STUDIES ON MECHANISMS OF HEPATIC INSULIN RESISTANCE IN CAFETERIA-FED RATS

Whether hyperinsulinemia causes insulin resistance or vice versa is controversial. The development of hyperinsulinemia and insulin resistance was tracked in the cafeteria-fed rat to determine which occurred first. After 3 days of cafeteria feeding the rats were obese, manifested a small but significant decrease in fasting glucose levels, and showed no change in fasting insulin levels, basal hepatic glucose production (HGP), insulin binding to hepatic membranes, and glucose utilization during a euglycemic hyperinsulinemic clamp, but the rats did demonstrate an increased glucose disappearance rate associated with an enhanced insulin response to intra-arterial glucose and hepatic insulin resistance during the clamp. After 7 days of cafeteria feeding, the results were similar except that fasting hyperglycemia and hyperinsulinemia, an enhanced basal HGP, and decreased insulin binding developed. After 6 wk of cafeteria feeding, both hepatic and peripheral insulin resistances were present. After 7 days of cafeteria feeding in rats given streptozotocin or etomoxir, an inhibitor of free fatty acid (FFA) oxidation, hepatic insulin resistance persisted despite elimination of hyperinsulinemia and reduction of FFA oxidation. These data do not support a causal role for either hyperinsulinemia or enhanced lipolysis of hypertrophied fat stores and subsequent FFA oxidation in the liver in the development of hepatic insulin resistance in this animal model of obesity.