Endocrine-disrupting chemicals: Mainstream recognition of health effects and implications for the practicing internist.

Rapidly advancing evidence documents that a broad array of synthetic chemicals found ubiquitously in the environment contribute to disease and disability across the lifespan. Although the early literature focused on early life exposures, endocrine-disrupting chemicals (EDCs) are now understood to contribute substantially to chronic disease in adulthood, especially metabolic, cardiovascular, and reproductive consequences as well as endocrine cancers. The contribution to mortality is substantial, with over 90,000 deaths annually and at least $39 billion/year in lost economic productivity in the United States (US) due to exposure to certain phthalates that are used as plasticizers in food packaging. Importantly, exposures are disproportionately high in low-income and minoritized populations, driving disparities in these conditions. Though non-Hispanic Blacks and Mexican Americans comprise 12.6% and 13.5% of the US population, they bear 16.5% and 14.6% of the disease burden due to EDCs, respectively. Many of these exposures can be modified through safe and simple behavioral changes supported by proactive government action to both limit known hazardous exposures and to proactively screen new industrial chemicals prior to their use. Routine healthcare maintenance should include guidance to reduce EDC exposures, and a recent report by the Institute of Medicine suggests that testing be conducted, particularly in populations heavily exposed to perfluoroalkyl substances-chemicals used in nonstick coatings as well as oil- and water-resistant clothing.

Polychlorinated biphenyls and incident coronary heart disease-related outcomes in Great Lakes fish consumers.

BACKGROUND: Exposure to polychlorinated biphenyls (PCBs) has been linked to risk factors for cardiovascular disease such as increased inflammation, accelerated atherosclerosis, diabetes, and sex hormone dysregulation. Furthermore, there is increasing evidence suggesting associations between internal dose of PCBs and cardiovascular outcomes. OBJECTIVES: The purpose of this study is to investigate longitudinal associations of PCBs with coronary heart disease (CHD)-related outcomes in a cohort of Great Lakes sport fish consumers. METHODS: The Great Lakes Sport Fish Consumer cohort was established in the early 1990's. Eight hundred nineteen participants were followed from 1993 to 2017. Serum PCBs were measured in 1994/1995 (baseline), in 2001, and in 2004, while health history questionnaires were administered in 1996, 2003, 2010, and 2017. Cox models were used to prospectively investigate associations of total PCBs and PCB groupings, based on aryl hydrocarbon receptor activity, with incident self-reported physician diagnosis of coronary heart disease (CHD), myocardial infarction (MI), and angina pectoris. RESULTS: A 2-fold increase in phenobarbital-type PCBs was associated with a 72% increase in likelihood of self-reported incident diagnosis of CHD (HR=1.72, 95% CI: 1.06-2.81; p=0.0294). Similar results were observed for total PCBs (HR=1.68, 95% CI: 1.05-2.69; p=0.0306) and mixed methacholine/phenobarbital type (mixed-type) PCBs (HR=1.60, 95% CI: 1.02-2.52; p=0.0427), but not methacholine-type PCBs. PCBs were not strongly associated with risk of MI or angina. CONCLUSIONS: This study presents evidence that exposure to PCBs increases the risk of developing coronary heart disease. Given the large number of risk factors and causal pathways for CHD, future research is required to better understand biological mechanisms of action for PCBs on CHD.

Endocrine disruptors in plastics alter ß-cell physiology and increase the risk of diabetes mellitus.

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 ß-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 ß-cell mass and serum levels of insulin, leptin, and adiponectin. These studies reveal that disruption of ß-cell physiology by EDCs plays a key role in impairing glucose homeostasis by altering the mechanisms used by ß-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.

Associations of exposure to metal and metal mixtures with thyroid hormones: Results from the NHANES 2007-2012.

BACKGROUND: Disrupted thyroid homeostasis plays a role in neurocognitive dysfunction and metabolic disorders. Since individuals are exposed to multiple metals simultaneously, it is important to assess the effects of metal mixtures on thyroid hormone status. This study aimed to investigate the associations of metal mixtures and individual metals with thyroid hormone levels. METHODS: Data included 2399 men and 1988 women from the 2007-2012 National Health and Nutrition Examination Survey (2007-2012). Thyroid hormones measured included total triiodothyronine (T3), total thyroxine (T4), free forms of T3 (FT3) and T4 (FT4), and thyroid stimulating hormone (TSH). We included twelve metals (arsenic, barium, cobalt, cesium, molybdenum, antimony, thallium, tungsten, and uranium from urine; cadmium, lead, and mercury from blood) in traditional linear regression models controlling for 12 metals simultaneously and in quantile-based g-computation (QGC) to assess the relative contribution of each metal as well as the overall association with thyroid hormones as a metal mixture. RESULTS: There were associations of the total metal mixture with thyroid hormones for T3 (beta: -0.023, 95% CI: -0.04, -0.01, in women), T4 (beta: -0.03, 95% CI: -0.05, -0.01, in men; beta: -0.026, 95% CI: -0.04, -0.01, in women), and the T3:T4 ratio (beta: 0.026, 95% CI: 0.01, 0.05, in men). Arsenic had negative contributions to T3 and T4. Cadmium had a positive contribution to T4 but negative contributions to T3 and T3:T4. Lead had a positive contribution to T3 and T3:T4, but a negative contribution to T4. CONCLUSION: Multiple metals as a mixture were associated with thyroid hormone levels. Arsenic, cadmium, and lead were individually associated with multiple thyroid hormones. Examination of associations of metal mixtures and individual metals with thyroid hormones can contribute to an understanding of thyroid hormone homeostasis and provide evidence for developing intervention and guidance for health promotion.

Dimethyl sulfoxide acutely enhances regulated insulin secretion in the MIN6-K8 mouse insulinoma cell line.

Diabetes mellitus is a metabolic disorder projected to afflict 700 million people globally by 2045. Fundamental to the progression of diabetes is an insufficient supply of insulin to meet metabolic demand. The MIN6-K8 cell line is a mouse insulinoma model of pancreatic ß-cells frequently used to study the mechanisms of insulin secretion. Here, we evaluated the effects of short-term exposure to dimethyl sulfoxide (DMSO), a polar aprotic solvent commonly used in drug screening, on physiological characteristics of MIN6-K8 cells. Short-term exposure of MIN6-K8 cells to DMSO enhanced glucose-induced and tolbutamide-stimulated insulin secretion without significant effects on basal secretion or potassium responsiveness. Calcium influx was enhanced during glucose and tolbutamide treatments, suggesting that DMSO's mechanism of action is upstream of calcium-dependent insulin granule exocytosis. Based on these studies, investigators should use caution when conducting experiments with DMSO in the MIN6-K8 cell line and should report all DMSO concentrations when used as a solvent.

Impacts of food contact chemicals on human health: a consensus statement.

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.

Environmental neglect: endocrine disruptors as underappreciated but potentially modifiable diabetes risk factors.

Type 2 diabetes prevalence is increasing dramatically across the globe, imposing a tremendous toll on individuals and healthcare systems. Reversing these trends requires comprehensive approaches to address both classical and emerging diabetes risk factors. Recently, environmental toxicants acting as endocrine-disrupting chemicals (EDCs) have emerged as novel metabolic disease risk factors. EDCs implicated in diabetes pathogenesis include various inorganic and organic molecules of both natural and synthetic origin, including arsenic, bisphenol A, phthalates, polychlorinated biphenyls and organochlorine pesticides. Indeed, evidence implicates EDC exposures across the lifespan in metabolic dysfunction; moreover, specific developmental windows exhibit enhanced sensitivity to EDC-induced metabolic disruption, with potential impacts across generations. Importantly, differential exposures to diabetogenic EDCs likely also contribute to racial/ethnic and economic disparities. Despite these emerging links, clinical practice guidelines fail to address this underappreciated diabetes risk factor. Comprehensive approaches to stem the tide of diabetes must include efforts to address its environmental drivers.

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic ß-cells

In arsenic-endemic regions of the world, arsenic exposure correlates with diabetes mellitus. Multiple animal models of inorganic arsenic (iAs, as As3+) exposure have revealed that iAs-induced glucose intolerance manifests as a result of pancreatic ß-cell dysfunction. To define the mechanisms responsible for this ß-cell defect, the MIN6-K8 mouse ß-cell line was exposed to environmentally relevant doses of iAs. Exposure to 0.1-1 µM iAs for 3 days significantly decreased glucose-induced insulin secretion (GIIS). Serotonin and its precursor, 5-hydroxytryptophan (5-HTP), were both decreased. Supplementation with 5-HTP, which loads the system with bioavailable 5-HTP and serotonin, rescued GIIS, suggesting that recovery of this pathway was sufficient to restore function. Exposure to iAs was accompanied by an increase in mRNA expression of UDP-glucuronosyltransferase 1 family, polypeptide a6a (Ugt1a6a), a phase-II detoxification enzyme that facilitates the disposal of cyclic amines, including serotonin, via glucuronidation. Elevated Ugt1a6a and UGT1A6 expression levels were observed in mouse and human islets, respectively, following 3 days of iAs exposure. Consistent with this finding, the enzymatic rate of serotonin glucuronidation was increased in iAs-exposed cells. Knockdown by siRNA of Ugt1a6a during iAs exposure restored GIIS in MIN6-K8 cells. This effect was prevented by blockade of serotonin biosynthesis, suggesting that the observed iAs-induced increase in Ugt1a6a affects GIIS by targeting serotonin or serotonin-related metabolites. Although it is not yet clear exactly which element(s) of the serotonin pathway is/are most responsible for iAs-induced GIIS dysfunction, this study provides evidence that UGT1A6A, acting on the serotonin pathway, regulates GIIS under both normal and pathological conditions.

The Impact of the Affordable Care Act Medicaid Expansion on Type 2 Diabetes Diagnosis and Treatment: A National Survey of Physicians.

In 2014, the Affordable Care Act (ACA) provided funding for states to expand Medicaid coverage to include citizens who earned up to 138% of the federal poverty line. We sought to ascertain whether physicians practicing in Medicaid expansion states reported an increase in Medicaid or newly insured patients with type 2 diabetes in their panels, compared to physicians practicing in non-expansion states. We conducted a 55-question cross-sectional survey of 356 physicians providing outpatient care for adults with type 2 diabetes. We used adjusted multivariate logistic regression analyses to compare responses from physicians who practiced in expansion versus non-expansion states regarding whether they observed an increase since 2014 in (1) the number of Medicaid or newly insured patients with diabetes and (2) the number of additional newly or previously diagnosed patients who were newly receiving care, in their panels, adjusting for physician, practice, and patient-level characteristics, weighted for the U.S. physician population. 41% of eligible recipients responded. 64.2% of physicians who practice in an expansion state report an increase in Medicaid or newly insured patients with diabetes compared with 46.1% who practice in non-expansion states (p = 0.05; Table 2). Compared with physicians who practice in non-expansion states, physicians who practice in Medicaid expansion states are more likely to report an increase in the number of Medicaid or newly insured patients with diabetes in their practice since 2014. The increased access associated with the Medicaid expansion may improve long-term outcomes for patients with type 2 diabetes.

Arsenic exposure induces glucose intolerance and alters global energy metabolism.

Environmental pollutants acting as endocrine-disrupting chemicals (EDCs) are recognized as potential contributors to metabolic disease pathogenesis. One such pollutant, arsenic, contaminates the drinking water of ~100 million people globally and has been associated with insulin resistance and diabetes in epidemiological studies. Despite these observations, the precise metabolic derangements induced by arsenic remain incompletely characterized. In the present study, the impact of arsenic on in vivo metabolic physiology was examined in 8-wk-old male C57BL/6J mice exposed to 50 mg/l inorganic arsenite in their drinking water for 8 wk. Glucose metabolism was assessed via in vivo metabolic testing, and feeding behavior was analyzed using indirect calorimetry in metabolic cages. Pancreatic islet composition was assessed via immunofluorescence microscopy. Arsenic-exposed mice exhibited impaired glucose tolerance compared with controls; however, no difference in peripheral insulin resistance was noted between groups. Instead, early insulin release during glucose challenge was attenuated relative to the rise in glycemia. Despite decreased insulin secretion, pancreatic ß-cell mass was not altered, suggesting that arsenic primarily disrupts ß-cell function. Finally, metabolic cage analyses revealed that arsenic exposure induced novel alterations in the diurnal rhythm of food intake and energy metabolism. Taken together, these data suggest that arsenic exposure impairs glucose tolerance through functional impairments in insulin secretion from ß-cells rather than by augmenting peripheral insulin resistance. Further elucidation of the mechanisms underlying arsenic-induced behavioral and ß-cell-specific metabolic disruptions will inform future intervention strategies to address this ubiquitous environmental contaminant and novel diabetes risk factor.

Underutilized and Under Threat: Environmental Policy as a Tool to Address Diabetes Risk.

PURPOSE OF REVIEW: Diabetes is a burgeoning threat to public health in the USA. Importantly, the burden of diabetes is not equally borne across society with marked disparities based on geography, race/ethnicity, and income. The etiology of global and population-specific diabetes risk remains incompletely understood; however, evidence linking environmental toxicants acting as endocrine-disrupting chemicals (EDCs), such as particulate matter and arsenic, with diabetes suggests that environmental policies could play an important role in diabetes risk reduction. RECENT FINDINGS: Evidence suggests that disproportionate exposures to EDCs may contribute to subgroup-specific diabetes risk; however, no federal policies regulate EDCs linked to diabetes based upon diabetogenic potential. Nevertheless, analyses of European Union data indicate that such regulation could reduce diabetes-associated costs and disease burden. Federal laws only regulate EDCs indirectly. The accumulating evidence linking these chemicals with diabetes risk should encourage policymakers to adopt stricter environmental standards that consider both health and economic impacts.

Adipocytes under assault: environmental disruption of adipose physiology.

The burgeoning obesity epidemic has placed enormous strains on individual and societal health mandating a careful search for pathogenic factors, including the contributions made by endocrine disrupting chemicals (EDCs). In addition to evidence that some exogenous chemicals have the capacity to modulate classical hormonal signaling axes, there is mounting evidence that several EDCs can also disrupt metabolic pathways and alter energy homeostasis. Adipose tissue appears to be a particularly important target of these metabolic disruptions. A diverse array of compounds has been shown to alter adipocyte differentiation, and several EDCs have been shown to modulate adipocyte physiology, including adipocytic insulin action and adipokine secretion. This rapidly emerging evidence demonstrating that environmental contaminants alter adipocyte function emphasizes the potential role that disruption of adipose physiology by EDCs may play in the global epidemic of metabolic disease. Further work is required to better characterize the molecular targets responsible for mediating the effects of EDCs on adipose tissue. Improved understanding of the precise signaling pathways altered by exposure to environmental contaminants will enhance our understanding of which chemicals pose a threat to metabolic health and how those compounds synergize with lifestyle factors to promote obesity and its associated complications. This knowledge may also improve our capacity to predict which synthetic compounds may alter energy homeostasis before they are released into the environment while also providing critical evidentiary support for efforts to restrict the production and use of chemicals that pose the greatest threat to human metabolic health. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Environmental endocrine disruption of energy metabolism and cardiovascular risk.

Rates of metabolic diseases have increased at an astounding rate in recent decades. Even though poor diet and physical inactivity are central drivers, these lifestyle changes alone fail to fully account for the magnitude and rapidity of the epidemic. Thus, attention has turned to identifying novel risk factors, including the contribution of environmental endocrine disrupting chemicals. Epidemiologic and preclinical data support a role for various contaminants in the pathogenesis of diabetes. In addition to the vascular risk associated with dysglycemia, emerging evidence implicates multiple pollutants in the pathogenesis of atherosclerosis and cardiovascular disease. Reviewed herein are studies linking endocrine disruptors to these key diseases that drive significant individual and societal morbidity and mortality. Identifying chemicals associated with metabolic and cardiovascular disease as well as their mechanisms of action is critical for developing novel treatment strategies and public policy to mitigate the impact of these diseases on human health.

Developmental programming: An exploratory analysis of pancreatic islet compromise in female sheep resulting from gestational BPA exposure.

Developmental exposure to endocrine disruptors like bisphenol A (BPA) are implicated in later-life metabolic dysfunction. Leveraging a unique sheep model of developmental programming, we conducted an exploratory analysis of the programming effects of BPA on the endocrine pancreas. Pregnant ewes were administered environmentally relevant doses of BPA during gestational days (GD) 30-90, and pancreata from female fetuses and adult offspring were analyzed. Prenatal BPA exposure induced a trend toward decreased islet insulin staining and ß-cell count, increased glucagon staining and α-cell count, and increased α-cell/ß-cell ratio. Findings were most consistent in fetal pancreata assessed at GD90 and in adult offspring exposed to the lowest BPA dose. While not assessed in fetuses, adult islet fibrosis was increased. Collectively, these data provide further evidence that early-life BPA exposure is a likely threat to human metabolic health. Future studies should corroborate these findings and decipher the molecular mechanisms of BPA's developmental endocrine toxicity.

Thyroid-related Hormones and Hypertension Incidence in Middle-Aged and Older Hispanic/Latino Adults: The HCHS/SOL Study.

Background: Thyroid-related hormones act to regulate metabolic pathways and blood pressure (BP). However, the relationship of TSH and peripheral thyroid hormones and the role of the hypothalamic-pituitary-thyroid axis on hypertension development is not fully understood. We assessed sex-specific associations of thyroid-related hormones with BP and hypertension in Hispanic/Latino adults followed for 6 years. Methods: We studied 1789 adults, ages 45 to 74, free of diabetes at baseline from a subcohort of the Hispanic Community Health Study/Study of Latinos. We assessed TSH, free T4 (FT4), T3, and various indicators of thyroid axis. Using multivariable linear and Poisson regression adjusted for survey design and confounding variables, we estimated a priori sex-specific associations of thyroid-related hormones with changes in BP and hypertension development. Results: In men and women, TSH and TSH/FT4 ratios were associated with changes in diastolic BP and T3 with changes in pulse pressure and the development of hypertension from prehypertension. In men, a 1-SD increase in TSH [incident rate ratio (IRR) = 1.42; 95% confidence interval (CI): 1.15, 1.75] and TSH/FT4 ratio (IRR = 1.20; 95% CI: 1.07, 1.35) were positively associated with the development of hypertension from prehypertension while the TSH/FT4 ratio (IRR = 0.85; 95% CI: .72, 1.00) was protective in women. We observed sex-specific differences in associations of the T3/FT4 ratio and indices of pituitary sensitivity to thyroid hormones with changes in pulse pressure and hypertension development. Conclusion: Thyroid-related hormones are associated with sex-specific changes in BP and hypertension among Hispanic/Latino adults consistent with selected studies conducted in other populations. Mechanisms underlying associations of pituitary sensitivity to thyroid hormones with BP and hypertension development warrant further study.

Predictors of Toxic Metal/Metalloid Exposures Among Mexican Americans in Starr County, Texas.

BACKGROUND: Arsenic, cadmium, and lead are toxic elements that widely contaminate our environment. These toxicants are associated with acute and chronic health problems, and evidence suggests that minority communities, including Hispanic/Latino Americans, are disproportionately exposed. Few studies have assessed culturally specific predictors of exposure to understand the potential drivers of racial/ethnic exposure disparities. OBJECTIVE: We sought to evaluate acculturation measures as predictors of metal/metalloid (hereafter "metal") concentrations among Mexican American adults to illuminate potential exposure sources that may be targeted for interventions. METHODS: As part of a longitudinal cohort, 510 adults, aged 35 to 69 years, underwent baseline interview, physical examination, and urine sample collection. Self-reported acculturation was assessed across various domains using the Short Acculturation Scale for Hispanics (SASH). Multivariable linear regression was used to assess associations between acculturation and urinary concentrations of arsenic, cadmium, and lead. Ordinal logistic regression was utilized to assess associations between acculturation and a metal mixture score. Lastly, best subset selection was used to build a prediction model for each toxic metal with a combination of the acculturation predictors. RESULTS: After adjustment, immigration factors were positively associated with arsenic and lead concentrations. For lead alone, English language and American media and food preferences were associated with lower levels. Immigration and parental heritage from Mexico were positively associated with the metal mixture, while preferences for English language, media, and food were negatively associated. CONCLUSION: Acculturation-related predictors of exposure provide information about potential sources of toxic metals, including international travel, foods, and consumer products. The findings in this research study provide information to empower future efforts to identify and address specific acculturation-associated toxicant exposures in order to promote health equity through clinical guidance, patient education, and public policy.

Thyroid Hormones and Diabetes in Euthyroid Hispanic/Latino Adults of Diverse Backgrounds: HCHS/SOL.

Context: Previous studies have demonstrated associations of endogenous thyroid hormones with diabetes; less is known about stages of diabetes development at which they are operative, mechanisms of associations, and the role of the hypothalamic-pituitary-thyroid axis. Objective: This study examined associations of thyroid hormones with incident prediabetes and diabetes and with changes in glycemic traits in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest cohort of Hispanic/Latino adults with diverse backgrounds in the United States. Methods: The study includes 592 postmenopausal euthyroid women and 868 euthyroid men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Baseline hormones included thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (T3), and indices calculated from thyroid hormones evaluating pituitary sensitivity to thyroid hormone. Transitions to diabetes and prediabetes, and changes in glycemic traits determined at the 6-year follow-up visit, were examined using multivariable Poisson and linear regressions. Results: Among women, T3 (incident rate ratio [IRR] = 1.65; 95% CI, 1.22-2.24; P = .001) and TSH (IRR = 2.09; 95% CI, 1.01-4.33; P = .047) were positively, while FT4 (IRR = 0.59; 95% CI, 0.39-0.88; P = .011) was inversely, associated with transition from prediabetes to diabetes. Among men, the T3/FT4 ratio was positively associated with transition from normoglycemia to prediabetes but not from prediabetes to diabetes. Indices measuring sensitivity of the pituitary to thyroid hormone suggested increased sensitivity in men who transitioned from prediabetes to diabetes. Conclusion: Positive associations in women of T3 and TSH and inverse associations of FT4, as well as inverse associations of thyroid indices in men with transition from prediabetes to diabetes, but not from normoglycemia to diabetes, suggest decreased pituitary sensitivity to thyroid hormones in women and increased sensitivity in men later in the development of diabetes.

The novel endocrine disruptor tolylfluanid impairs insulin signaling in primary rodent and human adipocytes through a reduction in insulin receptor substrate-1 levels.

Emerging data suggest that environmental endocrine disrupting chemicals may contribute to the pathophysiology of obesity and diabetes. In a prior work, the phenylsulfamide fungicide tolylfluanid (TF) was shown to augment adipocyte differentiation, yet its effects on mature adipocyte metabolism remain unknown. Because of the central role of adipose tissue in global energy regulation, the present study tested the hypothesis that TF modulates insulin action in primary rodent and human adipocytes. Alterations in insulin signaling in primary mammalian adipocytes were determined by the phosphorylation of Akt, a critical insulin signaling intermediate. Treatment of primary murine adipose tissue in vitro with 100nM TF for 48h markedly attenuated acute insulin-stimulated Akt phosphorylation in a strain- and species-independent fashion. Perigonadal, perirenal, and mesenteric fat were all sensitive to TF-induced insulin resistance. A similar TF-induced reduction in insulin-stimulated Akt phosphorylation was observed in primary human subcutaneous adipose tissue. TF treatment led to a potent and specific reduction in insulin receptor substrate-1 (IRS-1) mRNA and protein levels, a key upstream mediator of insulin's diverse metabolic effects. In contrast, insulin receptor-ß, phosphatidylinositol 3-kinase, and Akt expression were unchanged, indicating a specific abrogation of insulin signaling. Additionally, TF-treated adipocytes exhibited altered endocrine function with a reduction in both basal and insulin-stimulated leptin secretion. These studies demonstrate that TF induces cellular insulin resistance in primary murine and human adipocytes through a reduction of IRS-1 expression and protein stability, raising concern about the potential for this fungicide to disrupt metabolism and thereby contribute to the pathogenesis of diabetes.