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

Diabetologia. 2012 May;55(5):1446-57. doi: 10.1007/s00125-012-2477-5. Epub 2012 Feb 15.


Aims/hypothesis: We examined the role of protein kinase C-ι (PKC-ι) 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.

Methods: 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-ι inhibitors on aberrant signalling and downstream processes.

Results: In contrast with PKC-ι deficiency in diabetic muscle, which diminishes glucose transport, PKC-ι in diabetic hepatocytes was overproduced and overactive, basally and after insulin treatment, and, moreover, was accompanied by increased abundance of PKC-ι-dependent lipogenic, proinflammatory and gluconeogenic enzymes. Heightened PKC-ι 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-ι abundance and its overabundance in diabetic hepatocytes was reversed in vitro by both insulin deprivation and PKC-ι inhibitors; this suggested operation of an insulin-driven, feed-forward/positive-feedback mechanism. In contrast with PKC-ι, protein kinase B (Akt2) activity and activation by insulin was diminished, apparently reflecting IRS-1 deficiency. Treatment of diabetic hepatocytes with PKC-ι/λ inhibitors diminished abundance of lipogenic, proinflammatory and gluconeogenic enzymes.

Conclusions/interpretation: Our findings suggest that a vicious cycle of PKC-ι 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins / metabolism
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Male
  • Middle Aged
  • Phosphatidylinositol 3-Kinase / metabolism
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase C / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Hypoglycemic Agents
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Isoenzymes
  • Protein Kinase Inhibitors
  • Phosphatidylinositol 3-Kinase
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • protein kinase C lambda