Network Mendelian randomization study: exploring the causal pathway from insomnia to type 2 diabetes.

INTRODUCTION: Insomnia is a novel pathogen for type 2 diabetes mellitus (T2DM). However, mechanisms linking insomnia and T2DM are poorly understood. In this study, we apply a network Mendelian randomization (MR) framework to determine the causal association between insomnia and T2DM and identify the potential mediators, including overweight (body mass index (BMI), waist-to-hip ratio, and body fat percentage) and glycometabolism (HbA1c, fasting blood glucose, and fasting blood insulin). RESEARCH DESIGN AND METHODS: We use the MR framework to detect effect estimates of the insomnia-T2DM, insomnia-mediator, and mediator-T2DM associations. A mediator between insomnia and T2DM is established if MR studies in all 3 steps prove causal associations. RESULTS: In the Inverse variance weighted method, the results show that insomnia will increase the T2DM risk (OR 1.142; 95% CI 1.072 to 1.216; p=0.000), without heterogeneity nor horizontal pleiotropy, strongly suggesting that genetically predicted insomnia has a causal association with T2DM. Besides, our MR analysis provides strong evidence that insomnia is causally associated with BMI and body fat percentage. There is also suggestive evidence of an association between insomnia and the waist-to-hip ratio. At the same time, our results indicate that insomnia is not causally associated with glycometabolism. Higher BMI, waist-to-hip ratio, and body fat percentage levels are strongly associated with increased risk of T2DM. CONCLUSIONS: Genetically predicted insomnia has a causal association with T2DM. Being overweight (especially BMI and body fat percentage) mediates the causal pathway from insomnia to T2DM.

Education and stroke: evidence from epidemiology and Mendelian randomization study.

We aim to characterize the association between education and incident stroke (including total stroke, ischemic stroke, and hemorrhagic stroke) and assess whether there is a causal relationship between them. The final sample size was 11,509 in this study from the Atherosclerosis Risk in Communities (ARIC) study. Cox hazard regression models were used to explore the association between education level and incident stroke. Two-sample Mendelian randomization (MR) was used to estimate the causality. During a median follow-up of 25.3 years, 915 cases (8.0%) of stroke occurred. Participants with advanced education level were associated with 25% (HR 0.75; 95% CI 0.62, 0.91) decreased the rate of incident total stroke. Hazard ratio of intermediate and advanced education level for ischemic stroke were 0.82 (0.69, 0.98) and 0.73 (0.60, 0.90) separately. In the MR analysis, we observed evidence that education was likely a negetive causal risk factor for ischemic stroke (OR 0.764, 95% CI 0.585-0.998, P = 0.048). Higher education level was associated with a decreased rate of total stroke and ischemic stroke incident, but not hemorrhagic stroke incident. There might be a protective causal association between education and ischemic stroke (but not total stroke nor hemorrhagic stroke).

The effects of insulin and gliclazide therapy on endoplasmic reticulum stress and insulin sensitivity in liver of type 2 diabetic rats / 中华内科杂志

Objective To investigate the effect of insulin and gliclazide therapy on endoplasmic reticulum (ER) stress and insulin sensitivity in the liver of type 2 diabetic rats.Methods A high fat diet plus a low-dose of streptozotocin was implemented to create a type 2 diabetic rats which were randomly divided into diabetes mellitus (DM) group,insulin treatment (INS) group and gliclazide treatment (GT)group; and healthy rats were as normal control group.Diabetic rats in INS and GT groups were given neutral protamine hagedorn (NPH) insulin and gliclazide respectively for 3 weeks.Protein expression levels of immunoglobulin binding protein (Bip),spliced X-box binding protein 1 (XBP-ls),phosphorylated c-Jun on serine 73 (p-c-Jun),phosphorylated insulin receptor substrate 1 on serine 307 (p-IRS-1),and glucose-6-phosphatase (G6Pase) in liver homogenate were detected by Western blotting.Results Compared with the normal rats,Bip and XBP-Is in the DM group were up-regulated (0.28 ±0.07 vs 0.90 ±0.10 for Bip;0.41 ± 0.07 vs 0.95 ±0.07 for XBP-1 s; both P ＜ 0.01 ) ; p-c-Jun (0.59 ± 0.18 vs 1.94 ± 0.03 ),p-IRS-1( 1.73 ± 0.18 vs 5.32 ± 0.22) and G6Pase (0.11 ± 0.01 vs 0.45 ± 0.01 ) were increased ( all P values ＜0.01 ).In the INS group,all of aforementioned changes were reversed (0.90 ± 0.10 vs 0.25 ± 0.04 for Bip; 0.95 ±0.07 vs 0.47 ±0.01 for XBP-1s; 1.94 ± 0.03 vs 0.50 ±0.10 for p-c-Jun; 5.32 ± 0.22 vs 1.59 ±0.32 for p-IRS-1 ; 0.45 ±0.01 vs 0.15 ±0.02 for G6Pase,all P values ＜0.01 ).In the GT group,all of aforementioned changes were also attenuated ( 0.90 ± 0.10 vs 0.53 ± 00.02 for Bip ; 0.95 ± 0.07 vs 0.78±0.02 for XBP-1s; 1.94 ±0.03 vs 1.33 ±0.11 for p-c-Jun; 5.32 ±0.22 vs 3.13 ±0.02 for p-IRS-1; 0.45 ± 0.01 vs 0.25 ± 0.01 for G6Pase,all P values ＜ 0.05).Furthermore,all of aforementioned protein levels were down-regulated more obviously in the INS group comparing to the GT group ( all P values ＜ 0.01 ).Conclusions Both insulin and gliclazide therapy could relieve ER stress and e-Jun N-terminal kinase activity and improved insulin sensitivity.The effect of insulin on Bip,XBP-1s,p-c-Jun,p-IRS-1 and G6Pase protein expressions is more obvious than that of glilcazide,which indicates besides lowering glucose,insulin might have protective effects of anti-inflammation,anti-oxidative stress or stimulation of lipid redistribution.