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We studied the effect of propionate on glucose\u2010induced insulin secretion in isolated rat pancreatic islets. Evidence is presented that propionate, one of the major SCFA produced in the gut, inhibits insulin secretion induced by high glucose concentrations (11.1 and 16.7\u2009mM) in incubated and perfused pancreatic islets. This short chain fatty acid reduces [U\u2010<jats:sup>14<\/jats:sup>C]\u2010glucose decarboxylation and raises the conversion of glucose to lactate. Propionate causes a significant decrease of both [1\u2010<jats:sup>14<\/jats:sup>C]\u2010 (84%) and [2\u2010<jats:sup>14<\/jats:sup>C]\u2010pyruvate (49%) decarboxylation. These findings indicate pyruvate dehydrogenase as the major site for the propionate effect. These observations led us to postulate that the reduction in glucose oxidation and the consequent decrease in the ATP\/ADP ratio may be the major mechanism for the lower insulin secretion to glucose stimulus induced by propionate. 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