Identification of interactive loci linked to insulin and leptin in mice with genetic insulin resistance.
Mice double heterozygous (DH) for deletion of insulin receptor and insulin receptor substrate-1 are lean, insulin resistant, and have a phenotype that strongly depends on the genetic background of the mouse. On the C57BL/6 (B6) background, DH mice develop marked hyperinsulinemia and diabetes, whereas on the 129S6 background, DH mice exhibit only mild elevations of insulin and remain free of diabetes. F2 male mice created by an intercross between these two strains exhibit a 60% incidence of diabetes and a bell-shaped distribution of insulin levels as related to glucose, reminiscent of that in humans with type 2 diabetes. These mice also exhibit a wide range of leptin levels as related to body weight. A genome-wide scan of F2 mice reveals a quantitative trait locus (QTL) related to hyperinsulinemia on chromosome 14 (D14Mit55) with a peak logarithm of odds (LOD) score of 5.6, accounting for up to 69% of this trait. A QTL with a LOD score of 3.7 related to hyperleptinemia is present on chromosome 7 at D12Mit38 (a marker previously assigned to chromosome 12) in the area of the uncoupling protein 2/3 gene cluster. This locus also interacts synergistically with D14Mit55 in development of hyperinsulinemia and with a QTL on chromosome 12 (D12Mit231) related to hyperglycemia. These data demonstrate how multiple genetic modifiers can interact and influence the development of diabetes and the phenotype of animals with genetically programmed insulin resistance and provide evidence as to the location and nature of these genes.
Almind
Katrine
K
Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA. katrine.almind@joslin.harvard.edu
Kulkarni
Rohit N
RN
Lannon
Scott M
SM
Kahn
C Ronald
CR
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics; D007328:Insulin / Q000235:genetics*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics*; D054411:Receptors, Leptin; D013045:Species Specificity
D001786:Blood Glucose; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D020738:Leptin; D010750:Phosphoproteins; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D011972:Receptor, Insulin