Pancreatic Insulin Content Regulation by the Estrogen Receptor ERα

Abstract

The function of pancreatic β-cells is the synthesis and release of insulin, the main hormone involved in blood glucose homeostasis. Estrogen receptors, ERα and ERβ, are important molecules involved in glucose metabolism, yet their role in pancreatic β-cell physiology is still greatly unknown. In this report we show that both ERα and ERβ are present in pancreatic β-cells. Long term exposure to physiological concentrations of 17β-estradiol (E2) increased β-cell insulin content, insulin gene expression and insulin release, yet pancreatic β-cell mass was unaltered. The up-regulation of pancreatic β-cell insulin content was imitated by environmentally relevant doses of the widespread endocrine disruptor Bisphenol-A (BPA). The use of ERα and ERβ agonists as well as ERαKO and ERβKO mice suggests that the estrogen receptor involved is ERα. The up-regulation of pancreatic insulin content by ERα activation involves ERK1/2. These data may be important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.

The pancreatic β-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes

“…Therefore, E2 increases insulin gene expression and insulin biosynthesis, incrementing pancreatic insulin content. In addition, insulin 10 secretion in response to glucose was enhanced as previously described (Adachi et al, 2005).In both in vitro and in vivo studies, E2 actions were blocked by the antiestrogen ICI182,780 suggesting that either ER or ER are involved (Adachi et al, 2005;Alonso-Magdalena et al, 2006;Alonso-Magdalena et al, 2008). The existence of estrogen receptors in -cells has not been extensively studied until now.…”

“…Indeed, we have observed that BPA can mimic E2 effects with the same potency (Alonso-Magdalena et al, 2006;Alonso-Magdalena et al, 2008;Ropero et al, 2008b).…”

“…In both in vitro and in vivo studies, E2 actions were blocked by the antiestrogen ICI182,780 suggesting that either ER or ER are involved (Adachi et al, 2005;Alonso-Magdalena et al, 2006;Alonso-Magdalena et al, 2008). The existence of estrogen receptors in -cells has not been extensively studied until now.…”

Low-level phenolic estrogen pollutants impair islet morphology and β-cell function in isolated rat islets

“…More importantly, recent studies in rodents suggest that endocrine pancreas is the target of some phenolic estrogens (Alonso-Magdalena et al 2011). For example, long-term exposure to BPA or E 2 (between 100 and 1 nM) has been reported to disrupt pancreatic insulin gene expression, insulin content, and secretion in isolated mice islets (Adachi et al 2005, Alonso-Magdalena et al 2008. The stimulation of insulin release under both hypoglycemic and hyperglycemic conditions was also observed in beta TC-6 cells treated with 100 mg/l BPA (Makaji et al 2011).…”

“…Among the EDCs, alkyl phenols (for example, NP and octylphenol (OP)), phenolic estrogen mimics (such as BPA), and phenolic estrogens (such as diethylstilbestrol (DES)) are often studied as a group of environmental phenolic estrogens due to their structural similarity and estrogenic activity (Tapiero et al 2002, Lin et al 2008. These phenolic estrogens can act by mimicking the action of the sex hormone E 2 to bind to the classical ERs, ERa and ERb (Newbold 2004), and ERs are involved in important aspects of b-cell physiology, including the regulation of insulin biosynthesis and release (Wozniak et al 2005, Alonso-Magdalena et al 2008. However, little is known about whether the potencies of phenolic estrogen binding to ERs are correlated with their effects on insulin secretion in isolated rat islets.…”