THE ROLE OF SKELETAL MUSCLE IN THE METABOLIC SYNDROME

David E. Kelley, Obesity and Nutrition Research Centre, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Skeletal muscle has a complex network of substrate transport and trapping mechanisms for both fatty acids and glucose, consistent with the role of this tissue as a major site for substrate utilization. With respect to glucose metabolism, skeletal muscle accounts for the majority of insulin-stimulated glucose utilization and is the major site of insulin resistance in obesity and type 2 diabetes mellitus. Skeletal muscle insulin resistance in obesity and type 2 diabetes mellitus entails perturbations not only of glucose but also in fatty acid metabolism. In metabolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels and to effectively transition between these fuels in the transitions between fasting and fed conditions. We will review recent findings that indicate that in obesity, skeletal muscle manifests a loss of the capacity for transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle, as well as differences in fuel partitioning, are key pathophysiological characteristics that contribute to an altered composition of muscle in obesity and to the insulin resistance of muscle. Another concept that will be discussed is whether insulin resistance within skeletal muscle arises as a “protective” response of this tissue - limiting or curtailing additional uptake of substrates as a reaction to expanded intra-cellular fuel reserves. Starting with the concept that muscle lipid stores are increased in obesity, we will examine the mechanisms leading to this, and will examine the concept that defects in glucose metabolism, and even defects in the formation of glycogen, are related to impaired mitochondrial functional capacity and to a relative surplus of stored glycogen.