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Elevated levels of FFAs, often accompanied by obesity, have been considered as a major risk factor of ␤ -cell failure and insulin resistance, which contributes to the onset and progression of T2D ( 1 ). The FA-induced effect on ␤ -cell integrity and function depends on both the level of FA desaturation and the time of deposition ( 2 ). The prolonged exposure of ␤ -cells to high concentrations of FAs results in an impairment in insulin secretion, a decrease in insulin gene expression, the mitigation of proliferation, and subsequently the induction of lipoapoptosis ( 3 ). The molecular mechanisms that link FAs to ␤ -cell dysfunction still remain to be delineated. Several processes by which FAs mediate lipotoxicity have been suggested, including the generation of reactive oxygen species, de novo ceramide synthesis, endoplasmic reticulum (ER)-associated stress, and alterations in mitochondrial integrity and function ( 4-6 ). Saturated FAs (SFAs) were found to cause more severe effects on the insulin secretory capacity of ␤ -cells and rate of apoptosis compared with MUFAs ( 7,8 ).Stearoyl-CoA desaturase (SCD) is the pivotal lipid metabolism enzyme that catalyzes the biosynthesis of MUFAs by introducing a cis -double bond to a fatty-acyl CoA. The preferred desaturation substrates are palmitic acid (16:0) and stearic acid (18:0), which are converted to palmitoleate (16:1n-7) and oleate (18:1n-9), respectively ( 9 ). The resulting

Arachidonic acid metabolites are crucial mediators of inflammation in diabetes. Although eicosanoids are established modulators of pancreatic β-cell function, the role of prostacyclin (prostaglandin I2) is unknown. Therefore, this study aimed to analyze the role of prostacyclin in β-cell function. Prostacyclin synthase (PGIS) was weakly expressed in rat islet cells but nevertheless significantly increased by incubation with 30 mM glucose, especially in non-β-cells. PGIS was overexpressed in INS1E cells, and the regulation of insulin secretion was analyzed. PGIS overexpression strongly potentiated glucose-induced insulin secretion along with increased insulin content and ATP production. Importantly, overexpression of PGIS potentiated only nutrient-induced insulin secretion. The effect of PGIS overexpression was mediated by prostacyclin released from insulin-secreting cells and dependent on prostacyclin receptor (IP receptor) activation, with concomitant cAMP production. The cAMP-mediated potentiation of glucose-induced insulin secretion by prostacyclin was independent of the protein kinase A pathway but strongly attenuated by the knockdown of the exchange protein directly activated by cAMP 2 (Epac2), pointing to a crucial role for Epac2 in this process. Thus, prostacyclin is a powerful potentiator of glucose-induced insulin secretion. It improves the secretory capacity by inducing insulin biosynthesis and probably by stimulating exocytosis. Our findings open a new therapeutical perspective for an improved treatment of type 2 diabetes.

Mimitin, a novel mitochondrial protein, has been shown to act as a molecular chaperone for the mitochondrial complex I and to regulate ATP synthesis. During Type 1 diabetes development, pro-inflammatory cytokines induce mitochondrial damage in pancreatic β-cells, inhibit ATP synthesis and reduce glucose-induced insulin secretion. Mimitin was expressed in rat pancreatic islets including β-cells and decreased by cytokines. In the ob/ob mouse, a model of insulin resistance and obesity, mimitin expression was down-regulated in liver and brain, up-regulated in heart and kidney, but not affected in islets. To further analyse the impact of mimitin on β-cell function, two β-cell lines, one with a low (INS1E) and another with a higher (MIN6) mimitin expression were studied. Mimitin overexpression protected INS1E cells against cytokine-induced caspase 3 activation, mitochondrial membrane potential reduction and ATP production inhibition, independently from the NF-κB (nuclear factor κB)-iNOS (inducible NO synthase) pathway. Mimitin overexpression increased basal and glucose-induced insulin secretion and prevented cytokine-mediated suppression of insulin secretion. Mimitin knockdown in MIN6 cells had opposite effects to those observed after overexpression. Thus mimitin has the capacity to modulate pancreatic islet function and to reduce cytokine toxicity.

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