Journal article
A metabolic redox relay supports ER proinsulin export in pancreatic islet β-cells
JCI insight, Vol.9(15), e178725
08/08/2024
DOI: 10.1172/jci.insight.178725
PMCID: PMC11383593
PMID: 38935435
Abstract
Endoplasmic reticulum (ER) stress and proinsulin misfolding are heralded as contributing factors to β-cell dysfunction in Type 2 diabetes (T2D), yet how ER function becomes compromised is not well understood. Recent data identifies altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER. Using multiple β-cell models, we showed that loss of mitochondrial function or inhibition of cellular metabolism elicited ER hyperoxidation and delayed ER proinsulin export. Our data further demonstrated that β-cell ER redox homeostasis was supported by the metabolic supply of reductive redox donors. We showed that limiting NADPH and thioredoxin flux delayed ER proinsulin export, whereas Txnip suppression restored ER redox and proinsulin trafficking. Taken together, we propose that β-cell ER redox homeostasis is buffered by cellular redox donor cycles, which are maintained through active glucose metabolism.Endoplasmic reticulum (ER) stress and proinsulin misfolding are heralded as contributing factors to β-cell dysfunction in Type 2 diabetes (T2D), yet how ER function becomes compromised is not well understood. Recent data identifies altered ER redox homeostasis as a critical mechanism that contributes to insulin granule loss in diabetes. Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER. Using multiple β-cell models, we showed that loss of mitochondrial function or inhibition of cellular metabolism elicited ER hyperoxidation and delayed ER proinsulin export. Our data further demonstrated that β-cell ER redox homeostasis was supported by the metabolic supply of reductive redox donors. We showed that limiting NADPH and thioredoxin flux delayed ER proinsulin export, whereas Txnip suppression restored ER redox and proinsulin trafficking. Taken together, we propose that β-cell ER redox homeostasis is buffered by cellular redox donor cycles, which are maintained through active glucose metabolism.
Details
- Title: Subtitle
- A metabolic redox relay supports ER proinsulin export in pancreatic islet β-cells
- Creators
- Kristen E Rohli - University of IowaNicole J Stubbe - University of IowaEmily M Walker - University of Michigan–Ann ArborGemma L Pearson - University of Michigan–Ann ArborScott A Soleimanpour - University of Michigan–Ann ArborSamuel B Stephens - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.9(15), e178725
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- DOI
- 10.1172/jci.insight.178725
- PMID
- 38935435
- PMCID
- PMC11383593
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- US Department of Defense CDMRP: W81XWH-20-1-0200 JDRF: COE-2019-861, SRA-2023-1392 NIH: R01 DK135268, R01 DK108921, R01 DK135032, R01 DK127270, R01 DK136671, U01 DK127747, K01 DK133533 Department of Veterans Affairs: I01 BX004444 NIH Predoctoral Training Grants: T32GM008629, T32GM145441
We would like to thank Cierra Boyer, Sandra Blom, Thomas Rutkowski, Erica Gansemer, and Ling Yang for insightful discussions and suggestions. We are grateful for the support of the University of Iowa Cen-tral Microscopy Research Facility (Chantal Allamargot) , University of Iowa Metabolic Phenotyping Core (Eric Weatherford) , and University of Iowa Radiation and Free Radical Research Core Lab (Brett Wag-ner) . This work was supported by the US Department of Defense CDMRP (W81XWH-20-1-0200) and a Fraternal Order of Eagles Diabetes Research Center Pilot and Feasibility Catalyst grant to SBS, the JDRF (COE-2019-861 and SRA-2023-1392) , the NIH (R01 DK135268, R01 DK108921, R01 DK135032, R01 DK127270, R01 DK136671, U01 DK127747) , the Department of Veterans Affairs (I01 BX004444) to SAS, the NIH (K01 DK133533) to EMW, and NIH Predoctoral Training Grants (T32GM008629 and T32GM145441, principal investigator: Daniel Eberl) to KER. SBS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
- Language
- English
- Electronic publication date
- 06/27/2024
- Date published
- 08/08/2024
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984649059502771
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