Insulin signalling in hepatocytes of humans with type 2 diabetes: excessive production and activity of protein kinase C-? (PKC-?) and dependent processes and reversal by PKC-? inhibitors.

ABSTRACT: We examined the role of protein kinase C-? (PKC-?) in mediating alterations in the abundance of enzymes in hepatocytes of type 2 diabetic humans that contribute importantly to the development of lipid and carbohydrate abnormalities in type 2 diabetes.We examined (1) insulin signalling in isolated hepatocytes of non-diabetic and type 2 diabetic humans and (2) the effects of two newly developed small molecule PKC-? inhibitors on aberrant signalling and downstream processes.In contrast with PKC-? deficiency in diabetic muscle, which diminishes glucose transport, PKC-? in diabetic hepatocytes was overproduced and overactive, basally and after insulin treatment, and, moreover, was accompanied by increased abundance of PKC-?-dependent lipogenic, proinflammatory and gluconeogenic enzymes. Heightened PKC-? activity most likely reflected heightened activity of IRS-2-dependent phosphatidylinositol 3-kinase (PI3K), as IRS-1 levels and IRS-1/PI3K activity were markedly diminished. Importantly, insulin-stimulated PKC-? abundance and its overabundance in diabetic hepatocytes was reversed in vitro by both insulin deprivation and PKC-? inhibitors; this suggested operation of an insulin-driven, feed-forward/positive-feedback mechanism. In contrast with PKC-?, protein kinase B (Akt2) activity and activation by insulin was diminished, apparently reflecting IRS-1 deficiency. Treatment of diabetic hepatocytes with PKC-?/? inhibitors diminished abundance of lipogenic, proinflammatory and gluconeogenic enzymes.Our findings suggest that a vicious cycle of PKC-? overactivity and overproduction exists in hepatocytes of humans with type 2 diabetes and contributes importantly to maintaining overactivity of lipogenic, proinflammatory and gluconeogenic pathways, which underlies the lipid and carbohydrate abnormalities in type 2 diabetes.

SUBMITTER: Sajan MP 

PROVIDER: S-EPMC3543149 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature