Fuel selection in human skeletal muscle in insulin resistance: a reexamination.

Abstract

For many years, the Randle glucose fatty acid cycle has been invoked to explain insulin resistance in skeletal muscle of patients with type 2 diabetes or obesity. Increased fat oxidation was hypothesized to reduce glucose metabolism. The results of a number of investigations have shown that artificially increasing fat oxidation by provision of excess lipid does decrease glucose oxidation in the whole body. However, results obtained with rodent or human systems that more directly examined muscle fuel selection have found that skeletal muscle in insulin resistance is accompanied by increased, rather than decreased, muscle glucose oxidation under basal conditions and decreased glucose oxidation under insulin-stimulated circumstances, producing a state of "metabolic inflexibility." Such a situation could contribute to the accumulation of triglyceride within the myocyte, as has been observed in insulin resistance. Recent knowledge of insulin receptor signaling indicates that the accumulation of lipid products in muscle can interfere with insulin signaling and produce insulin resistance. Therefore, although the Randle cycle is a valid physiological principle, it may not explain insulin resistance in skeletal muscle. Diabetes 49:677-683, 2000 I n 1963, Sir Philip Randle outlined a principle that spawned an enormous amount of research over the following 4 decades. He performed a series of experiments that were designed to test the supposition that cardiac and skeletal muscle possessed mechanisms that allowed these tissues to shift readily back and forth between carbohydrate and fat as oxidative energy sources, depending primarily on the availability of free fatty acids (FFAs). In particular, these experiments eventually focused on the biochemical mechanisms that are involved in the switch from carbohydrate to fat oxidation (1-3). The main features of the model that was developed were that increased fat oxidation in muscle would inhibit both pyruvate dehydrogenase (PDH) and phosphofructokinase by accumulation of acetyl CoA and citrate, respectively. These roadblocks placed in the glycolytic pathway would lead to increased glucose 6-phosphate concentration, inhibiting hexokinase and resulting in reduced glucose uptake and oxidation. This homeostatic mechanism became known as the glucose fatty acid cycle or the Randle cycle (Fig. 1).Insulin-deficient rat models of diabetes, as well as people with type 1 diabetes, exhibit elevated rates of lipolysis, increased plasma FFAs and triglyceride concentrations, elevated blood ketone bodies, and decreased respiratory quotients (RQs). Thus, it was hypothesized that the glucose fatty acid cycle operated under these conditions to inhibit glucose metabolism and contribute to hyperglycemia (2). Later, as the extent of insulin resistance in obese and type 2 diabetic patients was discerned, investigators took note of the association between insulin resistance and increased plasma nonesterified fatty acids (4). It has been postulated that the Randle cycle might be responsible for insulin r...

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Testosterone therapy increased muscle mass and lipid oxidation in aging men

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“…In insulin-resistant conditions such as obesity and type 2 diabetes, measures of the respiratory quotient (RQ) across the tissue bed of the leg have demonstrated an increased glucose oxidation, a reduced lipid oxidation during fasting conditions, and a reduced insulin effect on the stimulation of glucose oxidation and on the suppression of lipid oxidation (Kelley and Mandarino 2000). The impaired ability to switch between lipid oxidation and glucose oxidation in response to insulin and fasting has been termed "metabolic inflexibility" (Kelley and Mandarino 2000).…”

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