ALTERATIONS IN INSULIN-INDUCED POSTRECEPTOR SIGNALING IN ADIPOCYTES OF THE OTSUKA LONG-EVANS TOKUSHIMA FATTY RAT STRAIN

The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a new spontaneous non-insulin-dependent diabetes mellitus (NIDDM) model rai strain deve loped in Tokushima, Japan. After 18 weeks of age, decreases of 45% and 40% respectively in insulin-and phorbol ester-stimulated [H-3]2-deoxy glucose (DOG) uptake were observed, compared with those in Long-Evans Tokushima (LETO) rats (control). Insulin-specific binding and 95 kDa a utophosphorylation of insulin receptor in OLETF rats were not differen t from those in LETO rats. Insulin-induced diacylglycerol (DG) product ion and Mono Q column-purified protein kinase C (PKC) translocation in adipocytes of OLETF rats were decreased compared with those of LETO r ats. Insulin-induced PKC beta translocation from cytosol to membrane w as also decreased in adipocytes of OLETF rats. Increases of the PKC be ta I, beta II, epsilon and zeta isoforms in membranes of OLETF rats we re markedly smaller than those of LETO rats. Analysis of mRNA levels o f PKC isoforms in adipocytes of OLETF rats showed decreases of basal l evel and insulin-induced delayed responses of PKC beta I, beta II, eps ilon and zeta mRNA in OLETF rats. On the other hand, insulin- or phorb ol ester-induced phosphatidylinositol 3-kinase (PI 3-kinase) activatio n was decreased in adipocytes of OLETF rats compared with those of LET O rats. These results suggest that insulin resistance in OLETF rats, a spontaneous NIDDM model rat, may be associated with deterioration of insulin-induced DG-PKC signaling and subsequent decrease in PI 3-kinas e activation.