Mesenchymal stem cells (MSCs) reportedly inhibit the mixed lymphocyte reaction. Whether this effect is mediated by dendritic cells (DCs) is still unknown. In this study, we used an in vitro model to observe the effects of MSCs and their supernatants on the development of monocyte-derived DCs. Phenotypes and the endocytosic ability of harvested DCs were determined by flow cytometry; interleukin 12 (IL-12) secreted by DCs was evaluated by enzyme-linked immunosorbent assay (ELISA); and the antigen-presenting function of DCs was evaluated by MLR. Our results show that MSCs inhibit the up-regulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of CD40, CD86, and CD83 expression during DC maturation. MSCs supernatants had no effect on DCs differentiation, but they inhibited the up-regulation of CD83 during maturation. Both MSCs and their supernatants interfered with endocytosis of DCs, decreased their capacity to secret IL-12 and activate alloreactive T cells. Thus, effects of MSCs on DCs contribute to immunoregulation and development.
The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cel-
SUMMARY Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult β-cell function. In this study, we traced the fate of adult β-cells after Pdx1 deletion. As expected, β-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of α-cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift which included de-repression of the α-cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of α-cells. These findings indicate that Pdx1 acts as a master regulator of β-cell fate by simultaneously activating genes essential for β-cell identity and repressing those associated with α-cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of β-cell identity contributes to the pathogenesis of type 2 diabetes.
Summary Insulin-resistant syndromes such as type II diabetes mellitus (T2DM) involve disrupted temporal coordination of hepatic metabolism such that synthesis and secretion of lipid and glucose are inappropriately engaged concurrently. Here we test the hypothesis that a combination of direct and indirect actions of insulin on liver can lead to the metabolic phenotype exhibited in T2DM without a defect in proximal hepatic insulin signaling. First, we show that the insulin-dependent inhibition of Foxo1 and activation of mTorc1 by Akt is both necessary and sufficient for the induction of lipogenesis and the lipogenic gene program. In marked contrast, insulin, acting in vivo independent of hepatocyte insulin signaling can suppress glucose production by reducing serum free fatty acids. These studies support the hypothesis that under conditions of obesity and diabetes, intact hepatic insulin signaling can maintain lipogenesis while excess circulating FFAs become a dominant positive regulator of HGP.
Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific to β cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations are associated with specific chromatin marks and transcription factor occupancy in young β cells. Strikingly, we find β cell function improved in aged mice, as predicted by the changes in methylome and transcriptome. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline.
Sleep disorders are a group of conditions that affect the ability to sleep well on a regular basis and cause significant impairments in social and occupational functions. Although currently approved medications are efficacious, they are far from satisfactory. Benzodiazepines, antidepressants, antihistamines and anxiolytics have the potential for dependence and addiction. Moreover, some of these medications can gradually impair cognition. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone produced by the pineal gland and released exclusively at night. Exogenous melatonin supplementation is well tolerated and has no obvious short-or long-term adverse effects. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. It is centrally involved in anti-oxidation, circadian rhythmicity maintenance, sleep regulation and neuronal survival. This narrative review aims to provide a comprehensive overview of various therapeutic functions of melatonin in insomnia, sleep-related breathing disorders, hypersomnolence, circadian rhythm sleep-wake disorders and parasomnias. Melatonin offers an alternative treatment to the currently available pharmaceutical therapies for sleep disorders with significantly less side effects.
Glutamate dehydrogenase (GDH) is regulated by both positive (leucine and ADP) and negative (GTP and ATP) allosteric factors. We hypothesized that the phosphate potential of ␤-cells regulates the sensitivity of leucine stimulation. These predictions were tested by measuring leucine-stimulated insulin secretion in perifused rat islets following glucose depletion and by tracing the nitrogen flux of [2-15 N]glutamine using stable isotope techniques. The sensitivity of leucine stimulation was enhanced by long time (120-min) energy depletion and inhibited by glucose pretreatment. After limited 50-min glucose depletion, leucine, not ␣-ketoisocaproate, failed to stimulate insulin release. ␤-Cells sensitivity to leucine is therefore proposed to be a function of GDH activation. Leucine increased the flux through GDH 3-fold compared with controls while causing insulin release. High glucose inhibited flux through both glutaminase and GDH, and leucine was unable to override this inhibition. These results clearly show that leucine induced the secretion of insulin by augmenting glutaminolysis through activating glutaminase and GDH. Glucose regulates ␤-cell sensitivity to leucine by elevating the ratio of ATP and GTP to ADP and P i and thereby decreasing the flux through GDH and glutaminase. These mechanisms provide an explanation for hypoglycemia caused by mutations of GDH in children.In addition to glucose, amino acids and other metabolic fuels are important stimulants of insulin secretion from pancreatic ␤-cells. Leucine, which has been studied intensively, may stimulate insulin release through two different mechanisms. The first involves transamination of leucine to ␣-ketoisocaproate (KIC) 1 and subsequent mitochondrial oxidation. The second promotes insulin release via allosteric activation of glutamate dehydrogenase (GDH) causing oxidation of glutamate to the Krebs cycle intermediate, ␣-ketoglutarate, plus ammonia. The importance of the latter mechanism has been highlighted recently by the discovery of a dominant form of congenital hyperinsulinism associated with mutations of GDH leading to a gain of enzyme activity, because sensitivity to inhibition by GTP and ATP is impaired (1-3). Affected children have increased ␤-cell responsiveness to leucine and are susceptible to acute hypoglycemia following a high protein meal (4). The involvement of GDH may explain the observation that, in contrast to other amino acids, leucine-stimulated insulin secretion (LSIS) is suppressed by high glucose. For example, Gao et al. (5) reported that glucose inhibits leucine stimulation of glutaminolysis and insulin secretion in isolated mouse islets, presumably by increasing intracellular ATP and GTP while decreasing ADP and thus inhibiting GDH activity.GDH has also been proposed by Maechler and Wollheim (6) to play an essential role in glucose-mediated insulin secretion by acting in the reverse direction to catalyze production of glutamate, which is hypothesized to work as a cofactor in the process leading to exocytosis of insulin granules. T...
Children with hypoglycemia due to recessive loss of function mutations of the ␤-cell ATP-sensitive potassium (K ATP ) channel can develop hypoglycemia in response to protein feeding. We hypothesized that amino acids might stimulate insulin secretion by unknown mechanisms, because the K ATP channel-dependent pathway of insulin secretion is defective. We therefore investigated the effects of amino acids on insulin secretion and intracellular calcium in islets from normal and sulfonylurea receptor 1 knockout (SUR1؊/؊) mice. Even though SUR1؊/؊ mice are euglycemic, their islets are considered a suitable model for studies of the human genetic defect. SUR1؊/؊ islets, but not normal islets, released insulin in response to an amino acid mixture ramp. This response to amino acids was decreased by 60% when glutamine was omitted. Insulin release by SUR1؊/؊ islets was also stimulated by a ramp of glutamine alone. Glutamine was more potent than leucine or dimethyl glutamate. Basal intracellular calcium was elevated in SUR1؊/؊ islets and was increased further by glutamine. In normal islets, methionine sulfoximine, a glutamine synthetase inhibitor, suppressed insulin release in response to a glucose ramp. This inhibition was reversed by glutamine or by 6-diazo-5-oxo-L-norleucine, a non-metabolizable glutamine analogue. High glucose doubled glutamine levels of islets. Methionine sulfoximine inhibition of glucose stimulated insulin secretion was associated with accumulation of glutamate and aspartate. We hypothesize that glutamine plays a critical role as a signaling molecule in amino acid-and glucosestimulated insulin secretion, and that ␤-cell depolarization and subsequent intracellular calcium elevation are required for this glutamine effect to occur.
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