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Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic β-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis by altering pancreatic β-cell physiology. However, their potential impact on glucagon-secreting pancreatic α-cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic MDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic α-cell line αTC1-9, we have explored the effects of these compounds on pancreatic α-cell viability, gene expression, and secretion. We found that cell viability was moderately affected after bisphenol-A (BPA), bisphenol-F (BPF), and perfluorooctanesulfonic acid (PFOS) exposure, although cytotoxicity was relatively low. In addition, all bisphenols, as well as di(2-ethylhexyl) phthalate (DEHP) and cadmium chloride (CdCl2), promoted a marked decreased on glucagon secretion, together with changes in the expression of glucagon and/or transcription factors involved in cell function and identity, such as Foxo1 and Arx. Overall, our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic α-cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic α-cell biology. [ABSTRACT FROM AUTHOR]

The function of the pancreatic [beta]-cell is the storage and release of insulin, the main hormone involved in blood glucose homeostasis. The results in this article show that the widespread [...]

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) is able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated the following two different pancreatic cell-based in vitro systems: the murine pancreatic β-cell line MIN6 as well as the human pancreatic β-cell line EndoC-βH1. Both were challenged with the following range of relevant concentrations of seven well-known EDCs: (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl2), and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable, deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic β-cell function, such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for the rapid screening of potential MDC effects on pancreatic β-cell physiology as well as for deciphering and better understanding the molecular mechanisms that underlie their action. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes mellitus (T2DM) are the most common metabolic disorders, with prevalence rates that are reaching epidemic proportions. Both are complex conditions affecting virtually all ages and with serious health consequences. The underlying cause of the problem is still puzzling, but both genetic and environmental factors including unhealthy diet, sedentary lifestyle, or the exposure to some environmental endocrine disrupting chemicals (EDCs) are thought to have a causal influence. In addition, the impact of early environment has recently emerged as an important factor responsible for the increased propensity to develop adult-onset metabolic disease. Suboptimal maternal nutrition during critical windows in fetal development is the most commonly studied factor affecting early programming of obesity and T2DM. In recent years, increasing experimental evidence shows that exposure to EDCs could also account for this phenomenon. In the present review, we will overview the most relevant findings that confirm the critical role of bisphenol-A, one of the most widespread EDCs, in the development of metabolic disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the base compound in the manufacture of polycarbonate plastics. In humans, epidemiological evidence has associated BPA exposure in adults with higher risk of type 2 diabetes and heart disease. OBJECTIVE: We examined the action of environmentally relevant doses of BPA on glucose metabolism in mice during pregnancy and the impact of BPA exposure on these females later in life. We also investigated the consequences of in utero exposure to BPA on metabolic parameters and pancreatic function in offspring. METHODS: Pregnant mice were treated with either vehicle or BPA (10 or 100 µg/kg/day) during days 9-16 of gestation. Glucose metabolism experiments were performed on pregnant mice and their offspring. RESULTS: BPA exposure aggravated the insulin resistance produced during pregnancy and was associated with decreased glucose tolerance and increased plasma insulin, triglyceride, and leptin concentrations relative to controls. Insulin-stimulated Akt phosphorylation was reduced in skeletal muscle and liver of BPA-treated pregnant mice relative to controls. BPA exposure during gestation had long-term consequences for mothers: 4 months postpartum, treated females weighed more than untreated females and had higher plasma insulin, leptin, triglyceride, and glycerol levels and greater insulin resistance. At 6 months of age, male offspring exposed in utero had reduced glucose tolerance, increased insulin resistance, and altered blood parameters compared with offspring of untreated mothers. The islets of Langerhans from male offspring presented altered Ca2+ signaling and insulin secretion. BrdU (bromodeoxyuridine) incorporation into insulin-producing cells was reduced in the male progeny, yet β-cell mass was unchanged. CONCLUSIONS: Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and that BPA may be a risk factor for diabetes. [ABSTRACT FROM AUTHOR]

Abstract: The estrogen receptor ERα is emerging as a key molecule involved in glucose and lipid metabolism. The main functions of pancreatic β-cells are the biosynthesis and release of insulin, the only hormone that can directly decrease blood glucose levels. Estrogen receptors ERα and ERβ exist in β-cells. The role of ERβ is still unknown, yet ERα plays an important role in the regulation of insulin biosynthesis, insulin secretion and β-cell survival. Activation of ERα by 17β-estradiol (E2) and the environmental estrogen bisphenol-A (BPA) promotes an increase of insulin biosynthesis through a non-classical estrogen-activated pathway that involves phosphorylation of ERK1/2. The activation of ERα by physiological concentrations of E2 may play an important role in the adaptation of the endocrine pancreas to pregnancy. However, if ERα is over stimulated by an excess of E2 or the action of an environmental estrogen such as BPA, it will produce an excessive insulin signaling. This may provoke insulin resistance in the liver and muscle, as well as β-cell exhaustion and therefore, it may contribute to the development of type II diabetes. [Copyright &y& Elsevier]

Abstract: Estrogens have been related to energy balance and glucose metabolism for a long time; however, the mechanisms involved in their actions are now being unveiled. The development of ERα and ERβ knockout mice has demonstrated the participation of these receptors in the regulation of many processes related to the control of energy homeostasis. These include food intake and energy expenditure, insulin sensitivity in the liver and muscle, adipocyte growth and its body distribution as well as the pancreatic β-cell function. In addition, other membrane receptors unrelated to ERα and ERβ function in key tissues involved in energy balance and glucose homeostasis, i.e. the islet of Langerhans and the hypothalamus. Along with naturally occurring estrogens, there are endocrine disrupters that act as environmental estrogens and can impair the physiological action of ERα, ERβ and other membrane ERs. New research is revealing a link between environmental estrogenic pollutants and the metabolic syndrome. [Copyright &y& Elsevier]

The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt β-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity. However, a precise understanding of the pancreatic β-cell response in ageing is still lacking. In this review, we summarize the age-related alterations, adaptations and/or failures of β-cells at the molecular, morphological and functional levels in mouse and human. Age-associated alterations include processes such as β-cell proliferation, apoptosis and cell identity that can influence β-cell mass. Age-related changes also affect β-cell function at distinct steps including electrical activity, Ca2+ signaling and insulin secretion, among others. We will consider the potential impact of these alterations and those mediated by senescence pathways on β-cells and their implications in age-related T2D. Finally, given the great diversity of results in the field of β-cell ageing, we will discuss the sources of this heterogeneity. A better understanding of β-cell biology during ageing, particularly at older ages, will improve our insight into the contribution of β-cells to age-associated T2D and may boost new therapeutic strategies. • Ageing is a risk factor for the development of impaired glucose homeostasis and diabetes. • Age-related alterations in the processes that regulate the pancreatic β-cell mass have been described. • Altered regulation of β-cell insulin secretion and the signaling pathways involved occur with ageing. • Impaired β-cell adaptation during ageing has a key role in the etiology of age-related diabetes. [ABSTRACT FROM AUTHOR]

Obesity is associated with insulin resistance and is known to be a risk factor for type-2 diabetes. In obese individuals, pancreatic beta-cells try to compensate for the increased insulin demand in order to maintain euglycemia. Most studies have reported that this adaptation is due to morphological changes. However, the involvement of beta-cell functional adaptations in this process needs to be clarified. For this purpose, we evaluated different key steps in the glucose-stimulated insulin secretion (GSIS) in intact islets from female ob / ob obese mice and lean controls. Obese mice showed increased body weight, insulin resistance, hyperinsulinemia, glucose intolerance and fed hyperglycemia. Islets from ob / ob mice exhibited increased glucose-induced mitochondrial activity, reflected by enhanced NAD(P)H production and mitochondrial membrane potential hyperpolarization. Perforated patch-clamp examination of beta-cells within intact islets revealed several alterations in the electrical activity such as increased firing frequency and higher sensitivity to low glucose concentrations. A higher intracellular Ca 2+ mobilization in response to glucose was also found in ob / ob islets. Additionally, they displayed a change in the oscillatory pattern and Ca 2+ signals at low glucose levels. Capacitance experiments in intact islets revealed increased exocytosis in individual ob / ob beta-cells. All these up-regulated processes led to increased GSIS. In contrast, we found a lack of beta-cell Ca 2+ signal coupling, which could be a manifestation of early defects that lead to beta-cell malfunction in the progression to diabetes. These findings indicate that beta-cell functional adaptations are an important process in the compensatory response to obesity. [ABSTRACT FROM AUTHOR]

Bisphenol-A (BPA) is a widespread endocrine disrupting chemical that constitutes a risk factor for type 2 diabetes mellitus (T2DM). Data from animal and human studies have demonstrated that early exposure to BPA results in adverse metabolic outcomes in adult life. In the present work, we exposed pregnant heterozygous estrogen receptor β (ERβ) knock out (BERKO) mice to 10 μg/kg/day BPA, during days 9–16 of pregnancy, and measured β-cell mass and proliferation in wildtype (WT) and BERKO male offspring at postnatal day 30. We observed increased pancreatic β-cell proliferation and mass in WT, yet no effect was produced in BERKO mice. Dispersed islet cells in primary culture treated with 1 nM BPA showed an enhanced pancreatic β-cell replication rate, which was blunted in pancreatic β-cells from BERKO mice and mimicked by the selective ERβ agonist WAY200070. This increased β-cell proliferation was found in male adult as well as in neonate pancreatic β-cells, suggesting that BPA directly impacts β-cell division at earliest stages of life. These findings strongly indicate that BPA during pregnancy upregulates pancreatic β-cell division and mass in an ERβ-dependent manner. Thus, other natural or artificial chemicals may use this ERβ-mediated pathway to promote similar effects. [ABSTRACT FROM AUTHOR]