Reduced peroxisomal function increases insulin secretion, promotes insulin oxidation, and impairs β cell maturity

J. Jason Collier; Caroline R. Cothern; Maggie P. Ducote; Thomas M. Martin; Melissa A. Linden; Robert C. Noland; David H. Burk; Samuel D. Dupuy; Michael D. Karlstad; Krisztian Stadler; Sarah S. Hirschbeck; Thanh D. Do; Anastasia Coldren; Marcela Brissova; Teayoun Kim; Kirk M. Habegger; Sujoy Ghosh; Zane A. Vickery; Qudus Sarumi; Shawn R. Campagna; Susan J. Burke

doi:10.1172/jci.insight.200202

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Linden, M. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

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¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Hirschbeck, S. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Do, T. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Coldren, A. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Brissova, M. in: PubMed | Google Scholar |

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Kim, T. in: PubMed | Google Scholar |

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Habegger, K. in: PubMed | Google Scholar |

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Ghosh, S. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Vickery, Z. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Sarumi, Q. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Campagna, S. in: PubMed | Google Scholar

¹Pennington Biomedical Research Center, Baton Rouge, United States of America

²Department of Surgery, The University of Tennessee Graduate School of Medicine, Knoxville, United States of America

³Department of Chemistry, The University of Tennessee, Knoxville, United States of America

⁴Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center, Nashville, United States of America

⁵Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, United States of America

⁶Pennington Biomedical Research Center, Knoxville, United States of America

Find articles by Burke, S. in: PubMed | Google Scholar

JCI Insight. https://doi.org/10.1172/jci.insight.200202.
Copyright © 2026, Collier et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 30, 2026 - Version history

Given the central role of peroxisomes in lipid metabolism and redox homeostasis, we hypothesized that peroxisomal activity is critical for sustaining β cell function and identity. Pex5 deletion models were employed to investigate loss of peroxisomal function on glucose-stimulated insulin secretion (GSIS), oxidative stress, and β cell maturity markers. Peroxisome deficiency in male mice resulted in elevated GSIS. Glucose intolerance developed despite increased insulin secretion. Ion mobility mass spectrometry revealed oxidation of insulin proteins, and a truncated insulin 2-derived peptide, in islets from mice with a tissue-specific deficiency in peroxisomes. Peroxisome loss of function increased multiple markers of oxidative stress, including altered metabolite profiles, lipid peroxidation, and protein carbonylation. These findings reveal that increased secretion of oxidized insulin protein is insufficient to regulate whole-body glucose homeostasis. Peroxisome deficiency also reduced markers of β cell maturity. Based on these outcomes, we identified the peroxisome organelle as a key regulatory component of glucose homeostasis by protecting insulin from oxidative modification and degradation and by supporting maintenance of mature β cells.

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Reduced peroxisomal function increases insulin secretion, promotes insulin oxidation, and impairs β cell maturity

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