PKC-theta Knockout Mice Are Protected From Fat-Induced Insulin Resistance

J Clin Invest. 2004 Sep;114(6):823-7. doi: 10.1172/JCI22230.

Abstract

Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-theta (PKC-theta), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-theta are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-theta KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. In contrast, PKC-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-theta is a potential therapeutic target for the treatment of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue / physiology*
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / therapy
  • Fatty Acids, Nonesterified / blood
  • Infusions, Intravenous
  • Insulin / blood
  • Insulin / physiology
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / genetics*
  • Isoenzymes / deficiency*
  • Isoenzymes / genetics*
  • Isoenzymes / therapeutic use
  • Lipids / administration & dosage
  • Lipids / pharmacology
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / physiology
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase C / deficiency*
  • Protein Kinase C / genetics*
  • Protein Kinase C / therapeutic use
  • Protein Kinase C-theta
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Isoenzymes
  • Lipids
  • Phosphoproteins
  • PRKCQ protein, human
  • Protein Kinase C
  • Protein Kinase C-theta