Biology subjects

Fadzeyeva, E.

Publications and source records attributed to Fadzeyeva, E..

3 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↗

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↗

bioRxiv2021

14-3-3ζ constrains insulin secretion in pancreatic β-cells by regulating mitochondrial function

While critical for neurotransmitter synthesis in the brain, members of the 14-3-3 protein family are often assumed to have redundant, over-lapping roles due to their high sequence homology and ubiquitous expression. Despite this assumption, various mammalian 14-3-3 isoforms have now been implicated in regulating cellular and organismal metabolism; however, these functions were primarily observed in cell lines or from systemic knockout mouse models. To date, we have begun to define the contributions of 14-3-3{zeta} in adipocytes, but whether 14-3-3{zeta} has additional metabolic roles in other cell types, such as the pancreatic {beta}-cell, is unclear. We previously documented a pro-survival role of 14-3-3{zeta} in MIN6 insulinoma cells, as depletion of 14-3-3{zeta} induced cell death, but paradoxically, whole-body deletion of 14-3-3{zeta} in mice resulted in significantly enlarged {beta}-cell area with no effects on insulin secretion. To better understand the role of 14-3-3{zeta} in {beta}-cells, we generated {beta}-cell-specific 14-3-3{zeta} knockout ({beta}14-3-3{zeta}KO) mice, and while no differences in {beta}-cell mass were observed, {beta}14-3-3{zeta}KO mice displayed potentiated insulin secretion due to enhanced mitochondrial function and ATP synthesis. Deletion of 14-3-3{zeta} led to profound changes to the {beta}-cell transcriptome, where pathways associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute treatment of mouse islets and human islets with pan-14-3-3 inhibitors recapitulated the potentiation in glucose-stimulated insulin secretion (GSIS) and mitochondrial function, suggesting that 14-3-3{zeta} is a critical isoform in {beta}-cells that regulates GSIS. In dysfunctional db/db islets and islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3{zeta}, was inversely associated with insulin secretory capacity, and pan-14-3-3 protein inhibition was capable of enhancing GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3{zeta} and its related isoforms in insulin secretion and mitochondrial function in {beta}-cells. A deeper understanding of how 14-3-3{zeta} influences {beta}-cell function will further advance our knowledge of how insulin secretion from {beta}-cells is regulated.

physiology↗