Interactions between Imidazoline and Insulin Receptors

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DESCRIPTION (provided by applicant): This R03 application from an underrepresented minority investigator responds to PAR-02-032 and addresses a new NIDDK research priority -- understanding the "crosstalk" between the insulin receptor and other receptors that may affect glucose metabolism. My postdoctoral studies on imidazoline receptor function in response to agonists used to treat hypertension have uniquely positioned me to establish an independent research program, relevant not only to cardiovascular disease, but also to type 2 diabetes and Metabolic Syndrome X. Metabolic Syndrome X affects 75 million Americans, and is a growing epidemic worldwide. Pharmacologic treatment options are limited and new agents are urgently needed. Imidazoline receptor agonists (rilmenidine, moxonidine) offer significant potential for the treatment of syndrome X and type 2 diabetes. Moxonidine, a known antihypertensive agent in Europe, ameliorate hyperinsulinemia and lower lipids in animal studies, while reducing insulin resistance and improving glucose disposal rates in humans. Our project goal is to discover the unknown mechanism by which imidazoline receptor agonists exert these beneficial effects. My general hypothesis is that imidazoline receptor agonists enhance insulin action via phosphorylation of insulin receptor substrates and protein kinase B. Using Western blot, microarray, molecular and pharmacologic methods, three specific aims will critically test this hypothesis by determining whether: [1] imidazoline receptors are coupled to additional isoforms of PKC and also JAK/STAT pathways [2] Imidazoline receptors are coupled to insulin receptor substrate proteins (IRS1-4), [3] imidazoline receptor activation is coupled to increased uptake of glucose via the Protein kinase B and phosphatidylinositol-3-kinase pathway. Establishing a link between imidazoline and insulin receptor pathways suggests that imidazoline agents are candidate drugs to treat diabetics with hypertension and reduce insulin resistance. This new knowledge will stimulate further development of these agents.