Mitochondrial Efflux of Citrate and Isocitrate Is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function

Diabetes. 2021 Aug;70(8):1717-1728. doi: 10.2337/db21-0037. Epub 2021 May 26.


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 (KO) mice and demonstrate that 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 CIC 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Citric Acid / metabolism*
  • Cytosol / metabolism
  • Glucose / pharmacology*
  • Homeostasis / drug effects
  • Insulin Secretion / drug effects*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Isocitrates / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism*


  • Isocitrates
  • Citric Acid
  • isocitric acid
  • Glucose

Associated data

  • figshare/10.2337/figshare.14666160