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

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

Jason K Kim  1 , 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
Affiliations

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

Jason K Kim et al. J Clin Invest. 2004 Sep.

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.

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Figures

Figure 1
Figure 1
Tissue-specific insulin action in WT (white bars) and PKC-θ KO (black bars) mice with saline or lipid infusion. (A) Steady-state glucose infusion rate, obtained from averaged rates of 90_120 minutes of hyperinsulinemic-euglycemic clamps. (B) Insulin-mediated percentage suppression of basal hepatic glucose production. (C) Insulin-stimulated whole-body glucose turnover in vivo. (D) Insulin-stimulated skeletal muscle (gastrocnemius) glucose uptake in vivo. Values are mean ± SE for five to seven experiments. *P < 0.05 versus WT mice (control).
Figure 2
Figure 2
Insulin-stimulated whole-body and skeletal muscle (gastrocnemius) glucose metabolic flux in WT (white bars) and PKC-θ KO (black bars) mice with saline or lipid infusion. (A) Insulin-stimulated whole-body glycolysis in vivo. (B) Insulin-stimulated whole-body glycogen plus lipid synthesis in vivo. (C) Insulin-stimulated skeletal muscle glycolysis in vivo. (D) Insulin-stimulated skeletal muscle glycogen synthesis in vivo. Values are means ± SE for five to seven experiments. *P < 0.05 versus WT mice (control).
Figure 3
Figure 3
Skeletal muscle (gastrocnemius) insulin signaling and glucose uptake in brown adipose tissue in WT (white bars) and PKC-θ KO (black bars) mice with saline or lipid infusion. (A) Insulin-stimulated glucose uptake in brown adipose tissue. (B) Insulin-stimulated tyrosine phosphorylation of IRS-1. (C) Insulin-stimulated IRS-1_associated PI3K activity. (D) Insulin-stimulated tyrosine phosphorylation of insulin receptor (IR). Values are means ± SE for five to seven experiments. *P < 0.05 versus WT mice (control).
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