Impaired translocation of protein kinase C activity in human non-insulin-dependent diabetes mellitus.
Calcium- and phospholipid-dependent protein kinase (protein kinase C; PKC) may be an important mediator in transduction of some of the cellular actions of insulin. We studied PKC activity in freshly isolated circulating mononuclear cells obtained from healthy subjects and patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM). The kinase activity was measured using a specific nonapeptide substrate, Ala-Ala-Ala-Ser-Phe-Lys-Ala-Lys-Lys-amide. There was negligible calcium- and phospholipid-independent kinase activity in cytosolic and particulate fractions of cells from both control and diabetic subjects. Total (cytosolic and particulate) PKC activity of mononuclear cells from poorly controlled diabetic patients was significantly reduced compared with controls; this reduction was mainly due to a decrease in the cytosolic kinase activity. Tumor-promoting phorbol ester (TPA, 0.1 mumol/L) induced translocation of PKC activity in control cells; in contrast, this subcellular redistribution was not observed in cells from a majority of poorly controlled diabetic subjects. Increased calcium influx into the cells caused by the calcium ionophore A23187-triggered translocation of PKC activity in control cells, while it was ineffective in cells from poorly controlled diabetic patients. Cells from well-controlled diabetic patients demonstrated TPA-induced translocation of the PKC activity approaching that of control cells. The total PKC activity in cells from patients with good glycemic control was normal. Impaired activation of PKC is thus associated with the insulin resistance found in patients with poorly controlled NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Nagy
K
K
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI.
Levy
J
J
Grunberger
G
G
D001786:Blood Glucose / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009000:Monocytes / Q000378:metabolism; D011493:Protein Kinase C / Q000097:blood*; D012016:Reference Values; D013347:Subcellular Fractions / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D001786:Blood Glucose; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium