Cyclin D3 promotes pancreatic ß-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes.

Type 1 diabetes is an autoimmune condition caused by the lymphocyte-mediated destruction of the insulin-producing ß cells in pancreatic islets. We aimed to identify final molecular entities targeted by the autoimmune assault on pancreatic ß cells that are causally related to ß cell viability. Here, we show that cyclin D3 is targeted by the autoimmune attack on pancreatic ß cells in vivo. Cyclin D3 is down-regulated in a dose-dependent manner in ß cells by leukocyte infiltration into the islets of the nonobese diabetic (NOD) type 1 diabetes-prone mouse model. Furthermore, we established a direct in vivo causal link between cyclin D3 expression levels and ß-cell fitness and viability in the NOD mice. We found that changes in cyclin D3 expression levels in vivo altered the ß-cell apoptosis rates, ß-cell area homeostasis, and ß-cell sensitivity to glucose without affecting ß-cell proliferation in the NOD mice. Cyclin D3-deficient NOD mice exhibited exacerbated diabetes and impaired glucose responsiveness; conversely, transgenic NOD mice overexpressing cyclin D3 in ß cells exhibited mild diabetes and improved glucose responsiveness. Overexpression of cyclin D3 in ß cells of cyclin D3-deficient mice rescued them from the exacerbated diabetes observed in transgene-negative littermates. Moreover, cyclin D3 overexpression protected the NOD-derived insulinoma NIT-1 cell line from cytokine-induced apoptosis. Here, for the first time to our knowledge, cyclin D3 is identified as a key molecule targeted by autoimmunity that plays a nonredundant, protective, and cell cycle-independent role in ß cells against inflammation-induced apoptosis and confers metabolic fitness to these cells.

Salicylates increase insulin secretion in healthy obese subjects.

CONTEXT: Conflicting results on the effects of salicylates on glucose tolerance in subjects with normal glucose tolerance or type 2 diabetes have been reported. OBJECTIVE: The objective of the study was to investigate the effects of a salicylate derivative (triflusal) on insulin sensitivity and insulin secretion. DESIGN, SETTING, AND PARTICIPANTS: This was a double-blind, randomized, crossover study with three treatment periods corresponding to two dose levels of triflusal and placebo in healthy obese subjects. MAIN OUTCOME MEASURES: Insulin sensitivity and insulin secretion, evaluated through frequently sampled iv glucose tolerance test that was performed after each treatment period, were measured. Insulin secretion was also evaluated in vitro in mice and human islets of Langerhans. RESULTS: The administration of triflusal led to decreased fasting serum glucose concentration in the study subjects. Insulin sensitivity did not significantly change after each treatment period. Insulin secretion, however, significantly increased in a dose-dependent fashion after each triflusal treatment period. The administration of 800 mum of the main triflusal metabolite to whole mice islets of Langerhans led to a sustained increase in intracellular calcium concentration level. This was followed by a significantly increase in insulin secretion. In human islets, 200 mum of 2-hydroxy-4-trifluoromethylbenzoic acid was sufficient to increase insulin release. CONCLUSIONS: The administration of a salicylate compound led to lowering of serum glucose concentration. We suggest that this effect was mediated through increased insulin secretion induced by salicylate directly on the beta-cell.

Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways.

Bisphenol-A (BPA) is an estrogenic monomer commonly used in the manufacture of numerous consumer products such as food and beverage containers. Widespread human exposure to significant doses of this compound has been reported. Traditionally, BPA has been considered a weak estrogen, based on its lower binding affinity to the nuclear estrogen receptors (ERs) compared to 17-ß estradiol (E2) as well as its low transcriptional activity after ERs activation. However, in vivo animal studies have demonstrated that it can interfere with endocrine signaling pathways at low doses during fetal, neonatal or perinatal periods as well as in adulthood. In addition, mounting evidence suggests a variety of pathways through which BPA can elicit cellular responses at very low concentrations with the same or even higher efficiency than E2. Thus, the purpose of the present review is to analyze with substantiated scientific evidence the strong estrogenic activity of BPA when it acts through alternative mechanisms of action at least in certain cell types.

Role of estrogen receptors alpha, beta and GPER1/GPR30 in pancreatic beta-cells.

Estrogen receptors (ER) are emerging as important molecules involved in the adaptation of beta-cells to insulin resistance. The onset of type 2 diabetes is marked by insulin secretory dysfunction and decreased beta-cell mass. During pregnancy, puberty and obesity there is increased metabolic demand and insulin resistance is developed. This metabolic state increases the demand on beta-cells to augment insulin biosynthesis and release. In this respect, ERalpha is directly implicated in the E2-regulation of insulin content and secretion, while ERbeta is in the E2-potentiation of glucose-induced insulin release. Both receptors develop their actions within the physiological range of E2. In addition, the G protein-coupled estrogen receptor (GPER1/GPR30) seems to be implicated in the E2-regulation of stimulus-secretion coupling in the three cell types of the islet. The increased demand of insulin production for long time may lead to beta-cell stress and apoptosis. ERalpha, ERbeta and GPER1/GPR30 are involved in preventing beta-cell apoptosis, impeding the loss of critical beta-cell mass. Therefore, estrogen receptors may play an essential role in the adaptation of the pancreas to insulin resistant periods.