[Abstract unavailable

Transplantation of pancreatic progenitors or insulin-secreting cells derived from human embryonic stem cells (hESCs) has been proposed as a therapy for diabetes. We describe a seven-stage protocol that efficiently converts hESCs into insulin-producing cells. Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro. Additional characterization using single-cell imaging and dynamic glucose stimulation assays revealed similarities but also notable differences between S7 insulin-secreting cells and primary human beta cells. Nevertheless, S7 cells rapidly reversed diabetes in mice within 40 days, roughly four times faster than pancreatic progenitors. Therefore, although S7 cells are not fully equivalent to mature beta cells, their capacity for glucose-responsive insulin secretion and rapid reversal of diabetes in vivo makes them a promising alternative to pancreatic progenitor cells or cadaveric islets for the treatment of diabetes.

Research on violent television and films, video games, and music reveals unequivocal evidence that media violence increases the likelihood of aggressive and violent behavior in both immediate and long-term contexts. The effects appear larger for milder than for more severe forms of aggression, but the effects on severe forms of violence are also substantial (r = .13 to .32) when compared with effects of other violence risk factors or medical effects deemed important by the medical community (e.g., effect of aspirin on heart attacks). The research base is large; diverse in methods, samples, and media genres; and consistent in overall findings. The evidence is clearest within the most extensively researched domain, television and film violence. The growing body of video-game research yields essentially the same conclusions. Short-term exposure increases the likelihood of physically and verbally aggressive behavior, aggressive thoughts, and aggressive emotions. Recent large-scale longitudinal studies provide converging evidence linking frequent exposure to violent media in childhood with aggression later in life, including physical assaults and spouse abuse. Because extremely violent criminal behaviors (e.g., forcible rape, aggravated assault, homicide) are rare, new longitudinal studies with larger samples are needed to estimate accurately how much habitual childhood exposure to media violence increases the risk for extreme violence. Well-supported theory delineates why and when exposure to media violence increases aggression and violence. Media violence produces short-term increases by priming existing aggressive scripts and cognitions, increasing physiological arousal, and triggering an automatic tendency to imitate observed behaviors. Media violence produces long-term effects via several types of learning processes leading to the acquisition of lasting (and automatically accessible) aggressive scripts, interpretational schemas, and aggression-supporting beliefs about social behavior, and by reducing individuals' normal negative emotional responses to violence (i.e., desensitization). Certain characteristics of viewers (e.g., identification with aggressive characters), social environments (e.g., parental influences), and media content (e.g., attractiveness of the perpetrator) can influence the degree to which media violence affects aggression, but there are some inconsistencies in research results. This research also suggests some avenues for preventive intervention (e.g., parental supervision, interpretation, and control of children's media use). However, extant research on moderators suggests that no one is wholly immune to the effects of media violence. Recent surveys reveal an extensive presence of violence in modern media. Furthermore, many children and youth spend an inordinate amount of time consuming violent media. Although it is clear that reducing exposure to media violence will reduce aggression and violence, it is less clear what sorts of interventions will produce a reduction in exposure. The sparse ...

Hyperinsulinemia is associated with obesity and pancreatic islet hyperplasia, but whether insulin causes these phenomena or is a compensatory response has remained unsettled for decades. We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain. Age-dependent increases in fasting insulin and β cell mass were absent in Ins1(+/-):Ins2(-/-) mice fed a high-fat diet when compared to Ins1(+/+):Ins2(-/-) littermate controls. Remarkably, Ins1(+/-):Ins2(-/-) mice were completely protected from diet-induced obesity. Genetic prevention of chronic hyperinsulinemia in this model reprogrammed white adipose tissue to express uncoupling protein 1 and increase energy expenditure. Normalization of adipocyte size and activation of energy expenditure genes in white adipose tissue was associated with reduced inflammation, reduced fatty acid spillover, and reduced hepatic steatosis. Thus, we provide genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications.

Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.