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Amyloid deposits comprise the normal beta cell secretory product, human islet amyloid polypeptide (hIAPP), the aggregation of which is toxic to beta cells. While the underlying mechanism(s) for toxicity remain unknown, it is likely to involve mitochondrial dysfunction. We have shown that the mitochondrial cholesterol transport protein, steroidogenic acute regulatory protein (StAR), is upregulated in beta cells following amyloid deposition. Here, we examined the role of StAR in the toxicity of islet amyloidosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Human islets from non-diabetic donors were cultured under amyloidogenic conditions and StAR expression was examined. StAR expression was also determined in islets isolated from transgenic mice expressing amyloidogenic hIAPP or non-transgenic littermates expressing non-amyloidogenic islet amyloid polypeptide, cultured under amyloidogenic conditions with or without the addition of an amyloid inhibitor. Total islet cholesterol content, mitochondrial cholesterol content, mitochondrial function and cell viability\/death were compared in transgenic hIAPP and non-transgenic islets cultured in amyloidogenic conditions. Additionally, StAR localisation to islet cells, as well as its intracellular localisation, was examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>StAR was present in human islets at the mRNA and protein level, and expression increased significantly with amyloid formation in vitro. Further, in hIAPP transgenic mouse islets, StAR expression was amyloid-dependent. StAR was predominantly expressed in beta cells, and the amyloid-induced increase in StAR protein was found specifically in the mitochondrial fraction. While total and mitochondrial cholesterol content was unchanged between non-transgenic and hIAPP transgenic mouse islets cultured under amyloidogenic conditions, increased StAR expression was associated with decreased mitochondrial glucose-stimulated respiration and increased cell death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/Interpretation<\/jats:title>\n                    <jats:p>These findings are consistent with StAR having a pathophysiological role in the beta cell in type 2 diabetes, where its upregulation under conditions of islet amyloid deposition could contribute to mitochondrial dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06749-8","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T12:33:58Z","timestamp":1779280438000},"page":"2294-2306","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human islet amyloid polypeptide aggregation upregulates the mitochondrial cholesterol transport protein StAR and induces mitochondrial dysfunction in beta cells"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5767-1599","authenticated-orcid":false,"given":"Meghan F.","family":"Hogan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6922-350X","authenticated-orcid":false,"given":"Rehana","family":"Akter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3346-9484","authenticated-orcid":false,"given":"Alfred C.","family":"Aplin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6241-9304","authenticated-orcid":false,"given":"Andrew T.","family":"Templin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1823-3817","authenticated-orcid":false,"given":"Nathalie","family":"Esser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3348-4657","authenticated-orcid":false,"given":"Daniel T.","family":"Meier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7936-471X","authenticated-orcid":false,"given":"Brendy-Sue","family":"Fountaine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4080-2545","authenticated-orcid":false,"given":"Joseph J.","family":"Castillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-7375","authenticated-orcid":false,"given":"Assam","family":"El-Osta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9690-4087","authenticated-orcid":false,"given":"Rebecca L.","family":"Hull-Meichle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4831-7034","authenticated-orcid":false,"given":"Sakeneh","family":"Zraika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7307-9002","authenticated-orcid":false,"given":"Steven E.","family":"Kahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"6749_CR1","doi-asserted-by":"publisher","first-page":"3629","DOI":"10.1210\/jc.2004-0405","volume":"89","author":"RL Hull","year":"2004","unstructured":"Hull RL, Westermark GT, Westermark P, Kahn SE (2004) Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. 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L. Eberhardt (Mayo Clinic and Foundation, Rochester, MN, USA) for providing the knockin mice; B. Barrow, D. Hackney, E. Giering, M. Teng, D. Threet, S. Mongovin, C. Weber-Schmidt (VA Puget Sound Health Care System, Seattle, WA, USA), and T. Y.-W. Hsu (University of Washington, Seattle, WA, USA) for excellent technical assistance. We are grateful to S. Soleimanpour (University of Michigan, Ann Arbor, MI, USA) for helpful discussions. Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) (RRID:SCR_014387) at City of Hope, NIH Grant 2UC4DK098085.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This study was supported by a Merit Review I01 BX001060 from the Department of Veterans Affairs (SEK), Dick and Julia McAbee Endowed Fellowship in Diabetes Research from the University of Washington and an American Diabetes Association Fellowship Award 1-18-PDF-174 (MFH) and a DEI Research Supplement Award I01 BX001060 from the Department of Veterans Affairs (RA). Salary support was provided by NIH grant T32 DK007247 (MFH, RA and ATT) and HL007028 (JJC), Belgian American Educational Foundation Postdoctoral Fellowship, French Society of Diabetes Young Francophone Researcher Postdoctoral Fellowship and Dick and Julia McAbee Endowed Fellowship in Diabetes Research from the University of Washington (NE), NIH grant F32 DK107022 and a CDA-2 IK2 BX004659 from the Department of Veterans Affairs (ATT), National Health and Medical Research Council Senior Research Fellowship 1154650 and 0526681 (AEO), and NIH grants R01 DK088082 (RLH) and R01 DK134502 (SZ). The University of Washington Diabetes Research Center funded by NIH grant P30 DK017047 provided support through the Metabolic and Cellular Phenotyping Core and Cellular and Molecular Imaging Core. NE is an F.R.S.-FNRS Post doctorate Clinical Master Specialist and a Collen-Francqui Start-up Fellow. The study sponsors\/funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"SEK reports in the past 36 months engaging with the following companies: consulting and advisory boards for Altpep, Amgen, Biomea Fusion, Congruence Therapeutics, Eli Lilly, General Medicines, Hoffman La-Roche, Kayothera, Merck, Neurimmune, and Novo Nordisk; and research support from Corcept Therapeutics. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"All authors made substantial contributions to the conception or design of the work; or the acquisition, analysis or interpretation of data; and drafting the article or reviewing it critically for important intellectual content; and gave final approval of the version to be published. MFH, RA and SEK are the guarantors of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}