OBESITY GENES AND DIABETES INDUCTION IN THE MOUSE

Obesity, a phenotype having high heritability in humans, constitutes t he major risk factor predisposing an individual to non-insulin-depende nt diabetes mellitus (NIDDM). However, most obese humans do not develo p NIDDM, indicating that diabetogenesis entails a complex interaction between obesity genes and other predisposing susceptibility traits. Th e possible nature of some of these background modifiers is being eluci dated by analysis of genetically obese mice. Mutations at loci on six different mouse chromosomes produce obesity, but development of insuli n-resistant diabetes requires an interaction between the obesity mutat ion and other factors in the genetic background. Analysis of the inter action between three distinct obesity genes expressed on the same gene tic background has shown that virilization of hepatic sex steroid meta bolism mediated via aberrant shifts in sex steroid sulfotransferase ac tivities is a prerequisite for diabetogenesis. The analogies between t he development of a hyperandrogenized tissue state in obese mice with obesity-diabetes syndromes in humans are discussed.