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

Casey J Bauchle; Kristen E Rohli; Cierra K Boyer; Vidhant Pal; Jonathan V Rocheleau; Siming Liu; Yumi Imai; Eric B Taylor; Samuel B Stephens

doi:10.2337/db21-0037

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

Journal article

Open access

Peer reviewed

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

Casey J Bauchle, Kristen E Rohli, Cierra K Boyer, Vidhant Pal, Jonathan V Rocheleau, Siming Liu, Yumi Imai, Eric B Taylor and Samuel B Stephens

Diabetes (New York, N.Y.), Vol.70(8), pp.1717-1728

08/2021

DOI: 10.2337/db21-0037

PMCID: PMC8385611

PMID: 34039628

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https://doi.org/10.2337/db21-0037View

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Abstract

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.

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

Details

Title: Subtitle: Mitochondrial Efflux of Citrate and Isocitrate Is Fully Dispensable for Glucose-Stimulated Insulin Secretion and Pancreatic Islet β-Cell Function
Creators: Casey J Bauchle - University of Iowa
Kristen E Rohli - Fraternal Order of Eagles
Cierra K Boyer - University of Iowa
Vidhant Pal - University Health Network
Jonathan V Rocheleau - University Health Network
Siming Liu - University of Iowa
Yumi Imai - Fraternal Order of Eagles
Eric B Taylor - University of Iowa
Samuel B Stephens - Fraternal Order of Eagles
Resource Type: Journal article
Publication Details: Diabetes (New York, N.Y.), Vol.70(8), pp.1717-1728
DOI: 10.2337/db21-0037
PMID: 34039628
PMCID: PMC8385611
NLM abbreviation: Diabetes
ISSN: 0012-1797
eISSN: 1939-327X
Grant note: I01 BX005107 / BLRD VA R01 DK090490 / NIDDK NIH HHS R01 DK104998 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS UC4 DK098085 / NIDDK NIH HHS CIHR
Language: English
Date published: 08/2021
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984297492702771

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