Diabetes care is characterized by the widespread use of plastics. With plastic-associated endocrine-disrupting chemicals (EDCs) implicated in diabetes pathogenesis, this review examines how medical plastics relate to diabetes and related disorders and proposes interventions to improve the situation. Plastic-associated EDCs and micro-/nanoplastics (MNPs) are linked to metabolic dysfunction. Medical care exposes patients to these agents; however, the precise contribution of diabetes care to these exposures and their associated adverse health effects remains poorly defined. Diabetes care is an increasingly important contributor to plastic pollution and climate change, yet inadequate systems exist to mitigate its environmental impact. Plastic-associated EDCs and MNPs remain an underappreciated metabolic health threat. Mitigating the deleterious impacts of plastics on human and planetary health requires concerted actions from manufacturers, scientists, policymakers, professional organizations, healthcare providers, and patients. Doing so has the potential to improve metabolic health and promote health equity.

This narrative review examines the potential role of plastic-derived chemicals and micro- and nanoplastics in metabolic diseases. It applies the recently proposed key characteristics (KCs) for metabolism-disrupting agents to evaluate chemicals commonly found in plastics and microplastic and nanoplastic particles. The KC framework, adapted from the KCs of toxicants originally developed for the identification of carcinogens, was applied to evaluate evidence from epidemiological, animal, and cellular studies. The review specifically evaluates compounds such as perfluorooctanoic acid (PFOA), bisphenol-S (BPS), and diisonyl phthalate (DINP), as well as emerging evidence relating to microplastics and nanoplastics (MNPs). Evidence shows that exposure to chemicals derived from plastics, including PFOA, BPA substitutes (eg, BPS) and phthalate substitutes, is linked to metabolic dysfunction, obesity, diabetes, and MASLD. BPS and DINP exhibit properties consistent with metabolism-disrupting agents, suggesting they are “regrettable substitutes.” Although human data on MNPs are limited, animal and cellular studies indicate they may also contribute to metabolic diseases, though mechanisms remain unclear. Rising exposure to chemicals in plastics poses significant risks to metabolic health. Identifying metabolic disruptors among thousands of plastic-associated chemicals is urgently needed. Increasing awareness and promoting the use of safer, inert, and reusable materials are essential steps to reduce health risks associated with plastic-derived pollutants and support more sustainable consumption.

Background: Gestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and children. GDM management provides an opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are not completely understood. In this study, we explore the role of transforming growth factor beta (TGF-(3) signaling in GDM, as this pathway reportedly affects pancreatic (3-cell development, function, and proliferation. Methods: We developed a GDM animal model. Serum circulating levels of TGF-(3 family ligands were measured in mice and human GDM. Pancreatic TGF-(3 signaling was investigated via gene and protein expression. Results: Our GDM animal model recapitulates the main pathophysiological features of human GDM, including glucose intolerance, decreased insulin sensitivity and pancreatic (3-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased (3-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF-(3/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic (3-cell function and regeneration capacity. Conclusions: Our data suggest that disruption of the pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway may represent a putative therapeutic target for GDM.

Diabetes mellitus has become one of the most devastating metabolic disorders of modern times. The causes behind the alarming increase in diabetes incidence are known to be multifactorial with exposure to some environmental chemicals as one important contributing factor. In the present article we will describe the most relevant effects of some widespread environmental chemicals on pancreatic β-cell function and thus on glucose homeostasis. Knowledge of environmental disruptors of β-cell physiology may contribute to a better understanding of the role of these compounds in the onset of diabetes.

The global prevalence of type 2 diabetes (T2D) continues to rise, and predictions indicate alarming records in coming decades. Although pancreatic β-cell dysfunction and insulin resistance are key factors in the etiology of T2D, the impairment of α-cells has been also implicated. Hyperglucagonemia and altered suppression of glucagon release can be frequently found in individuals with T2D, contributing to hyperglycemia. Bile acids have emerged as novel signaling molecules that regulate metabolism. A wealth of evidence shows that oral treatment with the bile acid TUDCA has therapeutic benefits in T2D, primarily by improving both insulin release from β-cells and insulin sensitivity in peripheral tissues. However, it is unknown whether TUDCA could affect other processes involved in the control of glucose metabolism. Here, we show that acute administration of TUDCA exerts a glucagonstatic action on mouse pancreatic islets and glucagon-releasing αTC1-9 cells. Pharmacological and/or molecular inhibition of the sphingosine-1-phosphate receptor 2 (S1PR2) and the PI3K pathway blunted the TUDCA effect on glucagon release. Additionally, TUDCA increased the activity of ATP-sensitive K+ (KATP) channels, decreased action currents and inhibited Ca2+ signaling in α-cells without directly affecting the exocytotic process. Glucose-induced suppression of glucagon secretion was found to be compromised under hyperglycemic conditions, yet TUDCA was able to inhibit α-cell function, highlighting its glucagonstatic effect in a pathological context. Collectively, these findings suggest that TUDCA-induced inhibition of glucagon secretion involves the opening of α-cell KATP channels and activation of the S1PR2/PI3K pathway, expanding the repertoire of potential therapeutic benefits of TUDCA in diabetes treatment.

Serious, rapid, and ongoing global changes in our environment since the 1950s present a major challenge to evolutionary conserved hormonal regulation processes. Hormones regulate development, growth, reproduction and maintenance of the metabolic function of intact organisms, species and populations, including humans. The multifactorial, simultaneous environmental changes create an immense, almost uncontrollable stress constellation for the regulatory capabilities of hormonal systems. Furthermore, the speed and scale of the triple planetary crisis exceed the capacity for genetic adaptation through biological progeny. Instead, the changing environment is leaving discernible epigenomic marks and changes that may have irreversible consequences for generations to come.

BACKGROUND:Gestational diabetes mellitus (GDM) is the most common metabolic disease during pregnancy and increases the prevalence of type 2 diabetes in both mothers and children. GDM management provides an opportunity to prevent and lower the global burden of diabetes across life. Molecular mechanisms underlying GDM are not completely understood. In this study, we explore the role of transforming growth factor beta (TGF-β) signaling in GDM, as this pathway reportedly affects pancreatic β-cell development, function, and proliferation. METHODS:We developed a GDM animal model. Serum circulating levels of TGF-β family ligands were measured in mice and human GDM. Pancreatic TGF-β signaling was investigated via gene and protein expression. RESULTS:Our GDM animal model recapitulates the main pathophysiological features of human GDM, including glucose intolerance, decreased insulin sensitivity and pancreatic β-cell malfunction. Islets from GDM mice showed impaired insulin secretion and content, altered ion channel activity, and decreased β-cell replication rate. This was accompanied by increased Smad2 signaling activation. Elevated serum activin-A and inhibin levels were found in mice and human GDM, suggesting their role as upstream signaling transducers of pancreatic Smad2 activation. Pharmacological inhibition of TGF-β/Activin-Smad2 signaling in mouse pancreatic islets resulted in improved pancreatic β-cell function and regeneration capacity. CONCLUSIONS:Our data suggest that disruption of the pancreatic Smad2 pathway plays a critical role in the pathogenesis of GDM, contributing to abnormal glucose homeostasis and inadequate insulin secretion. Attenuation of this signaling pathway may represent a putative therapeutic target for GDM.

Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca2+ signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.

Metabolism-disrupting agents (MDAs) are chemical, infectious or physical agents that increase the risk of metabolic disorders. Examples include pharmaceuticals, such as antidepressants, and environmental agents, such as bisphenol A. Various types of studies can provide evidence to identify MDAs, yet a systematic method is needed to integrate these data to help to identify such hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we developed 12 KCs of MDAs based on our knowledge of processes underlying metabolic diseases and the effects of their causal agents: (1) alters function of the endocrine pancreas; (2) impairs function of adipose tissue; (3) alters nervous system control of metabolic function; (4) promotes insulin resistance; (5) disrupts metabolic signalling pathways; (6) alters development and fate of metabolic cell types; (7) alters energy homeostasis; (8) causes inappropriate nutrient handling and partitioning; (9) promotes chronic inflammation and immune dysregulation in metabolic tissues; (10) disrupts gastrointestinal tract function; (11) induces cellular stress pathways; and (12) disrupts circadian rhythms. In this Consensus Statement, we present the logic that revealed the KCs of MDAs and highlight evidence that supports the identification of KCs. We use chemical, infectious and physical agents as examples to illustrate how the KCs can be used to organize and use mechanistic data to help to identify MDAs.

BACKGROUND:The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES:We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. DISCUSSION:We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.

ABSTRACT Ligand binding to estrogen receptors (ER), ERα and ERβ, controls the physiology of estrogen-responsive tissues through nuclear and extranuclear initiated pathways. We have found that ligands activate the extranuclear pathway by a mechanism involving proton transfer. The low affinity ligand and widespread endocrine disruptor Bisphenol-A (BPA) initiated nuclear and extranuclear actions. Concentrations similar to the receptor affinity initiated the nuclear pathway, whereas much lower concentrations initiated the extranuclear pathway. Experiments in different cell types using deuterated molecules of BPA and the ERβ agonist, diarylpropionitrile (DPN), indicated that a proton transfer from the hydroxyl groups to an amino acid acceptor within the ligand binding domain switches the extranuclear pathway. Activation of this pathway elicited a pattern of protein interactions with ERβ that regulated most of the important cellular functions. Thus, the extranuclear actions of ERβ are initiated by a molecular mechanism different from that of nuclear actions. This mechanism may work for other ligands and nuclear receptors.

Plastic pollution breaks a planetary boundary threatening wildlife and humans through its physical and chemical effects. Of the latter, the release of endocrine disrupting chemicals (EDCs) has consequences on the prevalence of human diseases related to the endocrine system. Bisphenols (BPs) and phthalates are two groups of EDCs commonly found in plastics that migrate into the environment and make low-dose human exposure ubiquitous. Here we review epidemiological, animal, and cellular studies linking exposure to BPs and phthalates to altered glucose regulation, with emphasis on the role of pancreatic β-cells. Epidemiological studies indicate that exposure to BPs and phthalates is associated with diabetes mellitus. Studies in animal models indicate that treatment with doses within the range of human exposure decreases insulin sensitivity and glucose tolerance, induces dyslipidemia, and modifies functional β-cell mass and serum levels of insulin, leptin, and adiponectin. These studies reveal that disruption of β-cell physiology by EDCs plays a key role in impairing glucose homeostasis by altering the mechanisms used by β-cells to adapt to metabolic stress such as chronic nutrient excess. Studies at the cellular level demonstrate that BPs and phthalates modify the same biochemical pathways involved in adaptation to chronic excess fuel. These include changes in insulin biosynthesis and secretion, electrical activity, expression of key genes, and mitochondrial function. The data summarized here indicate that BPs and phthalates are important risk factors for diabetes mellitus and support a global effort to decrease plastic pollution and human exposure to EDCs.

On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshop's objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity. The attendees agreed that environmental obesogens are real, significant, and a contributor at some degree to weight gain at the individual level and to the global obesity and metabolic disease pandemic at a societal level; moreover, it is at least, in theory, remediable.

Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults.

Introduction:Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic β-cell destruction. Interferon-α (IFNα) is a key player in early human type 1 diabetes pathogenesis. IFNα activates the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway, leading to inflammation, HLA class I overexpression, endoplasmic reticulum (ER) stress, and β-cell apoptosis (in synergy with IL-1β). As TYK2 inhibition has raised as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect β-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1β).Methods:All experiments were performed in the human EndoC-βH1 β-cell line. HLA class I expression, inflammation, and ER stress were evaluated by real-time PCR, immunoblotting, and/or immunofluorescence. Apoptosis was assessed by the DNA-binding dyes Hoechst 33342 and propidium iodide or caspase 3/7 activity. The promoter activity was assessed by luciferase assay.Results:Deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 activation and MHC class I hyperexpression, in a dose-dependent manner without affecting β-cell survival and function. A comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signaling pathway. Deucravacitinib protected β-cells from the effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β.Discussion:Our findings suggest that, by protecting β-cells against the deleterious effects of proinflammatory cytokines without affecting β-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.

Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here, we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem to be an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.

Aims/hypothesis Type 1 diabetes is characterised by pancreatic islet inflammation and autoimmune-driven pancreatic beta cell destruction. Type I interferons, such as IFNα, are key players in early human type 1 diabetes pathogenesis, as the activation of the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway induces inflammation, a long-lasting MHC class I overexpression, endoplasmic reticulum (ER) stress, and beta cell apoptosis (in synergy with IL-1β). As TYK2 inhibition has been suggested as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect beta cells against the damaging effects of IFNα and other proinflammatory cytokines (i.e. IFNγ and IL-1β). Methods Inflammation, ER stress, and apoptosis were evaluated by real-time PCR, immunoblot, immunofluorescence, and nuclear dyes. The promoter activity was assessed by luciferase assay and insulin secretion and content by ELISA. All experiments were performed in the human EndoC- βH1 cell line. Results Pre-treatment with deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 phosphorylation and protein expression as well as MHC class I hyperexpression, in a dose-dependent manner without affecting beta cell survival and function. Comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signalling pathway. Pre-treatment with deucravacitinib protected beta cells from the pro-apoptotic and proinflammatory effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially revert apoptosis and inflammation in cells previously treated with IFNα + IL-1β or IFNγ + IL-1β. Conclusions/interpretation Our findings suggest that, by protecting beta cells against the deleterious effects of proinflammatory cytokines without affecting beta cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes. Research in context What is already known about this subject? In type 1 diabetes, pancreatic beta cells are killed by the immune system In early insulitis, type I interferons are crucial for the dialogue between the immune system and pancreatic beta cells Activation of the TYK2-STAT pathway by IFNα induces inflammation, HLA class I overexpression, ER stress, and beta cell apoptosis. What is the key question? Could the TYK2 inhibitor deucravacitinib prevent the deleterious effects of IFNα and other cytokines in beta cells? What are the new findings? Deucravacitinib prevented IFNα effects in a dose-dependent manner without affecting beta cell function and survival Pre-treatment with deucravacitinib protected beta cells against apoptosis and inflammation induced by two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β Addition of deucravacitinib to cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β partially reverted apoptosis and inflammation induced by these cytokines How might this impact on clinical practice in the foreseeable future? Due to its protective effect against proinflammatory cytokines in beta cells, our findings suggest that deucravacitinib could be repurposed for the prevention or treatment of type 1 diabetes.

17β-estradiol protects pancreatic β-cells from apoptosis via the estrogen receptors ERα, ERβ and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ERα and ERβ, or in dispersed islet cells from ERβ knockout (BERKO) mice. However, the ERα and ERβ agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERβ form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as GPER activation by G1 decreased ERαβ heterodimers. We propose that ERαβ heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ERαβ heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.