Biology subjects

Grieco-St-Pierre, L.

Publications and source records attributed to Grieco-St-Pierre, L..

4 recordsLinked to original sources

bioRxiv2026

Casp1 and Ripk3 are required for homeostatic insulin secretion in mice

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.

physiology↗

bioRxiv2026

β-cell NCK1 is reduced in type 2 diabetes, leading to inefficient β-cell UPR and insulin secretion and revealing sex-specific adaptation during metabolic stress

Type 2 diabetes is characterized by failure of pancreatic {beta} cells to adapt insulin secretion to metabolic demand, due to impaired {beta}-cell function and/or reduced {beta}-cell mass. The unfolded protein response (UPR) is central to this adaptation by maintaining endoplasmic reticulum homeostasis and supporting insulin biosynthesis, secretion, proliferation, and survival. NCK1, is an adaptor protein that regulates diverse cellular processes, including insulin biosynthesis and UPR activation, positioning it at the crossroads of several processes essential for {beta}-cell function. Moreover its silencing is reported to enhance adaptive PERK signaling and {beta}-cell survival in vitro, suggesting that it could represent an important regulator of {beta}-cell adaptation. Here, we explored this potential role for NCK1 using {beta}-cell-specific knockout mice (NCK1{beta}KO) and human islets of both sexes. NCK1 expression was positively regulated by glucose yet reduced in islets from individuals living with type 2 diabetes. Loss of {beta}-cell NCK1 impaired insulin gene expression, insulin content, and glucose-stimulated insulin secretion in vitro, and disrupted UPR activation. In vivo, {beta}-cell NCK1 deletion led to sex-dependent adaptation to maintain glucose homeostasis. Under high-fat/high-sucrose diet, both NCK1{beta}KO male and female mice increased pancreatic insulin content, but only males showed improved insulin secretion associated with islet expansion and {beta}-cell proliferation. Females, in contrast, exhibited impaired insulin secretion despite preserved insulin stores, associated with increased numbers of small islets and altered PERK pathway activation. These findings identify NCK1 as a regulator of {beta}-cell insulin synthesis, secretion, and UPR signaling, and reveal sex-specific adaptive mechanisms to {beta}-cell stress. Reduced NCK1 in islets from people living type 2 diabetes may disrupt {beta}-cell adaptation to metabolic stress and contribute to diabetes.

physiology↗

bioRxiv2026

β-cell-specific Ahr expression is critical to high-fat diet-induced hyperinsulinemia

ObjectiveThe aryl hydrocarbon receptor (AhR) pathway primarily mediates pollutant responses by activating xenobiotic metabolism enzymes like cytochrome P450 1A1 and 1A2 (CYP1A). Although AhR has also been implicated in systemic metabolic dysfunction and is inducible in pancreatic islets, its role in islet physiology remains unclear. MethodsWe analyzed a publicly available bulk human islet transcriptomic dataset to identify pathways associated with CYP1A1 expression. We also assessed islet responses to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and glucolipotoxicity (GLT) in vitro using two mouse models: a global Cyp1a1/1a2 double knockout (CypKO) model, which disrupts canonical AhR-CYP1A signaling in whole islets, and a {beta}-cell-specific Ahr knockout ({beta}AhrKO) model, which abolishes AhR signaling selectively in {beta}-cells. We then examined the role of {beta}-cell Ahr in early adaptation to high-fat diet (HFD) feeding in vivo. ResultsXenobiotic and nutrient metabolism pathways were enriched in donors with high CYP1A1 expression. Global Cyp1a1/1a2 deletion increased susceptibility of female mouse islets to TCDD-induced impairments in insulin secretion but had minimal effects on GLT responses in either sex. In contrast, {beta}-cell Ahr deletion did not affect islet responses to TCDD, but exacerbated GLT-induced islet dysfunction in male islets and increased baseline insulin secretion in both vehicle- and GLT-exposed female islets in vitro. Lastly, {beta}-cell Ahr deletion prevented adaptive HFD-induced hyperinsulinemia in both sexes in vivo. ConclusionIslet AhR signaling shapes responses to chemical and nutrient stressors in a context- and sex-dependent manner. While the canonical AhR-CYP1A axis supports female islet resilience to TCDD, {beta}-cell AhR signaling more broadly regulates nutrient stress responses in both sexes.

physiology↗

bioRxiv2024

Cisplatin exposure dysregulates pancreatic islet function in male mice

Cancer survivors have an increased risk of developing new-onset Type 2 diabetes compared to the general population. Moreover, patients treated with cisplatin, a commonly used chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes compared to age- and sex-matched controls. Insulin-secreting beta cells--located within pancreatic islets--are critical for maintaining glucose homeostasis, and dysregulated insulin secretion is central to Type 2 diabetes pathophysiology. Surprisingly, the impact of cisplatin treatment on pancreatic islets has not been reported. In this study, we aimed to determine if murine islet function is adversely affected by direct or systemic exposure to cisplatin. In vitro cisplatin exposure to male mouse islets profoundly dysregulated insulin release, reduced oxygen consumption, and altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family. In vivo cisplatin exposure led to sustained hypoinsulinemia and hypoglycemia in male mice. Pancreas tissues from cisplatin-exposed male mice showed increased proinsulin accumulation and expression of DNA-damage markers in beta cells, but no change in average islet size or % insulin+ area per islet. Our data suggest both direct and systemic cisplatin exposure cause acute defects in insulin secretion and may have lasting effects on islet health in mice.

molecular biology↗