Virus-like infection induces human ß cell dedifferentiation.

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic ß cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than ß cell death, suggesting loss of ß cell identity. We undertook this study to examine whether viral infection could induce human ß cell dedifferentiation. Using the functional human ß cell line EndoC-ßH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in ß cell-specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-κB pathway and also in a paracrine non-cell-autonomous fashion through the secretion of IFN-α. Lastly, we identified SOX9 targets in human ß cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human ß cell dedifferentiation.

Mechanisms of Beta Cell Dysfunction Associated With Viral Infection.

Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D.

PTBP1 is required for glucose-stimulated cap-independent translation of insulin granule proteins and Coxsackieviruses in beta cells.

Glucose and GLP-1 stimulate not only insulin secretion, but also the post-transcriptional induction of insulin granule biogenesis. This process involves the nucleocytoplasmic translocation of the RNA binding protein PTBP1. Binding of PTBP1 to the 3'-UTRs of mRNAs for insulin and other cargoes of beta cell granules increases their stability. Here we show that glucose enhances also the binding of PTBP1 to the 5'-UTRs of these transcripts, which display IRES activity, and their translation exclusively in a cap-independent fashion. Accordingly, glucose-induced biosynthesis of granule cargoes was unaffected by pharmacological, genetic or Coxsackievirus-mediated inhibition of cap-dependent translation. Infection with Coxsackieviruses, which also depend on PTBP1 for their own cap-independent translation, reduced instead granule stores and insulin release. These findings provide insight into the mechanism for glucose-induction of insulin granule production and on how Coxsackieviruses, which have been implicated in the pathogenesis of type 1 diabetes, can foster beta cell failure.

Chronic sleep curtailment impairs the flexible implementation of task goals in new parents.

Chronic sleep curtailment is a major concern for health in Western societies. Yet, research on potential consequences of long-term sleep curtailment on cognitive functions is still scarce. The present study investigated the link between chronic sleep limitation and executive functions that enable adaptation to changing environmental demands, i.e. the ability to flexibly implement task goals. To address the effects of chronic sleep restriction under real-life conditions, we considered a sample of adults who often suffer from reduced sleep durations over many months. One-hundred and six new parents (infant's age: 6-18months) were assigned to a sleep-curtailed group (<7h of nighttime sleep) and a non-sleep-curtailed group (≥7h of nighttime sleep), respectively, based on their self-reported average nighttime sleep duration over the preceding 6months. The ability to implement task goals was addressed applying a task-switching paradigm in which participants randomly switched between two tasks. While the two groups did not differ with regard to overall performance level, number of nighttime awakenings, naps during the day, daytime sleepiness, mood, chronic stress level and subjectively perceived cognitive capability, sleep-curtailed new parents showed higher costs for switching between tasks compared with repeating a task than non-sleep-curtailed new parents. This finding on the group level was further substantiated by a negative correlation between nighttime sleep duration and switch costs. With this study, we provide the first evidence for an impairment of the ability to flexibly implement task goals in chronically sleep-deprived new parents and, thus, for a link between chronic sleep curtailment and executive functions.

Stress reduces use of negative feedback in a feedback-based learning task.

In contrast to the well-established effects of stress on learning of declarative material, much less is known about stress effects on reward- or feedback-based learning. Differential effects on positive and negative feedback especially have received little attention. The objective of this study, thus, was to investigate effects of psychosocial stress on feedback-based learning with a particular focus on the use of negative and positive feedback during learning. Participants completed a probabilistic selection task in both a stress and a control condition. The task allowed quantification of how much participants relied on positive and negative feedback during learning. Although stress had no effect on general acquisition of the task, results indicate that participants used negative feedback significantly less during learning after stress compared with the control condition. An enhancing effect of stress on use of positive feedback failed to reach significance. These findings suggest that stress acts differentially on the use of positive and negative feedback during learning.