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Am J Physiol Endocrinol Metab 282: E386-E394, 2002; doi:10.1152/ajpendo.00087.2001
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Vol. 282, Issue 2, E386-E394, February 2002

Inducible nitric oxide synthase plays a role in LPS-induced hyperglycemia and insulin resistance

Hiroki Sugita1, Masao Kaneki1, Eriko Tokunaga1, Michiko Sugita1, Chieko Koike2, Shingo Yasuhara1, Ronald G. Tompkins3, and J. A. Jeevendra Martyn1

Departments of 1 Anesthesia and Critical Care and 3 Surgery, Harvard Medical School, and Anesthesia and Surgical Services, Massachusetts General Hospital and Shriners Hospital for Children, Boston, Massachusetts 02114; and 2 Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The molecular mechanisms underlying endotoxin-induced insulin resistance remain unclear. Endotoxin or lipopolysaccharide (LPS) injection is a potent stimulator of inducible nitric oxide synthase (iNOS). This study in rats, using the specific iNOS inhibitor aminoguanidine, investigated the role of iNOS in endotoxin-induced hyperglycemia and insulin resistance. LPS injection led to hyperglycemia, insulin resistance, and increased iNOS protein expression and activity. Aminoguanidine prevented LPS-induced hyperglycemia without affecting insulin levels or iNOS expression. Aminoguanidine attenuated the LPS-induced insulin resistance, reflected by the requirement for a higher glucose infusion rate to maintain euglycemia during a hyperinsulinemic clamp study. Aminoguanidine completely blocked the LPS-elevated hepatic glucose output and also inhibited LPS-induced increases in hepatic glycogen phosphorylase activities and phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression, key enzymes for glycogenolysis and gluconeogenesis, respectively. Thus, these data demonstrate an important role for iNOS in LPS-induced insulin resistance, evidenced by the attenuation of LPS-induced hyperglycemia and reversal of increased hepatic glucose output by aminoguanidine. The protective effect of aminoguanidine on insulin resistance is probably by attenuation of hepatic glucose output via its inhibition of key enzymes for glycogenolysis and gluconeogenesis, including glycogen phosphorylase and PEPCK.

endotoxin; hepatic glucose output; euglycemic hyperinsulinemic clamp; aminoguanidine; glycogen phosphorylase; phosphoenolpyruvate carboxykinase


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