Abstract
ObjectiveUncoupling protein-2 (UCP2) overexpression impairs proinsulin processing to mature insulin. Here we tested the hypothesis that induction of endogenous UCP2 by saturated free fatty acid (FFA) would also decrease proinsulin processing. MethodsInsulinoma cells (INS-1) cells or rat islets were cultured with or without palmitic acid. Proinsulin processing was assessed by immunoblotting or ELISA for UCP2 along with changes in UCP2 expression, mitochondrial uncoupling, Adenosine-5′-triphosphate (ATP) and insulin secretion. ResultsPalmitate increased UCP2 expression and mitochondrial uncoupling and reduced ATP content. Palmitate glucose-dependently increased the proinsulin:insulin ratio up to ∼3-fold in INS-1 cells and rat islets, an effect reversed by knockdown of UCP2 in INS-1 cells. Palmitate increased basal insulin secretion, insulin content and mRNA in INS-1 cells. ConclusionsOne effect of palmitate on β-cells is reduced proinsulin processing, which is associated with mitochondrial uncoupling and reduced cellular ATP. Knockdown of UCP2 can prevent the effects of palmitate on proinsulin processing.
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