The effect of N-acetylcysteine on three in vivo models of insulin resistance

Insulin resistance (IR) is present in numerous metabolic disorders including Type 2 diabetes. Hyperglycemia, hexosamine biosynthetic pathway upregulation, and elevated plasma free fatty acids (FFAs), contribute to worsening IR. The contribution of oxidative stress (OXS) is unclear. Glucose utilization (Rd) and appearance (Ra) were calculated during euglycemic, hyperinsulinemic clamp studies in rats. Infusion of glucose, glucosamine, or Intralipid for 5–7 hours resulted in significant reduction in Rd that was prevented by coinfusion of N-Acetylcysteine (NAC), an antioxidant. Intralipidinduced increase of Ra was prevented by NAC coinfusion. NAC prevented hyperglycemia-, but not glucosamine-induced increase of muscle protein carbonyls (index of OXS). Hyperglycemia may have increased UDP-N-acetyl-hexosamines, but did not affect membrane content of novel and atypical PKCs in muscle. These data confirm a role for hyperglycemia, hexosamine biosynthetic pathway upregulation, and increased FFAs in IR. Furthermore, they suggest that OXS is a common mediator in all three models of IR.