To maintain whole-body glucose homeostasis, coordination of three different metabolic events is required: adequate secretion of insulin by pancreatic b-cells, suppression of hepatic glucose production, and stimulation of glucose uptake by insulin-sensitive tissues, primarily muscle. During an acute bout of exercise, the increased need for metabolic fuel is met by increases in both carbohydrate and fat utilization in the skeletal muscle. Glucose is taken up from blood into the working skeletal muscles. In people who do not have diabetes, unless the exercise is of extremely long duration, blood glucose concentrations do not decrease appreciably. This is because glucose output by the liver is precisely matched to glucose uptake in the muscle and because insulin secretion by the b-cells of the pancreas is reduced. In contrast, in people with type 2 diabetes who have moderate hyperglycemia, glucose concentrations can be decreased with moderate-intensity exercise, an important health benefit of exercise.
Skeletal muscle is the major organ in the body responsible for glucose disposal and consequently is of prime importance in metabolic disorders such as IGT and type 2 diabetes. Three potential rate-controlling steps and molecules for insulin-stimulated muscle glucose metabolism (i.e., synthesis of glycogen from glucose) have been identified: glucose transporter 4 (GLUT4), hexokinase, and glycogen synthase. Each of these steps is defective in people with type 2 diabetes.
The major physiological stimulators of muscle glucose uptake are exercise and insulin. These stimuli enhance glucose transport into the muscle cells, where it can be used for adenosine triphosphate (ATP) production or stored in the form of glycogen. Glucose transport in skeletal muscle occurs primarily by facilitated diffusion, using glucose transport carrier proteins. In mammalian tissues, glucose transporters constitute a family of structurally related proteins (isoforms) with tissue-specific expression patterns. There are 12 different glucose transporter isoforms, GLUT4 being the most abundant isoform present in skeletal muscle. Glucose transport is the rate-limiting step in muscle glucose utilization. In response to exercise or insulin, GLUT4 moves from an intracellular location to the plasma membranes and tubules (translocation). The amount of GLUT4 in the plasma membrane is tightly regulated by exercise and insulin, exerting a fine control on glucose disposal and metabolism within the muscle.