Protein kinase C activity is acutely regulated by plasma glucose concentration in human monocytes in vivo

Activation of protein kinase C (PKC) by hyperglycemia is implicated in the pathogenesis of long-term diabetic complications. Monocyte activation and t ransformation into macrophages is a key step in the atherosclerotic process . Therefore, in this study, we sought to determine 1) the effect of hypergl ycemia on monocyte PKC activity and on the distribution of Ca2+-dependent a nd diacylglycerol-sensitive PKC isoforms; and 2) whether the effects on the se parameters are determined by hyperglycemia per se, independent of the di abetic state. The studies were performed in 19 type 2 diabetic patients and 14 control subjects. Plasma glucose concentration was higher and insulin s ensitivity lower (both P < 0.01) in diabetic patients than in control subje cts. Monocytes from diabetic patients showed similar cytosol PKC activity t o those from control subjects but higher membrane PKC activity (78 +/- 6 vs . 50 +/- 5 pmol . min(-1) . mg(-1) protein; P < 0.01). A direct correlation was observed between fasting plasma glucose and membrane PKC activity (r(2 ) = 0.4008, P = 0.0001). In contrast, a reciprocal correlation was observed between membrane PKC activity and insulin sensitivity index (r2 = 0.28, P < 0.05). Using immunoblotting analysis, we found that membrane P,, but not cw, isoform of PKC was more abundant in monocytes from diabetic patients. I n diabetic patients, when euglycemia was acutely induced, membrane PKC acti vity decreased by similar to 42% and P, isoform by similar to 15%. In two n ormal subjects in whom hyperglycemia was induced, membrane PKC increased fr om 63 and 57 to 92 and 128.6 pmol min(-1) mg(-1) protein, respectively. Thi s increase was associated with an increase in the membrane isoform beta(2); alpha isoform was unchanged. We conclude that 1) monocytes express the glu cose-sensitive beta(2) isoform of PKC; 2) the prevailing plasma glucose acu tely regulates the activity of the membrane PKC and the content of membrane PKC beta(2) isoform; and 3) this effect appears to be a direct effect of g lucose per se, since the phenomenon was observed in normal control subjects when hyperglycemia, was induced. Monocyte PKC activation may account for t he accelerated atherosclerosis of patients with type 2 diabetes.