Apocynin, an NADPH Oxidase Inhibitor, Prevents Hepatic and Peripheral Insulin Resistance Induced by Short-Term Lipid Infusion

Free Fatty Acid (FFA)-induced oxidative stress causes hepatic and peripheral insulin resistance. Antioxidants can alleviate this insulin resistance through reactive oxygen species (ROS)-scavenging activity. The sources of ROS in in vivo FFA-induced insulin resistance are, however, unclear. We used apocynin, an inhibitor of NADPH oxidase, to test whether NADPH oxidase-derived ROS are involved in insulin resistance in a model of short-term (7h) lipid infusion in rodents. Chronically cannulated Wistar rats (250-300g, n=4-8/group), after an overnight fast, were intravenously infused with saline or Intralipid plus heparin (IH, 20% Intralipid + 20 U/ml heparin, 5.5^l/min) for 7h to increase plasma FFA by approximately twofold, with or without co-infusion of apocynin (0.5μmol-kg^-1min^-1). During the last 2h, a hyperinsulinemic (5 mU-kg^-1min^-1) euglycemic clamp with concomitant tritiated glucose methodology was performed to assess hepatic and peripheral insulin sensitivity. As expected, IH diminished whole body and peripheral insulin sensitivity, as measured by glucose infusion rate and glucose utilization, and decreased insulin-mediated suppression of endogenous glucose production (p<0.05). Apocynin reversed the IH-induced decrease in insulin-induced suppression of endogenous glucose production (% change from basal, IH: 2.8±10.8%; IH+Apocynin: -31.8±10.9%; p<0.05 vs IH) to levels that did not differ from controls (Saline: -31.2±3.9%). Co-infusion of IH and apocynin also restored whole body insulin sensitivity (p<0.05 vs IH), as indicated by the rate of glucose infusion during the clamp, and peripheral insulin sensitivity (Glucose utilization in μmol-kg">¹min">¹, Saline: 201±13, IH: 133±8, IH+Apocynin: 173±13, p<0.05 vs IH). Thus, 1) NADPH oxidase is causally implicated in hepatic and peripheral insulin resistance induced by short-term elevation of circulating FFA and 2) NADPH oxidase inhibitors may be of therapeutic interest to restore insulin sensitivity in conditions of high FFA flux, such as obesity-associated type 2 diabetes.