Antidiabetic Actions of an Estrogen Receptor β Selective Agonist

The estrogen receptor β (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. We evaluated the role and antidiabetic actions of the ERβ selective agonist WAY200070 as an insulinotropic molecule. We demonstrate that WAY200070 enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single administration of WAY200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release and pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide–induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes.This work was supported by Generalitat Valenciana grant PROMETEO/2011/080, Ministerio de Economia y Competitividad BFU2011-28358, and Ministerio de Economía y Competitividad BFU2010-21773 and BFU2008-1942; the Swedish Cancer Fund; the Emerging Technology Fund of Texas; and the Robert A. Welch Foundation (E-0004)

Rapid Insulinotropic Action of Low Doses of Bisphenol-A on Mouse and Human Islets of Langerhans: Role of Estrogen Receptor β

Bisphenol-A (BPA) is a widespread endocrine-disrupting chemical (EDC) used as the base compound in the manufacture of polycarbonate plastics. It alters pancreatic β-cell function and can be considered a risk factor for type 2 diabetes in rodents. Here we used ERβ−/− mice to study whether ERβ is involved in the rapid regulation of KATP channel activity, calcium signals and insulin release elicited by environmentally relevant doses of BPA (1 nM). We also investigated these effects of BPA in β-cells and whole islets of Langerhans from humans. 1 nM BPA rapidly decreased KATP channel activity, increased glucose-induced [Ca2+]i signals and insulin release in β-cells from WT mice but not in cells from ERβ−/− mice. The rapid reduction in the KATP channel activity and the insulinotropic effect was seen in human cells and islets. BPA actions were stronger in human islets compared to mouse islets when the same BPA concentration was used. Our findings suggest that BPA behaves as a strong estrogen via nuclear ERβ and indicate that results obtained with BPA in mouse β-cells may be extrapolated to humans. This supports that BPA should be considered as a risk factor for metabolic disorders in humans

acids and GIP

The insulinogenic effect of whey protein is partially mediated by a direct effect of amin

The insulinogenic effect of whey protein is partially mediated by a direct effect of amino acids and GIP on beta-cells

Background: Whey protein increases postprandial serum insulin levels. This has been associated with increased serum levels of leucine, isoleucine, valine, lysine, threonine and the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). We have examined the effects of these putative mediators of whey's action on insulin secretion from isolated mouse Langerhans islets. Methods: Mouse pancreatic islets were incubated with serum drawn from healthy individuals after ingestion of carbohydrate equivalent meals of whey protein (whey serum), or white wheat bread (control serum). In addition the effect of individual amino acid combinations on insulin secretion was also tested. Furthermore, the stimulatory effects of whey serum on insulin secretion was tested in vitro in the absence and presence of a GIP receptor antagonist ((Pro(3)) GIP[mPEG]). Results: Postprandial amino acids, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were higher after whey compared to white wheat bread. A stimulatory effect on insulin release from isolated islets was observed with serum after whey obtained at 15 min (+87%, P < 0.05) and 30 min (+139%, P < 0.05) postprandially, compared with control serum. The combination of isoleucine, leucine, valine, lysine and threonine exerted strong stimulatory effect on insulin secretion (+270%, P < 0.05), which was further augmented by GIP (+558% compared to that produced by glucose, P < 0.05). The stimulatory action of whey on insulin secretion was reduced by the GIP-receptor antagonist (Pro(3)) GIP[mPEG]) at both 15 and 30 min (-56% and -59%, P < 0.05). Conclusions: Compared with white wheat bread meal, whey causes an increase of postprandial insulin, plasma amino acids, GIP and GLP-1 responses. The in vitro data suggest that whey protein exerts its insulinogenic effect by preferential elevation of the plasma concentrations of certain amino acids, GIP and GLP-1

Model of BPA action on pancreatic β-cells.

<p>In the presence of stimulatory glucose concentrations, low concentrations of BPA rapidly decrease K_ATP channel activity through ERβ, enhancing glucose-induced [Ca²⁺]_i signals and insulin release. ERα is involved in the regulation of pancreatic insulin biosynthesis in response to BPA. In addition to ERβ, GPR30/GPER1 or another yet unidentified non-classical membrane estrogen receptor may participate in the insulinotropic effect of BPA on pancreatic β-cells. At the moment, this model applies to rodent beta cells. In humans, the receptors involved in the BPA regulation of K_ATP channel activity and insulin release are still undetermined.</p

K_ATP channel activity in pancreatic β-cells from WT and ERβ−/− mice in presence of 1 nM BPA.

<p>A, BPA at 1 nM decreased K_ATP channel activity in pancreatic β-cells from WT mice. The records show channel activity before application of BPA (upper trace), 7 min after application of BPA (1 nM BPA trace), 8 min after application of 8 mM Glucose (8 mM glucose trace) and 2 min after application of diazoxide (100 µM diazoxide trace) (n = 7). B, percentage of activity of the K_ATP channels elicited by vehicle and 1 nM BPA. C, 1 nM BPA had no significant effect on K_ATP channel activity in pancreatic ERβ−/− mice. As in A, the records show K_ATP channel activity before application of BPA, 7 min after application of 1 nM BPA, 8 min after application of 8 mM glucose and 3 min after application of 100 µM diazoxide (n = 5 cells for 3 different mice). D, percentage of activity of K_ATP channels elicited by vehicle and 1 nM BPA. *, P<0.05 Student's test comparing 1 nM BPA with control.</p

Effect of 1 nM BPA on glucose induced [Ca²⁺]_i oscillations in pancreatic β-cells from WT and ERβ−/− mice.

<p>A, Application of 8 mM glucose elicited a [Ca²⁺]_i transient followed by a plateau with [Ca²⁺]_i oscillations in pancreatic β-cells from both WT and ERβ−/− mice. B, application of 8 mM glucose in the presence of 1 nM BPA enhanced [Ca²⁺]_i oscillations frequency in WT islets but not in ERβ−/− islets. Recordings are representatives of at least 8 different islets from at least 4 different mice. C, frequency of [Ca²⁺]_i oscillations in pancreatic islets from WT and ERβ−/−mice in the absence of BPA (black bar) and in the presence of 1 nM BPA (white bar). Each point is the mean of at least eight different experiments. The analysis of the frequency was done during 5 min period, always taken when a steady state was reached, usually 8–10 min after 8 mM glucose application. *, P<0.05 Student's test.</p

BPA regulation of K_ATP channel activity in human pancreatic β-cells.

<p>A, Application of 1 nM BPA decreased K_ATP channel activity in isolated human pancreatic β-cells in absence of glucose. The records show K_ATP channel activity in absence of glucose (vehicle trace), 5 min after application of 1 nM BPA, 8 min after application of 8 mM glucose and 3 min after application of 100 µM diazoxide. B, Both 8 mM glucose and 1 nM BPA depolarized membrane potential and action currents were generated (see * and ** in second and third traces in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031109#pone-0031109-g002" target="_blank">figure 2A</a>). C, Percentage of activity of K_ATP channel elicited by vehicle, 1 nM BPA and 8 mM glucose in single β-cells (n = 5 cells). **, P<0.01 Student's test comparing 1 nM BPA and 8 mM glucose with control.</p