Diet-Induced Muscle Insulin Resistance in Rats Is Ameliorated by Acute Dietary Lipid Withdrawal or a Single Bout of Exercise: Parallel Relationship Between Insulin Stimulation of Glucose Uptake and Suppression of Long-Chain Fatty Acyl-CoA

Abstract

Chronic high-fat feeding in rats induces profound whole-body insulin resistance, mainly due to effects in oxidative skeletal muscle. The mechanisms of this reaction remain unclear, but local lipid availability has been implicated. The aim of this study was to examine the influence of three short-term physiological manipulations intended to lower muscle lipid availability on insulin sensitivity in high-fat-fed rats. Adult male Wistar rats fed a high-fat diet for 3 weeks were divided into four groups the day before the study: one group was fed the normal daily high-fat meal (FM); another group was fed an isocaloric low-fat high-glucose meal (GM); a third group was fasted overnight (NM); and a fourth group underwent a single bout of exercise (2-h swim), then were fed the normal high-fat meal (EX). In vivo insulin action was assessed using the hyperinsulinemic glucose clamp (plasma insulin 745 pmol/l, glucose 7.2 mmol/l). Prior exercise, a single low-fat meal, or fasting all significantly increased insulin-stimulated glucose utilization, estimated at either the whole-body level (P < 0.01 vs. FM) or in red quadriceps muscle (EX 18.2, GM 28.1, and NM 19.3 vs. FM 12.6 +/- 1.1 micromol x 100 g(-1) x min(-1); P < 0.05), as well as increased insulin suppressibility of muscle total long-chain fatty acyl-CoA (LC-CoA), the metabolically available form of fatty acid (EX 24.0, GM 15.5, and NM 30.6 vs. FM 45.4 nmol/g; P < 0.05). There was a strong inverse correlation between glucose uptake and LC-CoA in red quadriceps during the clamp (r = -0.7, P = 0.001). Muscle triglyceride was significantly reduced by short-term dietary lipid withdrawal (GM -22 and NM -24% vs. FM; P < 0.01), but not prior exercise. We concluded that muscle insulin resistance induced by high-fat feeding is readily ameliorated by three independent, short-term physiological manipulations. The data suggest that insulin resistance is an important factor in the elevated muscle lipid availability induced by chronic high-fat feeding.

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

“…High IMCL is not only associated with insulin resistance in obese and type 2 diabetic patients but also with lower insulin-stimulated glucose disposal rate in persons at risk like lean offspring of two parents with type 2 diabetes, and in insulin resistance induced by lipid infusion (reviewed in Kelley et al 28 ). A similar association was observed in rodents using different approaches to alter muscle lipid content: in transgenic mice overexpressing lipoprotein lipase in skeletal muscle 29 in rats fed a high fat diet 30 in rats given etomoxir, an inhibitor of CPT-1, the rate limiting step in fatty acid oxidation. 31 In contrast, prevention of muscle lipid accumulation is associated with improved insulin sensitivity.…”

“…32 Similarly, dietary fat withdrawal and physical exercise in rodents reduced both intracellular lipids and insulin resistance. 30 A reduction of lipid accumulation in skeletal muscle may be one of the insulin-sensitizing mechanisms of thiazolidinediones. 33 Excessive accumulation of intramuscular triglycerides may result from increased uptake of circulating FFA, and/or reduced oxidation.…”

Inhibition of adipose tissue lipolysis increases intramuscular lipid use in type 2 diabetic patients

“…6 Changes in whole-body insulin sensitivity (as determined by plasma glucose disappearance rate (μmol kg −1 min −1 ) divided by the plasma glucose (mmol/l) and the plasma insulin concentration (mU/l) at rest (a), during exercise (b) and during post-exercise recovery (c) in the CON (white bars) and LFA (black bars) trial. Data represent means±SEM; * p<0.05 for difference between trials improve insulin sensitivity, like dietary lipid withdrawal [2], acute exercise [2,25] and the use of thiazolidinediones [46] have all been associated with a reduction in skeletal muscle lipid content. Recently, we as well as others [31], have shown that pharmacological inhibition of adipose tissue lipolysis can prevent the downregulation of IMTG use with time during prolonged exercise, which was shown to be associated with the concomitant increase in plasma NEFA concentrations.…”

“…Numerous studies have reported the association between elevated plasma NEFA concentrations, intramyocellular triacylglycerol (IMTG, often also abbreviated to IMCL) accumulation and the development of insulin resistance and/or type 2 diabetes [1][2][3][4][5][6][7]. The Randle (glucose-fatty acid) cycle has often been used to explain the mechanism behind skeletal muscle insulin resistance induced by fatty acid (FA) [8].…”

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin

“…While there is some evidence that PPARγ plays a functional role in skeletal muscle [4], its expression levels in muscle and liver are extremely low compared with adipocytes. Secondly, TZDs lower circulating levels of lipids and lipid accumulation in non-adipose tissues including skeletal and cardiac muscle, liver and pancreatic islets [2,5,6,7,8,9]. However, alternative mechanisms have been proposed for the metabolic effects of TZDs, including a role for altered adipokines, particularly adiponectin [10,11].…”