Aim:

Pancreatic beta-cells are extremely sensitive to oxidative stress. Consequently, increased generation of reactive oxygen species (ROS) resulting from overnutrition is decisive for beta-cell failure during diabetes type-2 development. The present study investigated whether interference with complex II (succinate dehydrogenase, SDH) of mitochondrial respiratory chains is involved in ROS-dependent beta-cell damage.

Methods:

Islets were isolated from C57Bl/6 mice. FAD and NAD(P)H were measured by changes in autofluorescence. Insulin release was quantified by a radioimmunoassay.

Results:

Inhibition of SDH by 3-nitropropionic acid (3-NPA) resulted in a rise in intracellular FAD concentration indicating a decrease in FADH₂ synthesis without any obvious changes in NAD(P)H fluorescence. Acute application of 3-NPA had only marginal effects on the mitochondrial membrane potential. However, preincubation with the SDH inhibitor significantly reduced glucose-induced mitochondrial membrane hyperpolarization. In agreement with impaired mitochondrial ATP synthesis, 3-NPA dose-dependently decreased glucose-stimulated insulin secretion. Activation of antioxidant enzymes by K_ATP channel inhibition attenuated the harmful effect of 3-NPA. Interestingly, H₂O₂, whose endogenous synthesis is known to be elevated under conditions of supra-physiological nutrient supply, also reduced FADH₂ formation. This effect was almost completely prevented by 3-NPA.

Conclusion:

Our data suggest that SDH inhibition contributes to the toxic effect of H₂O₂ against beta-cells. Inhibition of complex II prevents FADH₂ recycling thereby reducing glucose-mediated activation of mitochondrial respiratory chains. As the concomitant loss of glucose-stimulated insulin release can be dampened by manoeuvres increasing antioxidant capacity, SDH seems to be an important player in ROS-induced beta-cell damage.