Skeletal Muscle Insulin Resistance in Rats Fed a High Fat Diet and Treated with Acipimox

Abstract

The mechanism by which a high fat diet causes insulin resistance is not yet understood. It has been proposed by some investigators that elevations in the circulating levels of free fatty acids are responsible for the development of insulin resistance. PURPOSE: The purpose of this study was to determine if the skeletal muscle insulin resistance induced by a high fat diet would persist in the context of a weeklong treatment to reduce plasma FFAs with acipimox. METHODS: Rats were fed standard chow or a high fat diet in which 50% of calories come from fat (lard and corn oil) for a period of 4 weeks. During the 5th week, a subset of the rats fed a high fat diet were given 2 doses (100mg/kg) per day of Acipimox, which inhibits lypolysis and reduces plasma FFA concentrations. Glucose uptake, Glucose tolerance, fat pad weights, and plasma FFA were measured to determine the metabolic profile and insulin resistance in these animals. RESULTS: the concentration of plasma FFA's were reduced in response to Acipimox treatment in high fat fed rats (0.75±0.08 and 0.38±0.07 mM in High fat fed and High fat+acipimox, respectively). Whole animal glucose tolerance was improved with acipimox treatment, and was not significantly different from that of the chow animals. Skeletal muscle insulin resistance was evident in the animals fed a high fat diet alone as well as rats that received acipimox. The insulin stimulated 2-Deoxyglucose uptake in the epitrochlearis muscle was 1.17±0.11, 0.82±0.11, and 0.68±0.10 μmol 2DG/ml/20min in chow, HF and Acip+HF groups respectively. High fat feeding caused a significant increase in total abdominal fat pad weights and acipimox treatment caused a further increase in fat pad mass (7.01±0.32, 12.80±0.71 and 15.75±0.43 gms fat in Chow, High Fat and High Fat+ acipimox, respectively). CONCLUSION: Lowering of plasma FFA with Acipimox improved overall insulin action, yet did not improve insulin resistance measured in epitrochlearis muscle.