Nephrin Is Expressed on the Surface of Insulin Vesicles and Facilitates Glucose-Stimulated Insulin Release

Nephrin, an immunoglobulin-like protein essential for the function of the glomerular podocyte and regulated in diabetic nephropathy, is also expressed in pancreatic beta-cells, where its function remains unknown. The aim of this study was to investigate whether diabetes modulates nephrin expression in human pancreatic islets and to explore the role of nephrin in beta-cell function. Nephrin expression in human pancreas and in MIN6 insulinoma cells was studied by Western blot, PCR, confocal microscopy, subcellular fractionation, and immunogold labeling. Islets from diabetic (n = 5) and nondiabetic (n = 7) patients were compared. Stable transfection and siRNA knockdown in MIN-6 cells/human islets were used to study nephrin function in vitro and in vivo after transplantation in diabetic immunodeficient mice. Live imaging of green fluorescent protein (GFP)-nephrin-transfected cells was used to study nephrin endocytosis. Nephrin was found at the plasma membrane and on insulin vesicles. Nephrin expression was decreased in islets from diabetic patients when compared with nondiabetic control subjects. Nephrin transfection in MIN-6 cells/pseudoislets resulted in higher glucose-stimulated insulin release in vitro and in vivo after transplantation into immunodeficient diabetic mice. Nephrin gene silencing abolished stimulated insulin release. Confocal imaging of GFP-nephrin-transfected cells revealed nephrin endocytosis upon glucose stimulation. Actin stabilization prevented nephrin trafficking as well as nephrin-positive effect on insulin release. Our data suggest that nephrin is an active component of insulin vesicle machinery that may affect vesicle-actin interaction and mobilization to the plasma membrane. Development of drugs targeting nephrin may represent a novel approach to treat diabetes

Why Central Banks (and Money) 'Rule the Roost'

Some have argued that a significant decrease in the demand for money, due to financial innovations, could imply that central banks are unable to implement effective monetary policies. This paper argues that central banks are always able to influence the economy's interest rates, because their liability is the economy's unit of account. In this sense, central banks rule the roost. In the 1930s, starting from Keynes's ideas and referring to money in general, Kaldor had followed a similar line of analysis. In principle, a new unit of account could displace conventional money and, hence, central banks. But this process meets relevant obstacles, which essentially derive from the externalities and network effects that characterize money. Money is a social relation. Money and central banks are the outcome of complex social and economic processes. Their displacement will occur through equally complex processes, rather than through mere innovation

Sociality, selection, and survival: Simulated evolution of mortality with intergenerational transfers and food sharing

Why do humans survive so long past reproductive age, and why does juvenile mortality decline after birth, both contrary to the classic theory of aging? Previous work has shown formally that intergenerational transfers can explain both these patterns. Here, simulations confirm those results under weaker assumptions and explore how different social arrangements shape life-history evolution. Simulated single-sex hunter–gatherers survive, forage, reproduce, and share food with kin and nonkin in ways guided by the ethnographic literature. Natural selection acts on probabilistically occurring deleterious mutations. Neither stable population age distributions nor homogeneous genetic lineages are assumed. When food is shared only within kin groups, an infant death permits reallocation of its unneeded food to the infant's kin, offsetting the fitness cost of the death and weakening the force of selection against infant mortality. Thus, evolved infant mortality is relatively high, more so in larger kin groups. Food sharing with nonkin reduces the costs to kin of child rearing, but also reduces the resources recaptured by kin after an infant death, so evolved infant mortality is lower. Postreproductive adults transfer food to descendants, enhancing their growth and survival, so postreproductive survival is selected. The force of selection for old-age survival depends in complicated ways on the food-sharing arrangements. Population-level food sharing with nonkin leads to the classic pattern of constant low mortality up to sexual maturity and no postreproductive survival

Perfect genetic correlation between number of offspring and grandoffspring in an industrialized human population

Reproductive success is widely used as a measure of fitness. However, offspring quantity may not reflect the genetic contribution to subsequent generations if there is nonrandom variation in offspring quality. Offspring quality is likely to be an important component of human fitness, and tradeoffs between offspring quantity and quality have been reported. As such, studies using offspring quantity as a proxy for fitness may yield erroneous projections of evolutionary change, for example if there is little or no genetic variance in number of grandoffspring or if its genetic variance is to some extent independent of the genetic variance in number of offspring. To address this, we performed a quantitative genetic analysis on the reproductive history of 16,268 Swedish twins born between 1915 and 1929 and their offspring. There was significant sex limitation in the sources of familial variation, but the magnitudes of the genetic and environmental effects were the same in males and females. We found significant genetic variation in number of offspring and grandoffspring (heritability = 24% and 16%, respectively), and genetic variation in the two variables completely overlapped - i.e., there was a perfect genetic correlation between number of offspring and grandoffspring. Shared environment played a smaller but significant role in number of offspring and grandoffspring; again, there was a perfect shared environmental correlation between the two variables. These findings support the use of lifetime reproductive success as a proxy for fitness in populations like the one used here, but we caution against generalizing this conclusion to other kinds of human societies

Differential fitness costs of reproduction between the sexes

Natural selection does not necessarily favor maximal reproduction because reproduction imposes fitness costs, reducing parental survival, and offspring quality. Here, we show that parents in a preindustrial population in North America incurred fitness costs from reproduction, and women incurred greater costs than men. We examined the survivorship and reproductive success (Darwinian fitness) of 21,684 couples married between 1860 and 1895 identified in the Utah Population Database. We found that increasing number of offspring (parity) and rates of reproduction were associated with reduced parental survivorship, and significantly more for mothers than fathers. Parental mortality resulted in reduced survival and reproduction of offspring, and the mothers' mortality was more detrimental to offspring than the fathers'. Increasing family size was associated with lower offspring survival, primarily for later-born children, indicating a tradeoff between offspring quantity versus quality. Also, we found that the costs of reproduction increased with age more for women than men. Our findings help to explain some puzzling aspects of human reproductive physiology and behavior, including the evolution of menopause and fertility declines associated with improvements in women's status (demographic transitions)

Reproductive protein protects functionally sterile honey bee workers from oxidative stress

Research on aging shows that regulatory pathways of fertility and senescence are closely interlinked. However, evolutionary theories on social species propose that lifelong care for offspring can shape the course of senescence beyond the restricted context of reproductive capability. These observations suggest that control circuits of aging are remodeled in social organisms with continuing care for offspring. Here, we studied a circuit of aging in the honey bee (Apis mellifera). The bee is characterized by the presence of a long-lived reproductive queen caste and a shorter-lived caste of female workers that are life-long alloparental care givers. We focus on the role of the conserved yolk precursor gene vitellogenin that, in Caenorhabditis elegans, shortens lifespan as a downstream element of the insulin/insulin-like growth factor signaling cascade. Vitellogenin protein is synthesized at high levels in honey bee queens and is abundant in long-lived workers. We establish that vitellogenin gene activity protects worker bees from oxidative stress. Our finding suggests that one mechanistic explanation for patterns of longevity in bees is that a reproductive regulatory pathway has been remodeled to extend life. This perspective is of considerable relevance to research on longevity regulation that builds largely on inference from solitary model species