International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


ORAL PRESENTATION

TUESDAY 11 NOVEMBER
11:45 – 12:00 HRS

NEW MOUSE MODELS OF TYPE II DIABETES FROM A SENSITISED N-ETHYL-N-NITROSOUREA (ENU) MUTAGENESIS SCREEN

Goldsworthy M
Diabetes, QTL and Modifier Loci Group, MRC Harwell, Oxfordshire

Co-Authors: 1) Mijat V, 1) Haynes A E, 1) Hugill A, 1) Paul C L, 1) Bentley E, 2) Horner E J, 1+3) Anstee Q M, 1) Cox R D
Institutions: 1) Diabetes, QTL and Modifier Loci Group, MRC Harwell, Oxfordshire 2) Etiologics Ltd, Harwell, Oxfordshire 3) Department of Medicine, Imperial College, London

Type II diabetes is a complex genetic disease with some rare monogenic subtypes. In order to identify new diabetes genes and develop new mouse models for basic research and for therapeutics development we have initiated a sensitised ENU mutagenesis screen. Mice heterozygous for either the Insulin Receptor (IR) or the Insulin Receptor Substrate 1 (IRS-1) are treated with ENU and offspring assayed for diabetic phenotypes. 1292 F1 mice have been generated and assayed for glucose tolerance utilising an IPGTT. To date 20 F1 mice have entered inheritance testing, 4 have additionally entered genotyping, lines IGT/4 and IGT/10 being localised to chromosomes 13 and 14 respectively. Fine mapping and candidate gene analysis is currently underway for these two lines.

Additionally, histological analysis of various tissues from these four lines is currently underway; IGT/3 and IGT/6 show marked hyperinsulinaemia and a compensatory increase in islet cell mass, IGT/6 mice are also significantly heavier, initial analysis of liver sections indicates this line may additionally show steatosis and inflammation and is being investigated further as a model for Nonalcoholic Steatohepatitis (NASH), kidney sections from all lines are currently being assayed for an increase in mesangial matrix area, an indicator of diabetic nephropathy.

A sensitised ENU approach utilising existing KO strains of mice can be successfully applied to generate new polygenic mouse models of type II diabetes. New models generated to date additionally suffer from many of the diabetic complications observed in human patients and may represent more accurate models of type II diabetes.


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