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Our research efforts are both basic and clinical. Our basic work focuses on understanding mechanisms for glucose toxicity in pancreatic islet beta cells. Our findings strongly suggest that the adverse effects of chronically exposing beta cells to supraphysiological concentrations of glucose involve induction of defective PDX-1 and Maf A gene expression, and consequently defective insulin gene expression. Most recently, we have demonstrated that glucotoxic effects on insulin and PDX-1 and Maf A gene expression in animals can be prevented by treatment with antioxidants and by adenoviral overexpression of glutathione peroxidase in beta cells. Other work involves cyclooxygenase-2 (COX-2), which we have demonstrated is dominantly expressed over COX-1 in islets and mediates adverse effects of interleukin-1 beta on the islet. Grants supporting this work: NIH R01 DK 38325 and an ADA mentor-based Post-doctoral Fellowship.
Our clinical investigation involves metabolic studies in diabetic patients who are recipients of pancreas and pancreatic islet transplantation. We have demonstrated that successful recipients of pancreas transplants have normal HbA1c levels, normal insulin secretion, and normal hormonal counterregulatory responses to hypoglycemia as long as 20 years post-transplantation. I am the Program Director of the Human Islet Transplantation in Seattle (HITS) consortium. We perform extensive metabolic studies after islet transplantation in autoislet and alloislet recipients. Grant supporting this work: NIH R01 DK 39994.
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