ALTERED REGULATION OF INSULIN SIGNALING COMPONENTS IN ADIPOCYTES OF INSULIN-RESISTANT TYPE-II DIABETIC GOTO-KAKIZAKI RATS

We investigated the cellular mechanism(s) of insulin resistance associ ated with non-insulin-dependent diabetes mellitus (NIDDM) using adipoc ytes isolated from non-obese, insulin-resistant type II diabetic Goto- Kakizaki (GK) rats, a well-known genetic rat model for type II diabeti c humans. In adipocytes isolated from control rats, insulin (5 nmol/L) stimulated particulate serine/threonine protein phosphatase-l (PP-1) activity (56% increase over the basal value after 5 minutes). In contr ast, adipocytes from diabetic GK rats exhibited a 32% decrease in basa l (P < .05) and a 65% decrease in insulin-stimulated PP-1 activity com pared with values in control Wistar rats, Conversely, cytosolic PP-2A activity was elevated in diabetic GK rats in the basal state (twofold increase v controls, P < .05). Insulin treatment resulted in a 50% to 60% inhibition in PP-2A activity in control rats, but failed to inhibi t PP-2A activity in diabetic GK rat adipocytes. The defects in PP-1/PP -2A activation/inactivation were accompanied by inhibition of insulin' s effect on mitogen-activated protein kinase (MAPK) activation. In add ition, insulin-stimulated tyrosine phosphorylation of insulin receptor (IR) substrate-1 (IRS-1) was decreased more than 90% compared with co ntrol values, while a twofold increase in basal IRS-1 phosphorylation status was observed in diabetic GK rats. The abnormalities in IRS-1 ph osphorylation were accompanied by a severe impairment of insulin-media ted targeting of the Grb2/Sos complex to the plasma membrane. We concl ude that (1) a rapid activation of PP-1 along with concomitant inhibit ion of cytosolic PP-2A may be important in the mechanism of insulin ac tion in a normal cell, and (2) the resistance to insulin in terms of g lucose uptake and glycogen synthesis observed in diabetic GK rats is p artly due to defective regulation of PP-1, PP-2A, and MAPK caused by m ultiple defects in the upstream insulin signaling components (IRS-l/ph osphatidylinositol-3-kinase [PI3-kinase] and Grb2/Sos) that participat e in insulin-mediated activation of PP-1 and inactivation of PP-2A. Co pyright (C) 1998 by W.B. Saunders Company.