{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T23:12:45Z","timestamp":1790550765628,"version":"4.1.0"},"reference-count":50,"publisher":"American Diabetes Association","issue":"9","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,9,1]]},"abstract":"<jats:p>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 (\u0394 of increment over baseline 0.7 \u00b1 0.5 or 0.5 \u00b1 0.3 pmol\/islet in islets exposed to glucose or FFA vs. 12.0 \u00b1 0.6 in control islets, n = 3; P &amp;lt; 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-\u03b3 contents by Western blot and the effects of a PPAR-\u03b3 antagonist. PPAR-\u03b3 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-\u03b3 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-\u03b3 pathway.<\/jats:p>","DOI":"10.2337\/diabetes.51.9.2749","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"2749-2756","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":132,"title":["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-\u03b3 Inhibition"],"prefix":"10.2337","volume":"51","author":[{"given":"Giovanni","family":"Patane\u0300","sequence":"first","affiliation":[{"name":"From the Institute of Internal Medicine, Endocrinology and Metabolism, \u201cSignorelli\u201d Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Anello","sequence":"additional","affiliation":[{"name":"From the Institute of Internal Medicine, Endocrinology and Metabolism, \u201cSignorelli\u201d Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Piro","sequence":"additional","affiliation":[{"name":"From the Institute of Internal Medicine, Endocrinology and Metabolism, \u201cSignorelli\u201d Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Vigneri","sequence":"additional","affiliation":[{"name":"From the Institute of Internal Medicine, Endocrinology and Metabolism, \u201cSignorelli\u201d Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Purrello","sequence":"additional","affiliation":[{"name":"From the Institute of Internal Medicine, Endocrinology and Metabolism, \u201cSignorelli\u201d Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata Maria","family":"Rabuazzo","sequence":"additional","affiliation":[{"name":"From the Institute of Internal Medicine, Endocrinology and Metabolism, \u201cSignorelli\u201d Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031222542444300_R1","doi-asserted-by":"crossref","unstructured":"Cavaghan MK, Ehrmann DA, Polonsky KS: Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. 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