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Glucolipotoxicity: Fuel Excess and β-Cell Dysfunction

Montreal Diabetes Research Center (V.P.), Centre de Recherche du Centre Hospitalier de l'Université de Montréal, and Departments of Medicine, Nutrition, and Biochemistry, Université de Montréal, Montréal, Québec, Canada H1W 4A4; and Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122; and Departments of Medicine and Pharmacology (R.P.R.), University of Washington, Seattle, Washington 98195

Correspondence: Address all correspondence and requests for reprints to: Vincent Poitout, D.V.M., Ph.D., Montreal Diabetes Research Center, CR-CHUM, Technopole Angus, 2901 Rachel Est, Montreal, Quebec, Canada H1W 4A4. E-mail: vincent.poitout{at}umontreal.ca

Glucotoxicity, lipotoxicity, and glucolipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the β-cell. In addition to their contribution to the deterioration of β-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for lipotoxicity to occur, the term glucolipotoxicity, rather than lipotoxicity, is more appropriate to describe deleterious effects of lipids on β-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is presented first, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucolipotoxicity on insulin secretion, insulin gene expression, and β-cell death, and the role of glucose in the mechanisms of glucolipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of β-cell compensation, decompensation, and failure during the course of type 2 diabetes.

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