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Cisplatin exposure dysregulates insulin secretion in male and female mice

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posted on 2025-01-14, 16:24 authored by Lahari Basu, Lili Grieco-St-Pierre, Ma. Enrica Angela Ching, John D. H. Stead, Antonio A. Hanson, Jana Palaniyandi, Erin P. van Zyl, Myriam P. Hoyeck, Kelsea S. McKay, Kyle A. van Allen, Hyojin Lee, Xiao-Qing Dai, Austin Bautista, Evgenia Fadzeyeva, Erin E. Mulvihill, Carole L. Yauk, Jan A. Mennigen, Patrick E. MacDonald, Jennifer E. Bruin

Cancer survivors have an increased risk of developing Type 2 diabetes compared to the general population. Patients treated with cisplatin, a common chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes than age- and sex-matched controls. Surprisingly, the impact of cisplatin on pancreatic islets has not been reported. Our study aimed to determine if mouse islet function is adversely affected by systemic (in vivo) or direct (in vitro) exposure to cisplatin. In vivo cisplatin exposure led to deficits in glucose-stimulated plasma insulin levels in both male and female mice, despite no differences in glucose tolerance. In vitro cisplatin exposure to mouse islets dysregulated insulin release and reduced oxygen consumption in a non-sex specific manner. When shifting our focus to male mouse islets, cisplatin altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family as early as 6-hours post-exposure. Genome-wide expression analysis confirmed the pronounced downregulation of genes within the insulin secretion pathway in cisplatin-exposed mouse islets. Data from 3 human organ donors confirms that the detrimental effects of cisplatin on insulin secretion and gene expression are reproduced in human islets. Our findings indicate that cisplatin exposure causes significant defects in insulin secretion and may have lasting effects on islet health.

Funding

This research was supported by a Diabetes Canada grant (OG-3-22-5610-JB to JEB), a Canadian Institute of Health Research (CIHR) grant (#148451 to PEM), and a research grant funded by CIHR, BreakthroughT1D Canada, and Diabetes Canada (5-SRA-2021-1149-S-B/TG 179092 to PEM and JEB). LB was supported by a CIHR CGS-D award and a Natural Sciences and Engineering Research Council (NSERC) CREATE award on behalf of the Canadian Islet Research Training Network (CIRTN-R2FIC). LG was supported by Master’s and Doctoral training scholarships from Fonds de recherche du Québec – Santé (FRQS). MEAC was supported by NSERC CGS-M and NSERC CGS-D awards. JP was supported by the Guiding interdisciplinary Research On Women’s and girls’ health and Wellbeing (GROWW) scholarship and an Ontario Graduate Scholarship (OGS). EPvZ was supported by an NSERC-CREATE PDF award on behalf of CIRTN-R2FIC and a CIHR fellowship. MPH was supported by an OGS and CIHR CGS-D award. KAvA was supported by an NSERC-CREATE award on behalf of CIRTN-R2FIC. EEM is supported by Diabetes Canada grant (OG-3-21-5591-EM). CLY has support from the Canadian Foundation for Innovation (#233109) and the Canada Research Chairs Program (CRC-202-00060). JAM was supported by an NSERC discovery grant (RGPIN-2024-04456). PEM holds a Canada Research Chair in Islet Biology. JEB was supported by an Ontario Early Researcher Award.

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