Paternal sleep deprivation induces metabolic perturbations in male offspring via altered LRP5 DNA methylation of pancreatic islets.

Diabetes and metabolic perturbation are global health challenges. Sleep insufficiency may trigger metabolic dysregulation leading to diabetes. However, the intergenerational transmission of this environmental information is not clearly understood. The research objective was to determine the possible effect of paternal sleep deprivation on the metabolic phenotype of the offspring and to investigate the underlying mechanism of epigenetic inheritance. Male offspring of sleep-deprived fathers exhibit glucose intolerance, insulin resistance, and impaired insulin secretion. In these SD-F1 offspring, a reduction in beta cell mass and proliferation of beta cells were observed. Mechanistically, in pancreatic islets of SD-F1 offspring, we identified alterations in DNA methylation at the promoter region of the LRP5 (LDL receptor related protein 5) gene, a coreceptor of Wnt signaling, resulting in downregulation of downstream effectors cyclin D1, cyclin D2, and Ctnnb1. Restoration of Lrp5 in the pancreas of SD-F1 male mice could improve impaired glucose tolerance and expression of cyclin D1, cyclin D2, and Ctnnb1. This study might significantly contribute to our understanding of the effects of sleeplessness on health and metabolic disease risk from the perspective of the heritable epigenome.

Sitagliptin attenuates endothelial dysfunction independent of its blood glucose controlling effect.

Although the contributions of sitagliptin to endothelial dysfunction in diabetes mellitus were previously reported, the mechanisms still undefined. Autophagy plays an important role in the development of diabetes mellitus, but its role in diabetic macrovascular complications is unclear. This study aims to observe the effect of sitagliptin on macrovascular endothelium in diabetes and explore the role of autophagy in this process. Diabetic rats were induced through administration of high-fat diet and intraperitoneal injection of streptozotocin. Then diabetic rats were treated with or without sitagliptin for 12 weeks. Endothelial damage and autophagy were measured. Human umbilical vein endothelial cells were cultured either in normal glucose or in high glucose medium and intervened with different concentrations of sitagliptin. Rapamycin was used to induce autophagy. Cell viability, apoptosis and autophagy were detected. The expressions of proteins in c-Jun N-terminal kinase (JNK)-Bcl-2-Beclin-1 pathway were measured. Sitagliptin attenuated injuries of endothelium in vivo and in vitro. The expression of microtubuleassociated protein 1 light chain 3 II (LC3II) and beclin-1 were increased in aortas of diabetic rats and cells cultured with high-glucose, while sitagliptin inhibited the over-expression of LC3II and beclin-1. In vitro pre-treatment with sitagliptin decreased rapamycin-induced autophagy. However, after pretreatment with rapamycin, the protective effect of sitagliptin on endothelial cells was abolished. Further studies revealed sitagliptin increased the expression of Bcl-2, while inhibited the expression of JNK in vivo. Sitagliptin attenuates injuries of vascular endothelial cells caused by high glucose through inhibiting over-activated autophagy. JNK-Bcl-2-Beclin-1 pathway may be involved in this process.

Evaluating the Effects of Different Sleep Supplement Modes in Attenuating Metabolic Consequences of Night Shift Work Using Rat Model.

PURPOSE: To study the effects of chronic-simulated night shift work using the rat model and examines if a particular sleep supplement mode could be better in alleviating the effects. METHODS: The male Wistar rats were randomly divided into the control (CTL: 8 rats) and night shift work (NW: 24 rats) groups of rats. Based on the sleep supplement strategy, the NW group was further segregated into three subgroups (8 rats each); late sleep supplement group (LSS), early sleep supplement group (ESS), and intermittent sleep supplement group (ISS). Sleep deprivation was achieved using the standard small-platform-over water method. Parameters such as animal body weight and food intake were measured daily. The intraperitoneal glucose tolerance test, fasting plasma insulin concentration, insulin resistance index and insulin sensitivity were measured twice, in the 4th and 8th weeks of the study. Plasma corticosterone concentration and pathological changes in islets (insulitis) were measured at the end of the 8th week. RESULTS: In NW group, night work resulted in a gain of body weight and albeit lower than that of the CTL group. NW rats also had higher food intake, showed impaired glucose metabolism and higher plasma corticosterone concentration. The sleep supplement experiments suggested that compared to the other modes, intermittent sleep supplement had significantly low changes in the body weight, glucose metabolism and the islet cells. CONCLUSION: Similar to previous studies, we also found that night shift work adversely impacts the body weight and glucose metabolism in rats. However, upon evaluating different sleep supplement strategies, we found the intermittent sleep supplement strategy to be most effective.