PKC-θ 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- (PKC-), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC- 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- KO mice following saline infusion. A 5-hour lipid infusion decreased insulinstimulated 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- inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC- is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC- is a potential therapeutic target for the treatment of type 2 diabetes. Nonstandard abbreviations used: 2-[ 14 C]DG, 2-deoxy-D-[1-14 C]glucose; 2-[ 14 C]DG-6-P, 2-[ 14 C]DG-6-phosphate; dpm, disintegrations per minute; HGP, hepatic glucose production; IRS-1, insulin receptor substrate-1; PKC-, protein kinase C-.