PKC-theta knockout mice are protected from fat-induced insulin resistance. Journal   The Journal of clinical investigation. Citation   J Clin Invest. 114(6):823-7 Publication date   2004 Sep Authors   Kim JK Fillmore JJ Sunshine MJ Albrecht B Higashimori T Kim DW Liu ZX Soos TJ Cline GW O'Brien WR Littman DR Shulman GI Investigators   Jason K. Kim Grant agencies   National Institute of Diabetes and Digestive and Kidney Diseases Grants   NIDDK P30 DK-45735 NIDDK R01 DK-40936 NIDDK U24 DK-59635 MeSH headings   Adipose Tissue Insulin Resistance Isoenzymes Protein Kinase C MeSH qualifiers   physiology genetics deficiency 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.