Regulation of metabolic effects in L6 muscle cells by sulfonylureas and the protein tyrosine phosphatase inhibitors vanadate and pervanadate

grantor: University of TorontoNon-insulin-dependent or Type II diabetes mellitus (NIDDM) is a disease characterized by insulin deficiency and insulin resistance. Treatment is directed at improving either one or both of these abnormalities. The most commonly used pharmacological agents to treat NIDDM are the sulfonylurea drugs. A controversial and unanswered question about sulfonylureas is whether they possess any direct actions on peripheral insulin target tissues. The effects of gliclazide and glyburide on glucose uptake in L6 skeletal muscle cells, a model of a major insulin target tissue, were investigated. These studies demonstrate that gliclazide and glyburide similarly increase glucose transport into L6 cells which is associated with an increase in total cellular and plasma membrane GLUT1 glucose transporter levels. The mechanism appears to involve stabilization of GLUT1 at the plasma membrane. Since many patients with NIDDM do not respond to currently available oral hypoglycemic agents, a great deal of research into understanding insulin action and resistance and the development of novel agents is ongoing. Vanadium compounds ape protein tyrosine phosphatase inhibitors which have been useful probes to study insulin signalling and have also been proposed as potential therapeutic agents. The effects of the vanadium compounds sodium orthovanadate and pervanadate on glucose and amino acid transport and their mechanism of action were investigated. The results demonstrate that vanadate and pervanadate mimic insulin to stimulate glucose transport in L6 cells but inhibit amino acid (MeAIB) transport by the insulin-sensitive system A transporter. The data suggest that this inhibition may be mediated by inhibition of a protein tyrosine phosphatase. It was also found that the stimulation of glucose transport by vanadate and pervanadate is mediated by a signaling pathway that differs from that of insulin and importantly is independent of PI 3-kinase, the enzyme involved in the insulin signalling of glucose transport. These findings contribute new knowledge to our understanding of the effects and mechanisms of action of the oral hypoglycemic sulfonylurea drugs and vanadium compounds. Taken together the results support the continued use of sulfonylureas and the potential use of vanadium compounds in disease associated with insulin resistance.Ph.D