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.

Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from in vitro tests that allow the identification of toxicant-induced changes of the cellular proteostasis, or of its underlying transcriptome network. Therefore, the ‘human embryonic stem cell (hESC)-derived novel alternative test systems (ESNATS)’ European commission research project established RT tests based on defined differentiation protocols of hESC and their progeny. Valproic acid (VPA) and methylmercury (MeHg) were used as positive control compounds to address the following fundamental questions: (1) Does transcriptome analysis allow discrimination of the two compounds? (2) How does analysis of enriched transcription factor binding sites (TFBS) and of individual probe sets (PS) distinguish between test systems? (3) Can batch effects be controlled? (4) How many DNA microarrays are needed? (5) Is the highest non-cytotoxic concentration optimal and relevant for the study of transcriptome changes? VPA triggered vast transcriptional changes, whereas MeHg altered fewer transcripts. To attenuate batch effects, analysis has been focused on the 500 PS with highest variability. The test systems differed significantly in their responses (<20 % overlap). Moreover, within one test system, little overlap between the PS changed by the two compounds has been observed. However, using TFBS enrichment, a relatively large ‘common response’ to VPA and MeHg could be distinguished from ‘compound-specific’ responses. In conclusion, the ESNATS assay battery allows classification of human DNT/RT toxicants on the basis of their transcriptome profiles.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-012-0967-3) contains supplementary material, which is available to authorized users.

Study background: The objective of this collated research paper is to highlight the anti-diabetic effects and mode of action of imeglimin, the first in a new tetrahydrotriazine-containing class of oral anti-diabetic agents: the glimins. Imeglimin acts on both insulin resistant organs (liver and muscle) and pancreatic β-cells (insulin secretion in response to glucose and protection against apoptosis). Methods:The aim of the investigations reported here is to present data on the mode of action of imeglimin and its anti-diabetic effects, demonstrating that it represents a promising treatment for type 2 diabetes by acting on the three key pathological defects of the disease, namely excessive hepatic glucose production, impaired peripheral glucose uptake by skeletal muscle, and insufficient insulin secretion.Results: Imeglimin significantly lowered fasting plasma glucose concentrations in a dose-dependent manner in STZ rats. HbA1c was significantly reduced (P<0.01) by imeglimin (6.2%) compared with controls (9.83%). At a 150 mg·kg -1 dose, imeglimin significantly improved glucose tolerance compared with controls (AUC 0-3h 2,402 vs 3,449 mmol·L·h -1 respectively). With regards to its mode of action, imeglimin significantly decreased the rate of hepatic gluconeogenesis, stimulated muscle glucose uptake, induced a potentiation of glucose-dependent insulin secretion, and decreased β-cell apoptosis. Conclusion:Our investigations found that imeglimin uniquely targets the three key defects of type 2 diabetes. It could provide more durable, sustained glycemic control than currently achieved with oral anti-diabetics and has the potential to be used at any stage in the disease continuum. Imeglimin's potential for combination with other oral antidiabetics is also under investigation.

A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(g 6-p-MeC 6 H 4 Pr i) 2 Ru 2 (SC 6 H 4-p-X) 3 ] ? (1 X is H, 2 X is Me, 3 X is Ph, 4 X is Br, 5 X is OH, 6 X is NO 2 , 7 X is OMe, 8 X is CF 3 , 9 X is F, 10 X is Pr i , 11 X is Bu t) have been synthesized from the reaction of [(g 6-p-MeC 6 H 4 Pr i)-RuCl 2 ] 2 with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(g 6-C 6 H 6) 2 Ru 2 (SC 6 H 5) 3 ] ? (12) and [(g 6-C 6 Me 6) 2 Ru 2 (SC 6 H 5) 3 ] ? (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50 % inhibition of cancer cell growth (IC 50 values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC 50 value of 0.03 lM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC 50 values and the turnover frequencies at about 50 % conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants r p) and the lipophilicity of the thiols p-XC 6 H 4 SH (calculated log P parameters).

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function. Liver receptor homologue-1 (LRH-1) is a nuclear receptor that represses inflammation in digestive organs, and protects pancreatic islets against apoptosis. Here, we show that BL001, a small LRH-1 agonist, impedes hyperglycemia progression and the immune-dependent inflammation of pancreas in murine models of T1DM, and beta cell apoptosis in islets of type 2 diabetic patients, while increasing beta cell mass and insulin secretion. Thus, we suggest that LRH-1 agonism favors a dialogue between immune and islet cells, which could be druggable to protect against diabetes mellitus.