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Diabetes 51:2749-2756, 2002
© 2002 by the American Diabetes Association, Inc.

Role of ATP Production and Uncoupling Protein-2 in the Insulin Secretory Defect Induced by Chronic Exposure to High Glucose or Free Fatty Acids and Effects of Peroxisome Proliferator-Activated Receptor-{gamma} Inhibition

Giovanni Patanè, Marcello Anello, Salvatore Piro, Riccardo Vigneri, Francesco Purrello, and Agata Maria Rabuazzo

From the Institute of Internal Medicine, Endocrinology and Metabolism, "Signorelli" Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy

In rat pancreatic islets chronically exposed to high glucose or high free fatty acid (FFA) levels, glucose-induced insulin release and mitochondrial glucose oxidation are impaired. These abnormalities are associated with high basal ATP levels but a decreased glucose-induced ATP production ({Delta} of increment over baseline 0.7 ± 0.5 or 0.5 ± 0.3 pmol/islet in islets exposed to glucose or FFA vs. 12.0 ± 0.6 in control islets, n = 3; P < 0.01) and, as a consequence, with an altered ATP/ADP ratio. To investigate further the mechanism of the impaired ATP formation, we measured in rat pancreatic islets glucose-stimulated pyruvate dehydrogenase (PDH) activity, a key enzyme for pyruvate metabolism and for the subsequent glucose oxidation through the Krebs cycle, and also the uncoupling protein-2 (UCP-2) content by Western blot. In islets exposed to high glucose or FFA, glucose-stimulated PDH activity was impaired and UCP-2 was overexpressed. Because UCP-2 expression is modulated by a peroxisome proliferator- activated receptor (PPAR)-dependent pathway, we measured PPAR-{gamma} contents by Western blot and the effects of a PPAR-{gamma} antagonist. PPAR-{gamma} levels were overexpressed in islets cultured with high FFA levels but unaffected in islets exposed to high glucose. In islets exposed to high FFA concentration, a PPAR-{gamma} antagonist was able to prevent UCP-2 overexpression and to restore insulin secretion and the ATP/ADP ratio. These data indicate that in rat pancreatic islets chronically exposed to high glucose or FFA, glucose-induced impairment of insulin secretion is associated with (and might be due to) altered mitochondrial function, which results in impaired glucose oxidation, overexpression of the UCP-2 protein, and a consequent decrease of ATP production. This alteration in FFA cultured islets is mediated by the PPAR-{gamma} pathway.


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Copyright © 2002 by the American Diabetes Association.