PROTEIN-KINASE-C IS INCREASED IN THE LIVER OF HUMANS AND RATS WITH NONINSULIN-DEPENDENT DIABETES-MELLITUS - AN ALTERATION NOT DUE TO HYPERGLYCEMIA

We tested the hypothesis that liver protein kinase C (PKC) is increase d in non-insulin-dependent diabetes mellitus (NIDDM). To this end we e xamined the distribution of PKC isozymes in liver biopsies from obese individuals with and without NIDDM and in lean controls, PKC isozymes alpha, beta, epsilon and zeta were detected by immunoblotting in both the cytosol and membrane fractions, Isozymes gamma and delta were not detected, There was a significant increase in immunodetectable PKC-alp ha (twofold), -epsilon (threefold), and -zeta (twofold) in the membran e fraction isolated from obese subjects with NIDDM compared with the l ean controls, In obese subjects without NIDDM, the amount of membrane PKC isozymes was not different from the other two groups. We next soug ht an animal model where this observation could be studied further. Th e Zucker diabetic fatty rat offered such a model system, Immunodetecta ble membrane PKC-alpha, -beta, -epsilon, and -zeta were significantly increased when compared with both the lean and obese controls, The inc rease in immunodetectable PKC protein correlated with a 40% elevation in the activity of PKC at the membrane, Normalization of circulating g lucose in the rat model by either insulin or phlorizin treatment did n ot result in a reduction in membrane PKC isozyme protein or kinase act ivity, Further, phlorizin treatment did not improve insulin receptor a utophosphorylation nor did the treatment lower liver diacylglycerol, W e conclude that liver PKC is increased in NIDDM, a change that is not secondary to hyperglycemia. It is possible that PKC-mediated phosphory lation of some component in the insulin signaling cascade contributes to the insulin resistance observed in NIDDM.