HORMONES 2010, 9(2):118-126
Bisphenol-A: a new diabetogenic factor?
Paloma Alonso-Magdalena1,2, Ana Belιn Ropero1,2, Sergi Soriano1,2, Ivan Quesada1,2, Angel Nadal1,2

1CIBER of Diabetes and Associated Metabolic Diseases, CIBERDEM, 2Institute of Bioengineering, University Miguel Hernαndez of Elche, Elche, Spain


The aim of this review was to analyze the potential effects of environmental chemicals on homeostatic control related to glycemia and energy balance. Many of the environmental chemicals can mimic or interfere with the action of hormones and are generally referred to as “endocrine disruptors”. Among these compounds, polychlorinated biphenyls, dioxins, phthalates and bisphenol-A have been correlated with alterations in blood glucose homeostasis in humans. In rodents it has been demonstrated that small doses of bisphenol-A have profound effects on glucose metabolism. Therefore, this altered blood glucose homeostasis may enhance the development of type 2 diabetes.


Bisphenol-A, Diabetes, Estradiol, Estrogen Receptors, Glucose Homeostasis, Islet of Langerhans

Read PDF


Over three and a half millennia have passed since the first description of diabetes. An Egyptian papyrus of 1550 BC mentions a rare disorder that causes the patient to urinate frequently and to lose weight. Some centuries later, the Greek physician Aretaeus would name this condition “Diabetes mellitus”, the first word meaning “a flowing through” and the complete appellation denoting the passing of large amounts of urine that is sweet because it contains sugar (glucose). Down through the ages different definitions were applied, but an in-depth understanding of the disease started to develop only during the last century.

Today, diabetes represents one of the most serious health problems worldwide. It has been estimated that more than 170 million people suffer from diabetes mellitus and this number is projected to increase to 366 million by the year 2030.1 Despite constant efforts, the number of patients is increasing continuously and it is now estimated that diabetes is responsible for 2.9 million deaths per year.

While the etiology of the problem remains puzzling, what is well accepted is that two factors are crucial in the development of type 2 diabetes: insulin resistance and β-cell dysfunction. Moreover, it is thought that this disease has a multifactorial origin in which genetic predisposition, obesity, diet and lack of exercise seem to be important players.

How does diabetes appear?

In order to maintain blood glucose concentration within the physiological levels, a complex communication between different tissues, including brain, adipose tissue, muscle, liver and pancreas is required. In the fasting state, plasma glucose concentration is low, which in turn keeps plasma insulin levels low. By contrast, the levels of counter-regulatory hormones like glucagon, adrenaline and corticosteroids increase, this increase accounting for the production of glucose by the liver. On the other hand, after a meal, when the level of blood glucose is high, insulin is secreted by pancreatic β-cells. Insulin will decrease blood glucose by promoting glucose uptake by adipocytes and muscle, as well as preventing the liver from producing glucose by suppressing glycogenolysis and gluconeogenesis.2-5

Insulin sensitivity is a non-linear process and fluctuations occur during a normal life cycle. Thus diminished insulin sensitivity is observed during pregnancy, puberty or aging, which means that the efficiency of insulin to promote glucose uptake in muscle or fat or to inhibit glucose production in the liver is decreased. In normal conditions, this insulin resistance is compensated by an increase of insulin release by the pancreas, thereby maintaining normal glucose tolerance.6,7 However, if this compensation fails, hyperglycemia will appear, which leads in turn to the development of type 2 diabetes.6-9


Current data indicate that estradiol (E2) is much more than a sex hormone, as it has been demonstrated for years that E2 plays an important role in the function of the cardiovascular, musculoskeletal, immune and central nervous systems.10 Moreover, recent studies have shown the importance of E2 for energy balance and glucose homeostasis.11,12

However, whether E2 has a positive or a negative effect on glucose homeostasis is still a matter of debate. Many authors consider that E2 at physiological levels is involved in the maintainance of normal insulin sensitivity, but outside the physiological range, E2 may promote insulin resistance and diabetes.13,14 The notion that high E2 concentration is detrimental to blood glucose homeostasis dates back to 1960s when it was reported that some women taking high-estrogen oral contraceptives developed insulin resistance.15,16 On the other hand, women with low serum levels of estrogens, as for example during menopause, are at greater risk of developing type 2 diabetes.13,15 Estrogen replacement in postmenopausal women, depending on dose and duration of treatment, is associated with an improvement of insulin sensitivity and a reduction of blood glucose, lipid, cholesterol levels and body fat.17-19

Aromatase knockout (ARKO) and ERα knockout (ERKO) mice provided the first evidence of the contribution of estrogen/ERα signaling to glucose metabolism by demonstrating that both animal models showed glucose intolerance and insulin resistance.20,21 Analogous findings were also found in humans; patients with aromatase deficiency suffered from impairment of glucose metabolism and presented insulin resistance.22 Regarding ERαfunction, only one case has been described in the literature. It concerns a male with estrogen deficiency due to an inactivating mutation of the ERαgene. The man showed glucose intolerance in association with high serum E2, estrone, FSH and LH levels.22,23 Moreover, genetic polymorphism of the ERα gene in humans has been associated with type 2 diabetes and the metabolic syndrome.24

Although up to now evidence has pointed to ERα as the main mediator of the regulatory effect of E2 on glucose homeostasis, both ERα and ERβ have been associated with the control of energy balance. The following is a brief overview of the action of both receptors in different tissues.

The disruption of ERα in the ventromedial nucleus of the hypothalamus leads to weight gain, increased visceral adiposity, hyperphagia, hyperglycaemia and impaired energy expenditure in female mice.25 Moreover, ERβ has been shown to have anorectic effects mediated via the central nervous system.26

In the liver, ERα is involved in the modulation of insulin sensitivity, proof of this being the fact that ERKO mice develop severe hepatic insulin resistance with an associated decreased glucose uptake in skeletal muscle.27

GLUT 4 is the major insulin-stimulated glucose transporter and constitutes the main rate-limiting step in insulin-stimulated glucose transport both in muscle and adipose tissue. In 2006, Barros et al reported that both receptors (ERα and ERβ can modulate GLUT4 expression in skeletal muscles of mice.28

Regarding adipose tissue, it has long been proposed that estrogens can control the distribution of body fat and metabolism, and this action is thought to be mediated by ERαand ERβ29-32 The absence of ERα produces adipocyte hyperplasia and hypertrophy in white adipose tissue and is followed by insulin resistance and glucose intolerance;21,29 meanwhile, ovariectomy of ERKO mice improves insulin resistance.31 In humans, both receptors may play an important role in fat metabolism. The ratio ERα/ERβ seems to be associated with obesity as well as with prolactin serum level and production of leptin in the omental adipose tissue in women.33

The role of estrogen receptors in the endocrine pancreas is gradually being elucidated. We have recently demonstrated that E2 increases insulin mRNA levels and insulin biosynthesis, incrementing insulin content and insulin release in an ERα dependent manner.34 Besides the role that ERαplays in the regulation of pancreatic insulin content, it can partly mediate the antiapoptotic effect that E2 has in pancreatic β-cells after streptozotocin treatment.35 Recently, we have reported that ERβ has a rapid insulinotropic action that involves the atrial natriuretic peptide receptor.36


Growing evidence accumulated over the last decade supports the hypothesis that many chemicals in the environmental can interfere with complex endocrine signaling mechanisms and cause adverse consequences. These chemicals are collectively termed endocrine disrupting chemicals (EDCs), endocrine disruptors or environmental estrogens. They have been defined by the Environmental Protection Agency (EPA) as “an exogenous agent that interferes with the production, release, transport, metabolism, binding, action, or elimination of natural hormones in the body responsible for the maintenance of homeostasis and the regulation of developmental processes”.37 A large number of EDCs act by mimicking the action of E2 38 and, based on this evidence, we hypothesized that exposure to an exogenous chemical acting as the natural hormone but in an inappropriate concentration and during an improper time window may affect multiple organ system development and function including control of energy balance and glucose homeostasis. Among the various EDCs we selected to focus our attention on the effects of bisphenol-A (BPA).

BPA from bench to human exposure

Bisphenol-A (BPA) was first synthesized by Dianin in 1891 and was reported to be a synthetic estrogen in the 1930s.39 At the same time, diethylstilbestrol (DES) was also tested and, due to its strong estrogenic activity, BPA essentially took a backseat. In the 1950s, BPA was rediscovered as a compound that could be polymerized to make polycarbonate plastic, and from that moment until the present day it has been commonly used in the plastics industry. BPA is one of the highest volume chemicals produced worldwide, with over 6 billion pounds produced each year and over 100 tons released into the atmosphere yearly.40 It is used as the base compound in the manufacture of polycarbonate plastic and the resin lining of food and beverage cans, as well as an additive in other widely used plastics such as polynil chloride and polyethylene terephthalate. It is present not only in food and beverage containers but also in some dental material.41 Numerous studies have found that BPA can leach from polycarbonate containers; heat and either acidic or basic conditions accelerate hydrolysis of the ester bond linking BPA monomers, leading to release of BPA and thus concomitant potential human exposure.42,43 Indeed, the potential for BPA exposure was demonstrated when BPA was detected in 95% of the urine samples in the USA.44 Its concentration in human serum ranges from 0.2 to 1.6 ng/ml (0.88-7.0 nM).45,46 Moreover, it has been detected in amniotic fluid, neonatal blood, placenta, cord blood and human breast milk.43

Concerning the potential risk of BPA, the lowest-observable adverse effect level (LOAEL) was set in the 1980s at 50 mg/kgBW/day and the Environmental Protection Agency (EPA) calculated a “reference dose” or safe dose of 50 µg/ kgBW/day. However, since that time, abundant scientific evidence has demonstrated that BPA can interfere with the endocrine signaling pathways at doses below the calculated safe dose, particularly after exposure during fetal, neonatal or perinatal periods, but also in adulthood. A review by Richter and colleagues provides a comprehensive account of the findings from in vivo studies of BPA exposure.47

Tissue-specific analysis of BPA. Effects on insulin sensitivity by using animal models

- Effects on peripheral tissues:

Recently, we have demonstrated that the administration of BPA in adult male mice provokes hyperinsulinemia and mild insulin resistance.48 This phenomenon, as is described below, is at least partly due to a direct effect of BPA on the endocrine pancreas, although the possibility exists that BPA may also have direct effects on peripheral tissues. Indeed, unpublished results from our group have shown that BPA can also alter insulin signaling in skeletal muscle and adipose tissue.

There are also some studies documenting the hepatic effects of BPA. It has been proposed that BPA can cause abnormalities in the liver of rats and mice, since administration of BPA induces oxidative stress by decreasing antioxidant enzymes both at low (0.2-20 µg/kg)49 and high doses (25-50 mg/kg).50

Regarding adipose tissue and energy balance, a significant reduction in body weight and food intake was reported when ovariectomized adult female rats were treated with high doses of BPA,51 while other studies did not find alteration in body weight, fat depots or trygliceride levels at low doses (33-333 µg/kg).52 On the other hand, Sakurai et al reported that BPA can affect glucose transport in adipocytes. They have demonstrated that in the presence of BPA there is an increase of basal and insulin-stimulated glucose transport due to an increased amount of GLUT4.53 Others have shown that BPA stimulates adipogenesis in 3T3-L1 adipocytes.54,55 Moreover, exposure of the fetus to low doses (25 µg/kg/day) of BPA in rats resulted in high birth weight.56,57 Interestingly, it has been reported that BPA at 1 and 10 nM concentrations inhibits adiponectin release, an important adipokine that protects humans from the metabolic syndrome.58

- Effects on the endocrine pancreas:

Generally, estradiol action is considered to occur in the nucleus and involves the direct participation of estrogen receptors (ERα and ERβ) as transcription factors. In addition, it has been shown that there are many other alternative pathways that can mediate estradiol action.10,59 It is thought that ERα and ERβ from outside the nucleus, in the cytosol and the plasma membrane, are able to activate other signaling cascades. Other novel membrane ERs have also been described; these novel receptors may be isoforms of ERs obtained by alternative splicing or completely new proteins encoded by different genes.60 Moreover, estradiol can act by binding directly to other neurotransmitter receptors and to ion channels.61,62 Most frequently, these alternative pathways occur within seconds or minutes after addition of estradiol and for that reason they have been named rapid estrogen effects.

a. Rapid effects of BPA on pancreatic α-cells

Diabetes mellitus denotes malfunction of the β-cell and decreased insulin secretion. However, we should keep in mind that α-cells also play an important role in the regulation of glycaemia and nutrient homeostasis and that diabetes is associated with disorders in the levels of both insulin and glucagon.63,64 Pancreaticα-cells represent 5-10% of the cell population of the islets of Langerhans and coexist along with insulin-secreting β-cells, δ-cells and PP cells. They secrete glucagon in response to low glucose concentration in a Ca2+ dependent manner. Glucagon enhances the synthesis and mobilization of glucose in the liver and, in addition, it has many extrahepatic effects, such as the increase of lipolysis in adipose tissue, a positive ionotropic effect in the heart, a role in the satiety control in the central nervous system and the regulation of the glomerular filtration rate.64 Little is known about the stimulus-secretion coupling in α-cells but it seems to contain a specific set of ion channels, including a voltage-dependent Na+ channel, responsible for their electrical activity;65-67 the intracellular calcium ion [Ca2+]i oscillating at low glucose concentration.68,69 Because of the calcium influx, the exocytotic machinery is initiated and glucagon is released.70,71 When the extracellular glucose concentration increases to the level required for insulin to be released, the frequency of [Ca2+]i oscillations diminishes and, as a result, glucagon release decreases.69,72

In previous studies we have demonstrated that the xenoestrogen BPA at a concentration of 1 nM suppresses low glucose-induced intracellular calcium ion oscillations. This action is characterized by rapid onset and is initiated at the level of plasma membrane. The intracellular pathway triggered by the binding of BPA involves a pertussis toxin sensitive G-protein, nitric oxide synthase, guanylate cyclase and PKG.73 These results suggest that BPA may alter both glucose and lipid metabolism.

b. Rapid effects of BPA on pancreatic β-cells

As with α-cells, β-cells are also excitable cells, their ion channels generating an oscillatory electrical activity that causes an intracellular oscillatory [Ca2+]i pattern. Remarkably, this oscillatory pattern triggers a pulsatile insulin secretion.

We have previously reported that estradiol provokes the closure of the KATP channel of pancreatic β-cells in a rapid manner. The maximum inhibition of the channel is reached 3 to 7 minutes after estradiol application and the effect is transient returning to normal levels 30 minutes later. As a consequence, there is an increased frequency [Ca2+] oscillations and a enhanced insulin secretion (rapid insulinotropic effect) that occurs when estradiol is applied along with a stimulatory glucose concentration. It has also been demonstrated that the fast modulation of insulin secretion by estradiol is not a genomic effect, since neither actinomycin-D nor cycloheximide prevent it. Mechanistically we know that ERβ but not ERα mediates a rapid estradiol effect on β-cells. We have proposed that, in synergy with glucose, when estradiol binds to ERβ the guanylate cyclase A receptor is activated through a yet unknown mechanism. As a consequence, KATP channel activity decreases in a cGMP/PKG-dependent manner, which finally potentiates an enhanced insulin secretion. These experiments have been done ex vivo.36,74

We have also demonstrated that the rapid insulinotropic effect of estradiol also occurs in vivo. Thus, the injection of 10 µg/kg of estradiol provoked a decrease of glycaemia 30 minutes after the administration, in parallel to an increase of plasma insulin levels.48

As regards BPA effect, it has been shown by experiments performed ex vivo that BPA rapidly enhances the frequency of glucose-induced [Ca2+] oscillations in pancreatic β-cells as does estradiol. This effect is triggered by remarkably low concentrations of BPA within the nanomolar range; 0.1 nM of BPA is enough to elicit a significant effect.75 The mechanism that mediates this effect is still unresolved, but unpublished experiments by our group indicate that it is most probably the same as that of estradiol.

In vivo, BPA rapidly change glycaemia by inducing a hypersecretion of insulin. As happens with estradiol, 30 min after the administration of 10 μg/kg of BPA there is an increase in plasma insulin levels.48

An additional rapid effect of BPA and E2 on isolated islet cells has also been observed; they increase the activation of the ubiquitous transcription factor cAMP response element binding protein (CREB) 5 min after stimulation at doses as low as 1 nM.76 This effect may be of great importance for the β-cell physiology, since CREB activation induces insulin gene expression77 and is implicated in β-cell survival.78

c. Long-term effects of BPA on pancreatic β-cells

In order to study the long-term action of BPA on the physiology of β-cells, we treated male mice with a daily dose of either 100 µg/kg BPA or E2 for 4 days. After the treatment, we observed a higher insulin content in β-cells compared to vehicle-treated mice. This effect followed an inverted U-dose response and the increase was already detected at day 2. Moreover, we demonstrated that this increase in insulin content leads to an enhanced insulin secretion. The β-cells from animals treated with BPA not only had more insulin but they also released more insulin when they were stimulated with high glucose concentrations.48 This result is consistent with the potentiation of insulin release observed in vitro in response to glucose after incubating rat islets with BPA for 24 h.79

At plasma level, the 4 days treatment with BPA generates a post-prandial hyperinsulinaemia. When a glucose tolerance test was performed in these mice under fasting conditions, an impaired glucose tolerance was observed, indicating that these animals were insulin resistant, which was confirmed by an insulin tolerance test; in response to a challenge of insulin, the hypoglycaemic response of BPA-treated mice was lower compared to vehicle treated mice.48

Whether insulin resistance precedes hyperinsulinaemia or hyperinsulinaemia precedes insulin resistance in the development of type 2 diabetes is controversial. The only clear conclusion is that they occur in parallel.80 We cannot rule out the possibi¬lity that peripheral insulin resistance contributes to the hyperinsulinaemia detected in BPA-treated mice. Nevertheless, we have demonstrated that BPA increases insulin content and insulin release when the islets of Langerhans are cultured in the presence of BPA, suggesting that BPA has a direct effect on the islets. BPA treatment did not have any effect on β-cell survival or β-cell mass, but it did have an impact on the insulin gene transcription, provoking an upregulation of the gene in an ERα-dependent manner.34

Epidemiological evidence for the link between BPA and metabolic disorders

Studies in animal models and in vitro studies provide clear evidence of the potential adverse effects of BPA, but the critical questions is: can we extrapolate these findings to the human disease process? This is a very difficult question to answer but, in fact, there is mounting epidemiological evidence that passive absorption of EDCs from the environment may well be related to the alarming rate of diabetes and obesity.

There is also evidence of persistent organic pollutants (POPs) exposure. Thus, white adipose tissue represents a reservoir of lipophilic environmental pollutants, especially those resistant to biological and chemical degradation, the so-called POPs. Some of these POPs, like dioxins, furans, polychlorinated biphenyls (PCBs) or organochlorine pesticides, have been strongly associated with diabetes and most of the components of the metabolic syndrome in several cross-sectional studies.81,82 This association is partly based on several epidemiological studies of serum γ-glutamyltransferase (γGT). Serum γGT activity may reflect amounts of glutathione conjugates formed during the metabolism of xenobiotics and it has been proposed that the association of serum γGT with type 2 diabetes reflects exposure to POPs and that POPs interact with obesity to cause type 2 diabetes.83

Regarding the potential detrimental action of BPA, a major epidemiological study has recently been published in which a significant relationship between BPA concentration in urine and type 2 diabetes, cardiovascular disease and liver enzyme abnormalities is established.84,85 To our knowledge, this is the first confirmation of adverse effects of BPA on humans namely, effects on insulin homeostasis and liver enzymes previously reported in animal models.


The data reviewed in this communication show that environmental estrogens, in particular BPA, are most likely implicated in the exacerbation and acceleration of type 2 diabetes development. In adult humans, epidemiological evidence points to BPA as an important risk factor for type 2 diabetes. In addition, there are casual links between BPA exposure and insulin resistance: alterations in insulin biosynthesis and secretion by β-cells of adult male mice and decrease of adiponectin in human adipocytes. Insulin resistance and decrease of adiponectin are highly likely to contribute to the development of type 2 diabetes, especially in subjects with a genetic susceptibility to β-cell failure.


    1.    Wild S, Roqlic C, Green A, Sicree R, King H, 2004 Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047-1053.
    2.    Herman MA, Kahn BB, 2006 Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest 116: 1767-1775.
    3.    Rosen ED, Spiegelman BM, 2006 Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444: 847-853.
    4.    Ropero AB, Alonso-Magdalena P, Quesada I, Nadal A, et al, 2008 The role of estrogen receptors in the control of energy and glucose homeostasis. Steroids 73: 874-879.
    5.    Fritsche L, Weigert C Haring HU, Lehmann R, 2008 How insulin receptor substrate proteins regulate the metabolic capacity of the liver--implications for health and disease. Curr Med Chem 15: 1316-1329.
    6.    Kahn CR, 2003 Knockout mice challenge our concepts of glucose homeostasis and the pathogenesis of diabetes. Exp Diabesity Res 4: 169-182.
    7.    Kahn SE, Hull RL, Utzschneider KM, et al, 2006 Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444: 840-846.
    8.    Kahn SE, Zraika S, Utzschneider KM, et al, 2009 The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 52: 1003-1012.
    9.    Biddinger SB, Kahn CR, 2006 From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 68: 123-158.
    10.    Heldring N, Pike A, Anderson S, et al, 2007 Estrogen receptors: how do they signal and what are their targets. Physiol Rev 87: 905-931.
    11.    Barros RP, Machado UF, Gustafsson JA, et al, 2006 Estrogen receptors: new players in diabetes mellitus. Trends Mol Med 12: 425-431.
    12.    Nadal A, Alonso-Magdalena P, Soriano S, et al, 2009 The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol 304: 63-68.
    13.    Livingstone C, Collison M, 2002 Sex steroids and insulin resistance. Clin Sci (Lond) 102: 151-166.
    14.    Godsland IF, 2005 Oestrogens and insulin secretion. Diabetologia 48: 2213-2220.
    15.    Godsland IF, 1996 The influence of female sex steroids on glucose metabolism and insulin action. J Intern Med Suppl 738: 1-60.
    16.    Wynn V, Doar JW, 1966 Some effects of oral contraceptives on carbohydrate metabolism. Lancet 2: 715-719.
    17.    Tchernof A, Calles-Escandon J, Sites CK, et al, 1998 Menopause, central body fatness, and insulin resistance: effects of hormone-replacement therapy. Coron Artery Dis 9: 503-511.
    18.    Bryzgalova G, Lundholm L, Portwood N, et al, 2008 Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab 295: E904-912.
    19.    Salpeter SR, Walsh JM, Ormiston TM, Greyber E, Buckley NS, Salpeter EE, 2006 Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 8: 538-554.
    20.    Jones ME, Thorburn AW, Britt KL, et al, 2000 Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA 97: 12735-12740.
    21.    Heine PA, Taylor JA, Iwamoto GA, et al, 2000 Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA 97: 12729-12734.
    22.    Zirilli L, Rochira V, Diazzi C, Caffagni G, Carani C, 2008 Human models of aromatase deficiency. J Steroid Biochem Mol Biol 109: 212-218.
    23.    Smith EP, Boyd J, Frank GR, et al, 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331: 1056-1061.
    24.    Gallagher CJ, Langefeld CD, Gordon CJ, et al, 2007 Association of the estrogen receptor-alpha gene with the metabolic syndrome and its component traits in African-American families: the Insulin Resistance Atherosclerosis Family Study. Diabetes 56: 2135-2141.
    25.    Musatov S, Chen W, Pfaff DW, et al, 2007 Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci U S A 104: 2501-2506.
    26.    Liang YQ, Akishita M, Kim S, et al, 2002 Estrogen receptor beta is involved in the anorectic action of estrogen. Int J Obes Relat Metab Disord 26: 1103-1109.
    27.    Bryzgalova G, Gao H, Ahren B, et al, 2006 Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 49: 588-597.
    28.    Barros RP, Machado UF, Warner M, Gustafsson JA, 2006 Muscle GLUT4 regulation by estrogen receptors ERbeta and ERalpha. Proc Natl Acad Sci USA 103: 1605-1608.
    29.    Cooke PS, Heine PA, Taylor JA, Lubahn DB, 2001 The role of estrogen and estrogen receptor-alpha in male adipose tissue. Mol Cell Endocrinol 178: 147-154.
    30.    Couse JF, Korach KS, 1999 Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 20: 358-417.
    31.    Naaz A, Zakroczymski M, Heine P, 2002 Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta). Horm Metab Res 34: 758-763.
    32.    Penza M, Montani C, Romani A, et al, 2006 Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner. Endocrinology 147: 5740-5751.
    33.    Shin JH, Hur JY, Seo HS, et al, 2007 The ratio of estrogen receptor alpha to estrogen receptor beta in adipose tissue is associated with leptin production and obesity. Steroids 72: 592-599.
    34.    Alonso-Magdalena P, Ropero AB, Carrera MP, et al, 2008 Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLoS One: 3 e2069.
    35.    Le May C, Chu K, Hu M, et al, 2006 Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci USA 103: 9232-9237.
    36.    Soriano S, Ropero AB, Alonso-Magdalena P, et al, 2009 Rapid regulation of K(ATP) channel activity by 17{beta}-estradiol in pancreatic {beta}-cells involves the estrogen receptor {beta} and the atrial natriuretic peptide receptor. Mol Endocrinol 23: 1973-1982.
    37.    Kavlock RJ, Daston GP, DeRosa C, et al, 1996 Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop. Environ Health Perspect 104: Suppl 4: 715-740.
    38.    Colborn T, 1995 Environmental estrogens: health implications for humans and wildlife. Environ Health Perspect 103: Suppl 7: 135-136.
    39.    Dodds EC, Lawson W, 1936 Synthetic estrogenic agents without the phenanthrene nucleus. Nature 137: 996.
    40.    Vandenberg LN, Maffini MV, Sonnenschein C, Rubin BS, Soto AM, 2009 Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev 30: 75-95.
    41.    Olea N, Pulgar R, Pιrez P, et al, 1996 Estrogenicity of resin-based composites and sealants used in dentistry. Environ Health Perspect 10: 298-305.
    42.    Kang JH, Kondo F, Katayama Y, 2006 Human exposure to bisphenol A. Toxicology 226: 79-89.
    43.    Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV, 2007 Human exposure to bisphenol A (BPA). Reprod Toxicol 24: 139-177.
    44.    Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Ekong J, Needham LL, 2005 Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population. Environ Health Perspect 113: 391-395.
    45.    Sajiki J, Takahashi K, Yonekubo J, 1999 Sensitive method for the determination of bisphenol-A in serum using two systems of high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 736: 255-261.
    46.    Takeuchi T, Tsutsumi O, 2002 Serum bisphenol a concentrations showed gender differences, possibly linked to androgen levels. Biochem Biophys Res Commun 291: 76-78.
    47.    Richter CA, Birnbaum LS, Farabollini F, et al, 2007 In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol 24: 199-224.
    48.    Alonso-Magdalena P, Morimoto S, Ripoll C, Fuentes E, Nadal A, 2006 The estrogenic effect of bisphenol A disrupts pancreatic beta-cell function in vivo and induces insulin resistance. Environ Health Perspect 114: 106-112.
    49.    Bindhumol V, Chitra KC, Mathur PP, 2003 Bisphenol A induces reactive oxygen species generation in the liver of male rats. Toxicology 188: 117-124.
    50.    Kabuto H, Hasuike S, Minagawa N, Shishibori T, 2003 Effects of bisphenol A on the metabolisms of active oxygen species in mouse tissues. Environ Res 93: 31-35.
    51.    Nunez AA, Kannan K, Giesy JP, Fang J, Clemens LG, 2001 Effects of bisphenol A on energy balance and accumulation in brown adipose tissue in rats. Chemosphere 42: 917-922.
    52.    Seidlova-Wuttke D, Jarry H, Christoffel J, Rimoldi G, Wuttke W, 2005 Effects of bisphenol-A (BPA), dibutylphtalate (DBP), benzophenone-2 (BP2), procymidone (Proc), and linurone (Lin) on fat tissue, a variety of hormones and metabolic parameters: a 3 months comparison with effects of estradiol (E2) in ovariectomized (ovx) rats. Toxicology 213: 13-24.
    53.    Sakurai K, Kawazuma M, Adachi T, et al, 2004 Bisphenol A affects glucose transport in mouse 3T3-F442A adipocytes. Br J Pharmacol 141: 209-214.
    54.    Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K, 2005 Bisphenol a accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicol Sci 84: 319-327.
    55.    Masuno H, Kidani T, Sekiya K, et al, 2002 Bisphenol A in combination with insulin can accelerate the conversion of 3T3-L1 fibroblasts to adipocytes. J Lipid Res 43: 676-684.
    56.    Rubin BS, Murray MK, Damassa DA, King JC, Soto AM, 2001 Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environ Health Perspect 109: 675-680.
    57.    Rubin BS, Soto AM 2009 Bisphenol A: Perinatal exposure and body weight. Mol Cell Endocrinol 304: 55-62.
    58.    Hugo ER, Brandebourg TD, Woo JG, Loftus J, Alexander JW, Ben-Jonathan N, 2008 Bisphenol A at environmentally relevant doses inhibits adiponectin release from human adipose tissue explants and adipocytes. Environ Health Perspect 116: 1642-1647
    59.    Nadal A, Alonso-Magdalena P, Ripoll C, Fuentes E, 2005 Disentangling the molecular mechanisms of action of endogenous and environmental estrogens. Pflugers Arch 44: 335-343.
    60.    Levin ER, 2005 Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol 1: 1951-1959.
    61.    Nadal A, Ropero AB, Fuentes E, Soria B, 2001 The plasma membrane estrogen receptor: nuclear or unclear? Trends Pharmacol Sci 22: 597-599.
    62.    Valverde MA, Rojas P, Amigo J, et al, 1999Acute activation of Maxi-K channels (hSlo) by estradiol binding to the beta subunit. Science 285: 1929-1931.
    63.    Dunning BE, Foley JE, Ahrén B, et al, 2005 Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 48: 1700-1713.
    64.    Quesada I, Tudurí E, Ripoll C, Nadal A, 2008 Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol 199: 5-19.
    65.    Gopel SO, Kanno T, Barg S, Weng XG, Gromada J, Rorsman P, 2000 Regulation of glucagon release in mouse-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528: 509-520.
    66.    Rorsman P, Hellman B, 1988 Voltage-activated currents in guinea pig pancreatic alpha 2 cells. Evidence for Ca2+-dependent action potentials. J Gen Physiol 91: 223-242.
    67.    Salehi A, Carlberg M, Henningson R, Lundquist I, 1996 Islet constitutive nitric oxide synthase: biochemical determination and regulatory function. Am J Physiol 270: C1634-1641.
    68.    Berts A, Ball A, Gylfe E, Hellman B, 1996 Suppression of Ca2+ oscillations in glucagon-producing alpha 2-cells by insulin/glucose and amino acids. Biochim Biophys Acta 1310: 212-216.
    69.    Nadal A, Quesada I, Soria B, 1999 Homologous and heterologous asynchronicity between identified alpha-, beta- and delta-cells within intact islets of Langerhans in the mouse. J Physiol 517: (Pt 1) 85-93.
    70.    Gopel S, Zhang Q, Eliasson L, et al, 2004 Capacitance measurements of exocytosis in mouse pancreatic alpha-, beta- and delta-cells within intact islets of Langerhans. J Physiol 556: 711-726.
    71.    Gromada J, Ding WG, Barg S, Renström E, Rorsman P, 1997 Multisite regulation of insulin secretion by cAMP-increasing agonists: evidence that glucagon-like peptide 1 and glucagon act via distinct receptors. Pflugers Arch 434: 515-524.
    72.    Opara EC, Atwater I, Go VL, 1988 Characterization and control of pulsatile secretion of insulin and glucagon. Pancreas 3: 484-487.
    73.    Alonso-Magdalena P, Laribi O, Ropero AB, et al, 2005 Low doses of bisphenol A and diethylstilbestrol impair Ca2+ signals in pancreatic alpha-cells through a nonclassical membrane estrogen receptor within intact islets of Langerhans. Environ Health Perspect 113: 969-977.
    74.    Nadal A, Rovira JM, Laribi O, et al, 1998 Rapid insulinotropic effect of 17beta-estradiol via a plasma membrane receptor. Faseb J 12: 1341-1348.
    75.    Nadal A, Ropero AB, Laribi O, Maillet M, Fuentes E, Soria B, 2000 Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta. Proc Natl Acad Sci USA 97: 11603-11608.
    76.    Quesada I, Fuentes E, Viso-León MC, Soria B, Ripoll C, Nadal A, 2002 Low doses of the endocrine disruptor bisphenol-A and the native hormone 17beta-estradiol rapidly activate transcription factor CREB. Faseb J 16: 1671-1673
    77.    Oetjen E, Diedrich T, Eggers A, Eckert B, Knepel W, 1994 Distinct properties of the cAMP-responsive element of the rat insulin I gene. J Biol Chem 269: 27036-27044.
    78.    Jhala US, Canettieri G, Screaton RA, et al, 2003 cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17: 1575-1580.
    79.    Adachi T, Yasuda K, Mori C, et al, 2005 Promoting insulin secretion in pancreatic islets by means of bisphenol A and nonylphenol via intracellular estrogen receptors. Food Chem Toxicol 43: 713-719.
    80.    Prentki M, Joly E, El-Assaad W, Roduit R, 2002 Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 51: Suppl 3: 405-413.
    81.    Lee DH, Lee IK, Porta M, Steffes M, Jacobs DR Jr, 2007 Relationship between serum concentrations of persistent organic pollutants and the prevalence of metabolic syndrome among non-diabetic adults: results from the National Health and Nutrition Examination Survey 1999-2002. Diabetologia 50: 1841-1851.
    82.    Lee DH, Lim JS, Song K, Boo Y, Jacobs DR Jr, 2006 Graded associations of blood lead and urinary cadmium concentrations with oxidative-stress-related markers in the U.S. population: results from the third National Health and Nutrition Examination Survey. Environ Health Perspect 114: 350-354.
    83.    Lee DH, Steffes MW, Jacobs DR Jr, 2008 Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes? Diabetologia 51: 402-407.
    84.    Lang IA, Galloway TS, Scarlett A, et al, 2008 Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300: 1303-1310.
    85.    vom Saal FS, Myers JP, 2008 Bisphenol A and risk of metabolic disorders. JAMA 300: 1353-1355.

Address for correspondence:
Paloma Alonso-Magdalena, Institute of Bioengineering, Miguel Hernandez University, 03202 Elche, Alicante, Spain
Τel.: +34 96 522 2164, Fax: +34 96 522 2033,
e-mail: palonso@umh.es

Received 30-10-09, Revised 12-01-10, Accepted 15-02-10