Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function
figureposted on 2021-05-27, 07:42 authored by Casey J. Bauchle, Kristen E. Rohli, Cierra K. Boyer, Vidhant Pal, Jonathan V. Rocheleau, Siming Liu, Yumi Imai, Eric B. Taylor, Samuel B. Stephens
The defining feature of pancreatic islet β-cell function is the precise coordination of changes in blood glucose levels with insulin secretion to regulate systemic glucose homeostasis. While ATP has long been heralded as a critical metabolic coupling factor to trigger insulin release, glucose-derived metabolites have been suggested to further amplify fuel-stimulated insulin secretion. The mitochondrial export of citrate and isocitrate through the citrate-isocitrate carrier (CIC) has been suggested to initiate a key pathway that amplifies glucose-stimulated insulin secretion, though the physiological significance of β-cell CIC to glucose homeostasis has not been established. Here, we generated constitutive and adult CIC β-cell knockout mice and demonstrate these animals have normal glucose tolerance, similar responses to diet-induced obesity, and identical insulin secretion responses to various fuel secretagogues. Glucose-stimulated NADPH production was impaired in β-cell CIC KO islets, whereas glutathione reduction was retained. Furthermore, suppression of the downstream enzyme, cytosolic isocitrate dehydrogenase, Idh1, inhibited insulin secretion in wild type islets, but failed to impact β-cell function in β-cell CIC KO islets. Our data demonstrate that the mitochondrial citrate-isocitrate carrier is not required for glucose-stimulated insulin secretion, and that additional complexities exist for the role of Idh1 and NADPH in the regulation of β-cell function.