glucose output
• notably, circulating free fatty acid concentrations remain normal

• in euglycemic-hyperinsulinemic clamp studies, 2-5-mo-old homozygotes show a ~50% reduction in total body insulin-dependent glucose disposal relative to wild-type mice
• insulin-stimulated hexose uptake into the glycolytic extensor digitorum longus (EDL) muscle is severely blunted in the presence of 0.33 nM insulin; however, no impairment is noted upon exposure of the mutant EDL to a higher insulin concentration (13.3 nM)
• insulin-stimulated deoxyglucose uptake into the oxidative soleus muscle is not significantly impaired at either an intermediate or maximal concentration of insulin

endocrine/exocrine glands
• pancreata from 2- to 3-month-old male homozygotes respond to insulin resistance with an increase in islet mass (~4-fold) and number (~2-fold) relative to wild-type mice

adipose tissue
• in euglycemic-hyperinsulinemic clamp studies, insulin-stimulated hexose uptake is mildly impaired in mutant adipocytes

Mouse Models of Human Disease
Diabetes Mellitus, Noninsulin-Dependent; NIDDM 125853 J:71491