GLYCOGEN-SYNTHASE - A PUTATIVE LOCUS FOR DIET-INDUCED HYPERGLYCEMIA

Inbred mouse strains fed a diabetogenic diet have different propensiti es to develop features analogous to type 2 diabetes mellitus. To defin e chromosomal locations that control these characteristics, recombinan t inbred strains from diabetes-prone C57BL/6J (B/6J) and diabetes-resi stant A/J strains were studied. Insulin levels and hyperglgcemia corre lated with two different regions of mouse chromosome 7 (two point LOD scores > 3.0). For insulin levels, 15 of 16 recombinant inbred strains were concordant with a region that contains the tubby mutation that r esults in hyperinsulinemia. For hyperglycemia, 19 of 23 strains were c oncordant with the D7Mit25 marker and 20 of 23 strains with the Gpi-1 locus on proximal mouse chromosome 7. Using more stringent criteria fo r hyperglycemia, 10 of 11 strains characterized as A/J or B/6J like we re concordant with D7Mit25. This putative susceptibility locus is cons istent with that of the glycogen synthase gene (Gys) recently suggeste d as a candidate locus by analyses of type 2 diabetes patients. Fracti onal glycogen synthase activity in isolated muscle was significantly l ower in normal B/6J diabetic-prone mice compared with normal diabetic- resistant A/J mice, a finding similar to that reported in relatives of human patients with type 2 diabetes. These data, taken together, rais e the possibility that defects in the Gys gene may in part be responsi ble for the propensity to develop type 2 diabetes.