Biology subjects

Bruin, J. E.

Publications and source records attributed to Bruin, J. E..

14 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-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↗

bioRxiv2026

Cisplatin exposure alters long-term metabolic phenotype of male, but not female, high-fat diet-fed mice.

Cancer survivors face an increased risk of metabolic complications compared to the general population. Our group demonstrated that cisplatin, a platinum-based chemotherapeutic agent, robustly disrupts insulin secretion in vitro in mouse and human islets, and reduces plasma insulin levels in mice 2 weeks post-in vivo exposure. The long-term effects of in vivo cisplatin exposure alongside a pre-existing metabolic stressor, such as high-fat diet (HFD) feeding, have not been characterized. In the present study, male and female mice fed either a standard rodent chow or a 45 kcal% HFD were exposed to vehicle or 2 mg/kg cisplatin every other day for 2 weeks and then tracked for 18 weeks. Cisplatin exposure substantially influenced the metabolic phenotype of HFD-fed males but had limited impact on female HFD-fed mice. Vehicle-HFD and cisplatin-HFD male mice were both glucose intolerant compared to chow-fed controls yet, cisplatin-HFD male mice were lean, lacked a compensatory hyperinsulinemia response, and displayed increased insulin sensitivity compared to vehicle-HFD and vehicle-chow male controls. Additionally, transcriptional changes in islets isolated at 18-weeks post-exposure were largely cisplatin-driven in male mice, but diet-driven in female mice. Our study demonstrates that HFD-fed male mice exposed to cisplatin display persistent and exacerbated metabolic dysregulation relative to controls. ARTICLE HIGHLIGHTSO_ST_ABSWhy did we undertake this study?C_ST_ABSWe previously characterized the short-term metabolic effects of cisplatin exposure in vivo, but the long-term metabolic effects of cisplatin remained unknown. What is the specific question(s) we wanted to answer?How does cisplatin treatment impact long-term metabolic health outcomes in mice and do outcomes differ in the presence of a metabolic stressor? What did we find?Cisplatin significantly alters the metabolic phenotype of high-fat diet-fed male mice. What are the implications of our findings?Understanding how cisplatin exposure and metabolic stress interact is critical to mitigate long-term metabolic dysregulation in cancer survivors.

physiology↗

bioRxiv2025

Generation and validation of an aryl hydrocarbon receptor knockout human embryonic stem cell line

Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the {beta}-cell, which secretes insulin in response to nutritional stimuli. We previously reported that the adverse metabolic effects of high-dose dioxin exposure in mice are regulated by the aryl hydrocarbon receptor (AHR) specifically in {beta}-cells. Additionally, fetal exposure to low-dose dioxin reduced {beta}-cell area in female mice at birth; however, the role of AHR in {beta}-cell development has not been explored. To characterize the AHR pathway in developing human {beta}-cells, we differentiated human embryonic stem cells (hESCs) into "islet-like" cell clusters (SC-islets) in vitro and treated cells with vehicle or dioxin for 24-hours at key stages of differentiation. Dioxin exposure robustly upregulated AHR gene targets (CYP1A1, AHRR) at all stages of differentiation but only had modest effects on markers of islet development and maturity. We next generated an AHR knock-out (KO) hESC line and found that basal CYP1A1 expression was profoundly suppressed in AHR-KO cells compared to parental cells at all stages of differentiation. Key markers of developing and mature pancreatic islets were largely unaffected by AHR deletion; however, G6PC2 was consistently downregulated in SC-islets from AHR-KO cells compared to parental cells. Interestingly, AHR-KO SC-islets also showed modestly increased insulin secretion relative to the parental line, suggesting a role for AHR in islet development. This novel AHR-KO cell line will allow for deeper investigation into the impact of AHR on development of human islets and other cell lineages.

developmental biology↗

bioRxiv2025

Acute PFOS exposure consistently dysregulates glucose-stimulated insulin secretion across model systems

Aims/hypothesisPoly- and perfluoroalkyl substances (PFAS) are fluorinated chemicals widely used in consumer and industrial products. Serum PFAS concentrations have been linked to increased type 2 diabetes risk, but whether this is caused by direct effects of PFAS on the endocrine pancreas remains unclear. This study expands on previous biodistribution data to better characterize PFAS accumulation in human pancreas. We also assessed the effects of perfluorooctane sulfonic acid (PFOS) on pancreatic beta cell function using various model systems. MethodsWe measured concentrations of three legacy PFAS (PFOS, PFOA, PFHxS) in plasma and pancreas from 88 human donors. We also modeled PFOS and PFOA exposure in mice to confirm our human biodistribution data. We next exposed immortalized INS-1 cells, primary human donor islets, and primary mouse islets to DMSO (vehicle) or PFOS (1, 10 or 100 M) either acutely during a glucose-stimulated insulin secretion (GSIS) assay or for 48h (prolonged) and GSIS was subsequently measured. We also assessed whether the acute effects of PFOS on GSIS in mouse islets were mediated by G-protein coupled receptor-40 (GPR40) and/or glucagon-like peptide-1 receptor (GLP-1R). Lastly, we exposed female mice to DMSO or 10 mg/kg PFOS with or without a 2 g/kg glucose bolus to assess the acute effects of PFOS on glucose homeostasis in vivo. ResultsPFOS was detected at higher concentrations in both plasma and pancreas compared to PFOA and PFHxS in our human donor population. Similarly, PFOS accumulated in pancreas at concentrations 2x higher than PFOA in our mouse model. We provide compelling evidence that PFOS exposure dysregulates insulin secretion in various model systems. Prolonged PFOS exposure suppressed GSIS in INS-1 832/3 cells and mouse islets, whereas acute PFOS exposure stimulated GSIS in mouse islets and in a subset of our human donor islets. We also show that the acute effects of PFOS on GSIS in mouse islets were partly mediated by GLP-1R. Importantly, acute PFOS exposure increased plasma insulin levels in female mice in vivo, but only when PFOS exposure was concurrent with a glucose bolus. ConclusionsLegacy PFAS chemicals are consistently detected in human pancreas tissue. We clearly show that PFOS exposure dysregulates insulin secretion in various model systems, although effects varied based on the model and duration of exposure. Collectively, our findings support emerging evidence that PFOS contribute to beta cell dysfunction and points to the importance of model selection when assessing toxicological effects of PFAS on islet function.

molecular biology↗

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↗

bioRxiv2024

Crosstalk between the aryl hydrocarbon receptor and hypoxia inducible factor 1α pathways impairs downstream dioxin response in human islet models

The incidence of type 2 diabetes (T2D) is increasing globally at a rate that cannot be explained solely by genetic predisposition, diet, or lifestyle. Epidemiology studies report positive associations between exposure to persistent organic pollutants, such as dioxins, and T2D. We previously showed that 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) activates the xenobiotic-sensitive aryl hydrocarbon receptor (AHR) in pancreatic islets. The AHR is known to crosstalk with the hypoxia inducible factor 1 (HIF1) in hepatocytes but whether this crosstalk occurs in islet cells remains unknown. We assessed AHR-HIF1 pathway crosstalk by treating human donor islets and stem cell-derived islets (SC-islets) with TCDD +/- hypoxia and examined the changes in downstream targets of both AHR (e.g., CYP1A1) and HIF1 (e.g., HMOX1). SC-islets showed consistent crosstalk between AHR and HIF1 pathways; co-treatment of SC-islets with TCDD + hypoxia robustly suppressed the magnitude of CYP1A1 induction compared with TCDD treatment alone. In human islets, only 2 of 6 donors showing suppressed CYP1A1 induction following TCDD + hypoxia co-treatment. In both SC-islets and human donor islets we observed an unexpected hypoxia-mediated suppression of glucose-6-phosphate catalytic subunit 2 (G6PC2) expression. Our study shows AHR-HIF1 crosstalk occurs in both SC-islets and primary human donor islets, but the response of human islets varied between donors. In both models, the HIF1 pathway dominated over the AHR pathway during TCDD + hypoxia co-treatment. Our study is the first to examine whether AHR-HIF1 crosstalk occurs in islet cells and presents novel data on the impact of hypoxia on G6PC2 gene expression.

molecular biology↗

bioRxiv2024

HumanIslets: An integrated platform for human islet data access and analysis

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com, an open resource for the research community. This platform, which presently includes data on 547 human islet donors, allows users to access linked datasets describing molecular profiles, islet function and donor phenotypes, and to perform various statistical and functional analyses at the donor, islet and single-cell levels. As an example of the analytic capacity of this resource we show a dissociation between cell culture effects on transcript and protein expression, and an approach to correct for exocrine contamination found in hand-picked islets. Finally, we provide an example workflow and visualization that highlights links between type 2 diabetes status, SERCA3b Ca2+-ATPase levels at the transcript and protein level, insulin secretion and islet cell phenotypes. HumanIslets.com provides a growing and adaptable set of resources and tools to support the metabolism and diabetes research community.

systems biology↗

bioRxiv2024

CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner

Aims/hypothesisThe aryl hydrocarbon receptor (AhR) pathway is involved in cellular responses to a broad range of external stressors, making it an excellent candidate for understanding the interaction between environmental factors and type 2 diabetes risk. Studies suggest deleting or downregulating AhR protects against metabolic dysfunction in high-fat diet (HFD) fed mice; however, the contribution of downstream AhR targets in driving this phenotype remains unexamined. Cytochrome P450 1A1 and 1A2 (CYP1A1/1A2) are canonical AhR targets that encode xenobiotic metabolism enzymes. Interestingly, we have demonstrated that HFD feeding increases Cyp1a1 expression in mouse islets, which suggests CYP1A enzymes are involved in the response to metabolic stress. Since CYP1A1/1A2 activity can produce reactive oxygen intermediates, we hypothesized that chronic activation of these enzymes in tissues critical for regulating glucose homeostasis (e.g., liver, adipose, islets) will contribute to metabolic dysfunction following HFD feeding. MethodsAt 29 to 31 weeks of age, male and female global Cyp1a1/1a2 knockout (CypKO) and wildtype littermate control (CypWT) mice were fed either a 45% HFD or standard rodent chow for 14 weeks. Metabolic assessments were conducted throughout the study. ResultsCypKO females were partially protected from HFD-induced glucose intolerance compared to CypWT females, but both genotypes exhibited similar levels of insulin resistance. CypKO females also had lower plasma insulin levels in vivo and suppressed insulin secretion in isolated islets ex vivo compared to CypWT females. Gene expression patterns in female islets were generally similar across genotype and diet groups. In contrast, CypWT males became hyperinsulinemic and insulin resistant within 2 weeks of HFD feeding, while CypKO males maintained normal plasma insulin levels and insulin sensitivity. HFD feeding upregulated Cyp1a1 in CypWT male islets and this was accompanied by elevation of other islet stress genes. Interestingly, HFD feeding did not induce these stress gene responses in CypKO male islets, suggesting the islet stress response is mediated by activation of CYP1A1. We expected the global deletion of Cyp1a1/1a2 to have pronounced effects in the liver, but surprisingly, changes in liver pathology were predominantly driven by diet and not genotype in both sexes. Similarly, overall adiposity and adipose tissue inflammation were not affected by genotype. ConclusionsOur study highlights a novel role of islet Cyp1a1/1a2 in shaping the systemic metabolic response to HFD feeding. Our data suggest that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and the islet stress response. Importantly, the effects of Cyp1a1/1a2 deletion are sex-dependent.

molecular biology↗

bioRxiv2023

CD8 T cell hyperfunction and reduced tumour control in models of advanced liver fibrosis

Immune dysfunction, both depression and hyperactivation, in liver disease contributes to significant morbidities and mortalities, depending on liver damage severity and etiology. The underlying causes of immune dysfunction in advanced liver disease, whether pathogen or host-mediated, remain unclear. We reported lasting generalized CD8+ T cell hyperfunction in individuals with advanced liver fibrosis in chronic HCV infection. The separation of viral and fibrosis-driven effects or the association of this phenomenon with clinical outcomes of advanced liver fibrosis remains to be determined. Here, a hepatotoxic murine model of liver fibrosis was used to decouple liver fibrosis from viral infection. Carbon tetrachloride (CCl4)-treated mice presented progressive liver fibrosis within {approx}12 weeks, resulting in severe diffuse fibrosis, focal necrosis and surrounding mixed inflammation; pathology similar to that of chronic HCV infection. Taking advantage of this model, we investigated if liver fibrosis caused systemic CD8+ T cell hyperfunction and evaluated its impact on host immune response. At peak liver fibrosis, circulating CD8+ T cells presented increased expression of IFN-{gamma} and granzyme B (GrzB) in comparison to control animals. CD8+ T cell hyperfunction arose by 8 weeks of CCl4 treatment and was sustained with continued liver insult. As a result, fibrotic mice were unable to resist an ectopic tumour challenge and were less responsive to immunotherapy. Furthermore, CD8+ T cell dysfunction was observed in other contexts of chronic liver insult such as high fat diet-induced liver steatosis, even in the absence of significant fibrosis. Collectively, this study shows the impact of chronic liver insult on systemic CD8+ T cell function and its association with impaired immune response, such as tumour surveillance.

immunology↗

bioRxiv2023

The aryl hydrocarbon receptor in beta-cells mediates the effects of TCDD on glucose homeostasis in mice

Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 {micro}g/kg) in vivo reduced fasting and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant; whether these effects are driven by AhR activation in {beta}-cells requires investigation. Here we exposed female and male {beta}-cell specific AhR knockout ({beta}AhrKO) mice and littermate Ins1-Cre genotype controls ({beta}AhrWT) to a single high dose of 20 {micro}g/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from {beta}-cells increased insulin secretion ex vivo in female mouse islets and promoted modest weight gain in male mice under baseline conditions. Importantly, high-dose TCDD exposure impaired glucose homeostasis and {beta}-cell function in {beta}AhrWT mice, but these phenotypes were largely abolished in TCDD-exposed {beta}AhrKO mice. Our study demonstrates that AhR signaling in {beta}-cell is important for regulating baseline {beta}-cell function in female mice and energy homeostasis in male mice. We also show that {beta}-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both female and male mice, suggesting that the effects of TCDD on {beta}-cell function/health are driving metabolic phenotypes in peripheral tissues.

molecular biology↗

bioRxiv2020

Chronic low-dose dioxin exposure accelerates high fat diet-induced hyperglycemia in female mice

ObjectiveHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka "dioxin"), and increased diabetes risk, but rarely consider potential sex differences. We previously showed that a single high-dose TCDD exposure (20 {micro}g/kg) decreased plasma insulin levels in both male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. The purpose of the current study was to determine whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in either chow-fed or high fat diet (HFD)-fed mice. MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females at 12 weeks for Tempo-Seq(R) analysis. ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. TCDD caused a modest increase in islet area in males irrespective of diet, but reduced % beta cell area within islets in females. RNAseq analysis of female islets also revealed abnormal changes to endocrine and metabolic pathways in TCDD-exposed HFD-fed females compared chow-fed females. ConclusionsOur data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice, but promotes maladaptive metabolic responses in HFD-fed females.

pharmacology and toxicology↗

bioRxiv2019

Pancreas-specific miR-216a regulates proliferation and endocrine and exocrine cell function in vivo

Pancreas is a vital organ composed of exocrine and endocrine cells that aid digestion of food and regulate blood glucose levels. Perturbations in the function of pancreatic cells leads to the development of life-burdening and/or threatening diseases such as diabetes and pancreatic cancer. Thus, it is critical to understand the molecular check-points that maintain normal pancreas physiology. MicroRNAs (miRNAs) are small non-coding RNAs involved in regulating gene expression in normal and diseased tissues. Several miRNAs have tissue-specific patterns consistent with crucial functions in many biological processes. Yet, there is limited knowledge about the role of pancreas-specific miRNAs in pancreatic pathologies. Here, we report that miR-216a is a conserved, pancreas-specific miRNA that is expressed in both endocrine and exocrine cells. Deletion of miR-216a in mice leads to reduced {beta}-cell mass and a reduction in islet size under both chow and high-fat diet feeding conditions. We show that inhibition of miR-216a increases apoptosis and decreases cell proliferation in {beta}- and exocrine cells. Smad7 is upregulated in miR-216a deficient islets and cell cycle and proliferation are among the most significantly regulated biological processes in miR-216 knockout pancreata. Re-introduction of miR-216a in the pancreatic cancer line, PANC-1, increases cell migration more than 2-fold. In vivo, deletion of miR-216a in the pancreatic cancer prone mouse line KrasG12D;Ptf1aCreER inhibits the propensity of pancreatic cancer precursor lesions. Our study identifies miR-216a as an important pancreas-specific miRNA which may have implications for both diabetes and pancreatic cancer.

physiology↗

bioRxiv2019

Long-term metabolic consequences of acute dioxin exposure differ between male and female mice

Exposure to environmental pollutants is consistently associated with increased diabetes risk in humans. In male mice, acute dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) exposure supresses insulin secretion. This study investigated the long-term effects of a single TCDD injection (20 {micro}g/kg) on glucose metabolism and beta cell function in male and female mice. TCDD-exposed males displayed modest fasting hypoglycemia for [~]4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, and decreased beta cell area. TCDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or beta cell area in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can supress basal insulin levels long-term in both sexes, but effects on metabolism are sex-dependent.

pharmacology and toxicology↗