International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


M Goldsworthy
Medical Research Council

Bentley E, Mijat V, Moir L, Clay T, Ritson D, Clay J, Cox RD.

Type II diabetes is a disease with a complex genetic and environmental aetiology. Many mouse models of disease have been generated utilising knockout gene technologies, many of which mimic the rare monogenic early onset forms of disease. Mice inheriting a heterozygous KO in either the Insulin Receptor (IR) or Insulin Receptor Substrate-1 (IRS-1) show very low disease incidence or no disease respectively. However, 40% of mice doubly heterozygous for the IR and IRS-1 KOs on a mixed genetic background exhibit a diabetic phenotype. In order to generate new polygenic Type II Diabetes models we employed IR or IRS-1 heterozygous knockout mice in an ENU screen; thus sensitising the screen for mutations in genes that can act in synergy with mild defects in insulin signalling (insulin resistance) to result in a diabetic phenotype. F1 individuals generated were tested at 12 and 24 weeks of age using an IPGTT to identify individuals with impaired glucose tolerance (IGT).  Affected F1 individuals enter inheritance testing and to date 3 lines (IGT/3, IGT/4 and IGT/6) show clear inheritance of a sub diabetic phenotype. All 3 lines exhibit IGT at 12 weeks that becomes worse with age (24 weeks). Only IGT/3 and IGT/6 show a significant increase in body weight.  At 15 months of age lines IGT/3 and IGT/4 showed marker hyperglycaemia and hyperinsulinaemia. Further affected IGT/3 individuals exhibit massive beta-cell hyperplasia.  Additional phenotypic analysis and microsatellite mapping of BC animals is underway in order to map and identify the mutated genes.

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