Effects of the sulfonylureas on muscle glucose homeostasis

The sulfonylureas have pharmacologic effects both on insulin secretion by pancreatic beta cells and on responsiveness to insulin in peripheral tissues. The effects of the sulfonylureas on skeletal muscle may have a particularly significant influence on glucose homeostasis because of the important role of muscle as a peripheral site of glucose clearance. Under most physiologic conditions, the rate-limiting step for glucose utilization in muscle is its uptake across the plasma membrane; for this reason, the effects of the sulfonylureas on glucose transport have been a focus for study. In muscle tissue, the sulfonylureas appear to augment the stimulation of glucose uptake by insulin but not to alter glucose homeostasis in the absence of insulin. The mechanism of this effect, which requires several hours of exposure to a sulfonylurea, has not been defined. Although studies with cultured muscle cells have yielded inconsistent findings, recent work with the L6 rat skeletal muscle cell line demonstrated that the sulfonylureas exerted effects similar to those in muscle tissue both in time course and in requirement for co-stimulation by insulin. Mechanistic studies in L6 cells have shown that the sulfonylureas induce increased glucose transporter messenger ribonucleic acid levels and increased total cellular content of transporter proteins even in the absence of insulin, but that insulin is required for augmented glucose uptake activity. Based on these data, it has been suggested that insulin may cause the activation of transporters synthesized in response to sulfonylureas. The definition of the mechanism of this synergistic response to insulin and the sulfonylureas in L6 muscle cells may give insight into the in vivo molecular events involved in the action of the sulfonylureas in skeletal muscle.