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Mitochondrial Efflux of Citrate and Isocitrate is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function
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posted 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. StephensThe 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.