Fatty acids do not activate UCP2 in pancreatic beta cells: comparison with UCP1

Abstract

UCP2 is expressed in pancreatic β cells where its postulated uncoupling activity will modulate glucoseinduced changes in ATP/ADP ratio and insulin secretion. The consequences of UCP2 over/underexpression on β-cell function has mainly been studied in the basal state; however, a UCP has no uncoupling activity unless stimulated by fatty acids and/or reactive oxygen species. Here, UCP2 was overexpressed in INS-1 cells and parameters reflecting mitochondrial coupling measured in the basal state and after stimulation by fatty acids. For comparison, UCP1 was expressed to similar levels and the same parameters measured. Neither UCP1 expression nor UCP2 overexpression modified basal or glucose-stimulated metabolic changes. Upon addition of fatty acids, UCP1-expressing cells displayed the expected mitochondrial uncoupling effect, while UCP2 did not elicit any measurable change in mitochondrial function. Taken together, our data demonstrate that, in pancreatic β-cells, UCP2 has no uncoupling activity in the basal state or after fatty acid stimulation.

Uncoupling protein-2 attenuates glucose-stimulated insulin secretion in INS-1E insulinoma cells by lowering mitochondrial reactive oxygen species

“…In our hands, TTNPB does in fact inhibit GSIS, but in a UCP2-independent manner. Together with the recent observation that β-cell UCP2 is not activated by fatty acids [35], our data may suggest that UCP2 activity is not regulated acutely in cultured β cells, perhaps because the protein is permanently or constitutively activated. In that case, activity in these cells would be controlled exclusively by transcription and translation against a background of exceptionally rapid UCP2 protein degradation [22].…”

The Pancreatic β-Cell: A Bioenergetic Perspective

“…Galetti et al (165) induced an 11-fold overexpression of UCP2 in INS-1 cells, and a similar level of expression of UCP1 in a parallel preparation. Relative to control cells, no effect of these expression levels was observed on insulin secretion or ATP/ADP ratios.…”

Fatty acids and β-cell toxicity

“…As such, increased expression of UCP2 could underlie the loss of insulin secretory function caused by fatty acids, and it might also lead to longer-term impairment of metabolism [41,42]. However, new work by Galetti et al [43 ] suggests that UCP2 does not function as a metabolic uncoupler in b cells, even in the presence of fatty acids. Thus, the hypothesis that UCP2 expression underlies some of the detrimental effects of fatty acids may need to be revisited.…”