Insulin Resistance and Type 2 Diabetes as Microdomain Disease: Implication of Ganglioside GM3

Abstract

Caveolae are a subset of membrane microdomains (lipid raft) particularly abundant in adipocytes. Critical dependence of the insulin metabolic signal transduction on caveolae/microdomains in adipocytes has been demonstrated. These microdomains can be biochemically isolated with their detergent insolubility and were designated as detergent resistant microdomains (DRM). Gangliosides are known as structurally and functionally important components in microdomains. We demonstrated that increased GM3 expression was accompanied in the state of insulin resistance in mouse 3T3-L1 adipocytes induced by TNFα and in the adipose tissues of obese/diabetic rodent models such as Zucker fa/fa rats and ob/ob mice (Tagami et al. 2002). We examined the effect of TNFα on the composition and function of DRM in adipocytes and demonstrated that increased GM3 levels result in the elimination of insulin receptor (IR) from the DRM while caveolin and flotillin remain in the DRM, leading to the inhibition of insulin’s metabolic signaling (Kabayama et al. 2005). These findings are further supported by the report that mice lacking GM3 synthase exhibit enhanced insulin signaling (Yamashita et al. 2003). Thus, we present a new pathological feature of insulin resistance in adipocytes induced by TNFα.