Bariatric Surgery Influences beta-Cell Turnover in Non Obese Rats.

Manuscrito en proceso de revisión editorialThe aim of this study was to investigate the different bariatric surgeries relationship with pancreatic beta-cell turnover. We used healthy adult male Wistar rats to undergo the different techniques. We developed three surgical techniques (malabsorptive, Sleeve gastrectomy and Roux-Y Gastric Bypass-), and two control groups (Sham and fasting control). Pancreatic beta-cell mass was measured, as well as apoptosis, proliferation and neogenesis related to cellular turnover. Otherwise, we measured the functional issues to elucidate the physiological role that these surgical techniques trigger in the carbohydrate metabolism (e.g. food intake, weight gain, intraperitoneal glucose tolerance test, and basal glycaemia). Results included the differences that these parameters underwent in each surgical model. The -cell mass presented modifications that were related with proliferation processes. We reported significant increase of -cell mass in the malabsorptive technique. Other while the peripheral resistance to insulin trended to reduce in rats underwent with malabsorptive and mixed techniques. The goal of the present study was to present how different bariatric surgical techniques affected on pancreatic beta-cell turnover. We considered that these implications of surgery over the endocrine pancreas must be one of the mechanisms related to the improvement of type 2 Diabetes mellitus afterward the bariatric surgery.41 paginas, que recogen toda la documentación enviada a consideración editoria

Nitric Oxide Is a Mediator of Antiproliferative Effects Induced by Proinflammatory Cytokines on Pancreatic Beta Cells

Nitric oxide (NO) is involved in several biological processes. In type 1 diabetes mellitus (T1DM), proinflammatory cytokines activate an inducible isoform of NOS (iNOS) in β cells, thus increasing NO levels and inducing apoptosis. The aim of the current study is to determine the role of NO (1) in the antiproliferative effect of proinflammatory cytokines IL-1β, IFN-γ, and TNF-α on cultured islet β cells and (2) during the insulitis stage prior to diabetes onset using the Biobreeding (BB) rat strain as T1DM model. Our results indicate that NO donors exert an antiproliferative effect on β cell obtained from cultured pancreatic islets, similar to that induced by proinflammatory cytokines. This cytokine-induced antiproliferative effect can be reversed by L-NMMA, a general NOS inhibitor, and is independent of guanylate cyclase pathway. Assays using NOS isoform specific inhibitors suggest that the NO implicated in the antiproliferative effect of proinflammatory cytokines is produced by inducible NOS, although not in an exclusive way. In BB rats, early treatment with L-NMMA improves the initial stage of insulitis. We conclude that NO is an important mediator of antiproliferative effect induced by proinflammatory cytokines on cultured β cell and is implicated in β-cell proliferation impairment observed early from initial stage of insulitis

MTORC1 signaling and regulation of pancreatic β-cell mass

The capacity of β cells to expand in response to insulin resistance is a critical factor in the development of type 2 diabetes. Proliferation of β cells is a major component for these adaptive responses in animal models. The extracellular signals responsible for β-cell expansion include growth factors, such as insulin, and nutrients, such as glucose and amino acids. AKT activation is one of the important components linking growth signals to the regulation of β-cell expansion. Downstream of AKT, tuberous sclerosis complex 1 and 2 (TSC1/2) and mechanistic target of rapamycin complex 1 (mTORC1) signaling have emerged as prime candidates in this process, because they integrate signals from growth factors and nutrients. Recent studies demonstrate the importance of mTORC1 signaling in β cells. This review will discuss recent advances in the understanding of how this pathway regulates β-cell mass and present data on the role of TSC1 in modulation of β-cell mass. Herein, we also demonstrate that deletion of Tsc1 in pancreatic β cells results in improved glucose tolerance, hyperinsulinemia and expansion of β-cell mass that persists with aging

Loss of mTORC1 signalling impairs β-cell homeostasis and insulin processing

Deregulation of mTOR complex 1 (mTORC1) signalling increases the risk for metabolic diseases, including type 2 diabetes. Here we show that β-cell-specific loss of mTORC1 causes diabetes and β-cell failure due to defects in proliferation, autophagy, apoptosis and insulin secretion by using mice with conditional (βraKO) and inducible (MIP-βraKO(f/f)) raptor deletion. Through genetic reconstitution of mTORC1 downstream targets, we identify mTORC1/S6K pathway as the mechanism by which mTORC1 regulates β-cell apoptosis, size and autophagy, whereas mTORC1/4E-BP2-eIF4E pathway regulates β-cell proliferation. Restoration of both pathways partially recovers β-cell mass and hyperglycaemia. This study also demonstrates a central role of mTORC1 in controlling insulin processing by regulating cap-dependent translation of carboxypeptidase E in a 4EBP2/eIF4E-dependent manner. Rapamycin treatment decreases CPE expression and insulin secretion in mice and human islets. We suggest an important role of mTORC1 in β-cells and identify downstream pathways driving β-cell mass, function and insulin processing

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance

Architecture of Androgen Receptor Pathways Amplifying Glucagon-Like Peptide-1 Insulinotropic Action in Male Pancreatic β Cells

Male mice lacking the androgen receptor (AR) in pancreatic β cells exhibit blunted glucose-stimulated insulin secretion (GSIS), leading to hyperglycemia. Testosterone activates an extranuclear AR in β cells to amplify glucagon-like peptide-1 (GLP-1) insulinotropic action. Here, we examined the architecture of AR targets that regulate GLP-1 insulinotropic action in male β cells. Testosterone cooperates with GLP-1 to enhance cAMP production at the plasma membrane and endosomes via: (1) increased mitochondrial production of C

2124-P: Raptor Levels Are Critical in the Adaptation of Beta Cells to High-Fat Diet

mTORC1 signaling is a central regulator of autophagy and altered autophagic activity has been implicated in the beta-cells of patients with type 2 diabetes, and in the beta-cells of obese mice. The importance of mTORC1 signaling and Raptor in beta-cells has been recently demonstrated using raptor knock-out models (βraKO mice). These studies have shown that complete deletion of Raptor impairs beta-cell proliferation and survival of the beta-cell, and both in function and insulin processing. However, nothing is known whether reduced mTORC1 levels impair beta-cell adaptation to diabetogenic conditions. Therefore, we decided to study mice with haploinsufficiency of Raptor in beta-cells (βraHET). Mice with heterozygous deletion of Raptor in beta-cells were generated by crossing raptorf/f with Rip-Cre mice (βraHET). βraHET and control mice were fed regular chow (RC) or high-fat diet (HFD). Mice fed with RC showed no difference at the metabolic level, islets morphology, or beta-cell function. βraHET mice fed HFD for eight weeks showed an impaired Intraperitoneal Glucose Tolerance Test, fed insulin secretion and a decreased beta-cell mass, compared to control mice. Isolated islets from βraHET mice fed HFD for eight weeks showed impaired insulin secretion either measured by perifusion or static incubation compared to control islets. Next, we tested whether isolated islets from βraHET mice are more susceptible to beta-cell stressors. Beta-cell death determined by TUNEL and cleavage Caspase 3 was increased (50 and 60%) in the βraHET islets after 24 h exposure to palmitate. In addition, autophagy markers such as LC3 and p62 were increased in islets from βraHET treated with palmitate. The increase in cell death and autophagy is specific to lipotoxicity since there βraHET islets exhibited no increase in cleavage Caspase 3 in TUNEL when they were treated with proinflammatory cytokines or ER Stress inducers. In conclusion, we demonstrate that adequate levels of Raptor are critical in the adaptation of the beta-cell to HFD. Disclosure M. Blandino-Rosano: None. E. Bernal-Mizrachi: None