---
title: "Casp1 and Ripk3 jointly support homeostatic insulin secretion in mice"
id: "biorxiv-8-casp1-and-ripk3-are-required-for-homeostatic-insulin-secretion-in-mice"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-8-casp1-and-ripk3-are-required-for-homeostatic-insulin-secretion-in-mice"
content_type: "clinical_feed_article"
specialty: "Endocrinology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.01.748578v1?rss=1"
published_at: "2026-09-04T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Casp1 and Ripk3 jointly support homeostatic insulin secretion in mice
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-8-casp1-and-ripk3-are-required-for-homeostatic-insulin-secretion-in-mice
- **Specialty:** [Endocrinology](https://medichelpline.com/clinical-feed/endocrinology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.01.748578v1?rss=1)
- **Published At:** 2026-09-04T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study tested metabolic effects of deleting or inhibiting **Casp1** and **Ripk3** alone and together in mice fed a matched low-fat or a 60% kcal high‑fat diet. - Mouse genotypes included wild-type (WT), Casp1/11 knockout (KO), Ripk3 KO and Casp1/11/Ripk3 double knockout (DKO); both sexes were studied. - High‑fat feeding increased adiposity in male but not female mice across single and double KO genotypes and produced impaired glucose tolerance and insulin sensitivity markers. - In mice fed a low‑fat diet, dual loss or pharmacological inhibition of **Casp1** and **Ripk3** reduced glucose excursion after glucose challenge because of increased plasma **insulin** levels. - Increased glucose‑stimulated insulin secretion was reproduced ex vivo in isolated islets from DKO mice and with pharmacologic inhibitors in WT islets, indicating an islet‑intrinsic effect. - Islet cellular composition (proportions of α-, β-, and δ-cells) was not altered in DKO mice, indicating increased insulin release was independent of major changes in cell fractions. - DKO islets showed a reduction in urocortin‑3 (Ucn3)-positive β‑cells compared to controls, implicating altered Ucn3–somatostatin (Sst) signaling; however, only exogenous somatostatin (octreotide), not Ucn3, normalized the decreased glucose excursion in vivo. - The authors conclude endogenous **Casp1** and **Ripk3** coordinate normal glucose‑stimulated insulin release independent of their canonical roles in inflammation or programmed cell death. - The source did not report detailed statistical values, effect sizes, or full mechanistic pathways; those details were not provided in the preprint abstract and main text excerpt.
## Clinical Analysis & Structured Key Points
Casp1 and Ripk3 are required for homeostatic insulin secretion in mice | bioRxiv Skip to main content New Results Casp1 and Ripk3 are required for homeostatic insulin secretion in mice Madison D. Girouard , Conor O'Dwyer , View ORCID Profile Myriam P. Hoyeck , View ORCID Profile Cassandra A.A. Locatelli , Evgenia Fadzeyeva , View ORCID Profile Tyler K.T. Smith , Rui Yan Gao , Tanvi Ahluwalia , Sophia M. Perrakis , Andrew C. Clement , Antonio A. Hanson , View ORCID Profile Peyman Ghorbani , Lili Grieco-St-Pierre , View ORCID Profile Jianfan Nie , View ORCID Profile Mariam Hakoum , View ORCID Profile Julia R.C. Nunes , Aaron Reyes , View ORCID Profile Andrew R Pepper , View ORCID Profile Subash Sad , View ORCID Profile Erin E. Mulvihill , View ORCID Profile Jennifer E. Bruin , View ORCID Profile Morgan D. Fullerton doi: https://doi.org/10.64898/2026.09.01.748578 Madison D. Girouard 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Conor O'Dwyer 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Myriam P. Hoyeck 2 Carleton University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Myriam P. Hoyeck Cassandra A.A. Locatelli 3 University of Ottawa Heart Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Cassandra A.A. Locatelli Evgenia Fadzeyeva 3 University of Ottawa Heart Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tyler K.T. Smith 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tyler K.T. Smith Rui Yan Gao 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tanvi Ahluwalia 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sophia M. Perrakis 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew C. Clement 3 University of Ottawa Heart Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Antonio A. Hanson 3 University of Ottawa Heart Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peyman Ghorbani 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peyman Ghorbani Lili Grieco-St-Pierre 2 Carleton University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jianfan Nie 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jianfan Nie Mariam Hakoum 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mariam Hakoum Julia R.C. Nunes 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Julia R.C. Nunes Aaron Reyes 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew R Pepper 4 University of Alberta Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andrew R Pepper Subash Sad 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Subash Sad Erin E. Mulvihill 3 University of Ottawa Heart Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Erin E. Mulvihill Jennifer E. Bruin 2 Carleton University; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jennifer E. Bruin Morgan D. Fullerton 1 University of Ottawa; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Morgan D. Fullerton For correspondence: morgan.fullerton{at}uottawa.ca Abstract Info/History Metrics Preview PDF Abstract Objectives- Cell death and inflammatory pathways play important roles in adaptations to nutrient overload and metabolic dysfunction. This study investigates the metabolic consequences that arise from the dual disruption of both caspase 1 (Casp1) and receptor interacting protein kinase 3 (Ripk3) in mice fed a control or obesity-inducing diet. Methods- Male and female wild-type (WT), Casp1/11 knockout (KO), Ripk3 KO and Casp1/11/Ripk3 double knockout (DKO) mice were fed a matched low-fat or a 60% kcal high fat diet, followed by metabolic phenotyping. Islets were isolated from WT and DKO mice for measures of dynamic glucose-stimulated insulin and somatostatin (Sst) secretion. Islet architecture and cellular composition were assessed in WT and DKO mice by immunofluorescent staining of intact pancreatic sections. Pharmacological inhibition of Casp1 (Ac-YVAD-cmk) and Ripk3 (GSK872) was performed in WT and DKO mice using isolated islets and in vivo administration. Exogenous hormones were administered prior to glucose injection to test in vivo responses. Results- High-fat feeding resulted in increased adiposity in male, but not female mice, with single or double deletion of Casp1/11 and Ripk3. These mice also exhibited markers of impaired glucose tolerance and insulin sensitivity. Interestingly, when both Casp1 and Ripk3 were deleted or inhibited in mice fed a low-fat diet, mice experienced reductions in glucose excursion following administration of glucose due to increased plasma insulin levels. This increase in insulin secretion was recapitulated in isolated islets ex vivo and was independent of changes in the proportions of α-, β-, and δ-cells within the islet. There were significant reductions in the percentage of urocortin-3 (Ucn3)-positive β-cells in DKO mice compared to control, suggesting altered Ucn3-Sst signaling; however, only exogenous Sst (Octreotide) and not Ucn3 was able to correct the decreased glucose excursion. Conclusions- Loss or inhibition of both Casp1 and Ripk3 fundamentally alter islet responses to glucose. Our findings highlight that endogenous Casp1 and Ripk3 act independently of inflammatory or cell death signals to coordinate normal glucose-stimulated insulin release. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Diabetes Canada, https://ror.org/00arvcr78 , OG-3-22-5657-MF Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 04, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Casp1 and Ripk3 are required for homeostatic insulin secretion in mice Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Casp1 and Ripk3 are required for homeostatic insulin secretion in mice Madison D. Girouard , Conor O'Dwyer , Myriam P. Hoyeck , Cassandra A.A. Locatelli , Evgenia Fadzeyeva , Tyler K.T. Smith , Rui Yan Gao , Tanvi Ahluwalia , Sophia M. Perrakis , Andrew C. Clement , Antonio A. Hanson , Peyman Ghorbani , Lili Grieco-St-Pierre , Jianfan Nie , Mariam Hakoum , Julia R.C. Nunes , Aaron Reyes , Andrew R Pepper , Subash Sad , Erin E. Mulvihill , Jennifer E. Bruin , Morgan D. Fullerton bioRxiv 2026.09.01.748578; doi: https://doi.org/10.64898/2026.09.01.748578 Share This Article: Copy Citation Tools Casp1 and Ripk3 are required for homeostatic insulin secretion in mice Madison D. Girouard , Conor O'Dwyer , Myriam P. Hoyeck , Cassandra A.A. Locatelli , Evgenia Fadzeyeva , Tyler K.T. Smith , Rui Yan Gao , Tanvi Ahluwalia , Sophia M. Perrakis , Andrew C. Clement , Antonio A. Hanson , Peyman Ghorbani , Lili Grieco-St-Pierre , Jianfan Nie , Mariam Hakoum , Julia R.C. Nunes , Aaron Reyes , Andrew R Pepper , Subash Sad , Erin E. Mulvihill , Jennifer E. Bruin , Morgan D. 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