Tissue- and isoform-specific effects of aging in rats on protein kinase C in insulin-sensitive tissues

The mechanisms responsible for the age-related decline in insulin sensitivi ty have not been clearly identified, but activation of the diacylglycerol/p rotein kinase C (PKC) signalling pathway (often confined to individual isof orms of PKC) has recently been implicated in the pathogenesis of other insu lin-resistant states in both humans and animal models. Fasting serum glucos e, insulin and triacylglycerol (triglyceride) concentrations, and results o f oral glucose tolerance tests, were compared in groups of 6-week-old (n = 8) and 6-month-old (n = 8) Sprague-Dawley rats. Insulin-responsive tissues (liver, soleus muscle and epididymal fat pad) were collected to com pare le vels of diacylglycerol, PKC enzyme activity and protei n expression of indi vidual PKC isoforms in cytosol and membrane fractions. The older group were heavier (556 +/- 14 g, compared with 188 +/- 7 g) and relatively insulin-r esistant and hyperinsulinaemic (477 +/- 73 pM compared with 293 +/- 51 pM; P < 0.05) compared with young rats; they also had greater areas under the s erum glucose (old, 20.3 +/- 1.1; young, 17.3 +/- 0.7 mmol.h(-1).l(-1)) and insulin (old, 1254 +/- 76; young, 721 +/- 113 mmol.h(-1).l(-1)) profiles fo llowing an oral glucose tolerance test, and significantly higher fasting tr iacylglycerol levels (old, 1.24 +/- 0.06 mM; young, 0.92 +/- 0.07 mM; P < 0 .01). There were no age-related differences in diacylglycerol levels or PKC activity in muscle and liver, but membrane-associated PKC activity was 2.5 -fold higher in the adipose tissue of older rats (101 +/- 19 compared with 40 +/- 5 pmol.min(-1).mg(-1) protein; P < 0.05) due to increased translocat ion of PKC-beta(I), -beta(II) and -epsilon. Thus insulin resistance due to normal aging is associated with tissue- and isoform-specific changes in dia cylglycerol/PKC signalling. In contrast with diabetes and dietary-induced i nsulin resistance, there were no changes in diacylglycerol/PKC signalling i n skeletal muscle and liver, but isoform-specific translocation and higher PKC activity in adipose tissue may blunt the insulin-mediated inhibition of lipolysis and contribute to the increased triacylglycerol levels observed in older animals.