Casp1 and Ripk3 are required for homeostatic insulin secretion in mice
- 1University of Ottawa
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 -, {beta}-, and {delta}-cells within the islet. There were significant reductions in the percentage of urocortin-3 (Ucn3)-positive {beta}-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.
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BibTeX
@misc{girouard2026casp1,
title = {{Casp1 and Ripk3 are required for homeostatic insulin secretion in mice}},
author = {M. D. Girouard and C. O'Dwyer and M. P. Hoyeck and C. A. A. Locatelli and E. Fadzeyeva and T. K. T. Smith and R. Y. Gao and T. Ahluwalia and S. M. Perrakis and A. C. Clement and A. A. Hanson and P. Ghorbani and L. Grieco-St-Pierre and J. Nie and M. Hakoum and J. R. C. Nunes and A. Reyes and A. R. Pepper and S. Sad and E. E. Mulvihill and J. E. Bruin and M. D. Fullerton},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.01.748578},
url = {https://www.biorxiv.org/content/10.64898/2026.09.01.748578v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Casp1 and Ripk3 are required for homeostatic insulin secretion in mice
AU - M. D. Girouard
AU - C. O'Dwyer
AU - M. P. Hoyeck
AU - C. A. A. Locatelli
AU - E. Fadzeyeva
AU - T. K. T. Smith
AU - R. Y. Gao
AU - T. Ahluwalia
AU - S. M. Perrakis
AU - A. C. Clement
AU - A. A. Hanson
AU - P. Ghorbani
AU - L. Grieco-St-Pierre
AU - J. Nie
AU - M. Hakoum
AU - J. R. C. Nunes
AU - A. Reyes
AU - A. R. Pepper
AU - S. Sad
AU - E. E. Mulvihill
AU - J. E. Bruin
AU - M. D. Fullerton
PY - 2026
DA - 2026/09/01
PB - bioRxiv
DO - 10.64898/2026.09.01.748578
UR - https://www.biorxiv.org/content/10.64898/2026.09.01.748578v1
AB - 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 -, {beta}-, and {delta}-cells within the islet. There were significant reductions in the percentage of urocortin-3 (Ucn3)-positive {beta}-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.
ER -