PKC-theta knockout mice are protected from fat-induced insulin resistance.

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.

• Authors: Jason K Kim, Jonathan J Fillmore, Mary Jean Sunshine, Bjoern Albrecht, Takamasa Higashimori, Dong-Wook Kim, Zhen-Xiang Liu, Timothy J Soos, Gary W Cline, William R O'Brien, Dan R Littman, Gerald I Shulman
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 6 Pg. 823-7 (Sep 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15372106 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

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