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- Title
PKC-theta knockout mice are protected from fat-induced insulin resistance.
- Authors
Kim, Jason K; Fillmore, Jonathan J; Sunshine, Mary Jean; Albrecht, Bjoern; Higashimori, Takamasa; Kim, Dong-Wook; Liu, Zhen-Xiang; Soos, Timothy J; Cline, Gary W; O'Brien, William R; Littman, Dan R; Shulman, Gerald I
- 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
The Journal of clinical investigation, 2004, Vol 114, Issue 6, p823
- ISSN
0021-9738
- Publication type
Journal Article
- DOI
10.1172/JCI22230