p38 Mitogen Activated Protein Kinase Mediates Free Fatty Acid Induced Hepatic Insulin Resistance In Vivo

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2013-11

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Abstract

Elevated free fatty acids (FFA) contribute to the development of insulin resistance but the mechanisms are not completely understood. We have shown that p38 mitogen activated protein kinase (p38 MAPK) is activated in the liver by lipid infusion and we wished to determine whether it plays a causal role in hepatic insulin resistance after prolonged lipid exposure as shown in isolated hepatocytes. Intralipid and heparin (IH) infusion for 48 hours impaired insulin’s ability to suppress glucose production and tended to impair glucose utilization. Co-infusion of p38 MAPK inhibitor SB239063 with IH restored the insulin-induced suppression of glucose production but did not improve peripheral glucose utilization. IH-induced hepatic insulin resistance was accompanied by increased phosphorylated activating transcription factor 2 (ATF2), a p38 MAPK substrate and this was prevented by co-infusion of SB239063. Our results suggest that p38 MAPK activation mediates hepatic insulin resistance induced by prolonged exposure to FFA in vivo.

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hepatic insulin resistance, free fatty acids, hyperinsulinemic euglycemic clamp, p38 MAPK

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