应用连锁不平衡图谱的关联研究分析方法

目的提出一种对高通量单核苷酸多态位点(single nucleotide polymorphism,SNP)关联研究的数据分析方法。方法在160名上海地区中国人中进行754个SNP的基因型检测,分别构建病例组和对照组的连锁不平衡(linkage disequilibrium,LD)图谱,通过比较两组间染色体区域LD图谱随物理距离的变化趋势寻找与疾病相关的位点,并与传统LD分析以及SNP单点、单倍型分析进行比较。结果LD图谱的分析能判断出两组间LD存在差异的染色体区域,并且该区域SNP等位基因频率和单倍型频率在两组间分布存在统计学差异或差异趋势。结论可应用该方法对高通量SNP的关联研究进行数据分析。     

Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice

BackgroundObese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood.Purpose/ProceduresThe goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model.Main findingsContrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P < .05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P < .01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production.ConclusionsThis research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels.     

IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice

Background and ObjectiveInterleukin 6 (IL-6) has been identified as a key mediator in inflammation, immune responses and glucose metabolism. In this study, we assessed the effects of an IL-6 receptor antibody on diabetic nephropathy in a mouse model of type 2 diabetes mellitus.MethodsTwelve week old male db/db mice were treated with Tocilizumab (an IL-6 receptor antibody), normal IgG1 control antibody, insulin or normal saline for 12 weeks. Renal injury, inflammation and insulin resistance were assessed.ResultsDb/db mice treated with Tocilizumab exhibited reduced proteinuria and glomerular mesangial matrix accumulation compared to db/db + IgG controls. Additionally, Tocilizumab suppressed inflammatory response, oxidative stress and the IL-6 signaling pathway in the diabetic kidneys. It is noteworthy that blockade of IL-6 receptor blunted the activation of NLRP3 inflammasome partly through inhibition of IL-17A. Furthermore, insulin resistance assessed by glucose tolerance test, was ameliorated by Tocilizumab treatment.ConclusionsThe protective effects of an IL-6 receptor blockade against diabetic renal injury may be due to decreased insulin resistance and inhibition of the inflammasome.     

Changes in oxidative nucleic acid modifications and inflammation following one-week treatment with the bile acid sequestrant sevelamer: Two randomised,placebo-controlled trials

AimsSevelamer has been reported to have anti-oxidative and anti-inflammatory effects as well as effects on glycaemic control and plasma lipids. The aim of this study was to determine the effects of one-week treatment with sevelamer on oxidative nucleic acid modifications and inflammation markers.MethodsTwo double-blinded studies including 30 patients with type 2 diabetes (T2D) and 20 healthy individuals were conducted. Participants were randomised to one week of treatment with sevelamer (1600 mg three times daily) or placebo. RNA and DNA oxidation, measured by urinary excretion of 8-oxo-7,8-dihydroguanosine(8-oxoGuo) and (8-oxo-7,8-dihydro-2′-deoxyguanosine(8-oxodG), and markers of inflammation were determined before and after the intervention.ResultsIn patients with T2D there was no significant placebo-corrected reduction in 8-oxoGuo or 8-oxodG. However, a reduction in 8-oxoGuo was observed within the group treated with sevelamer (∆8-oxoGuo/creatinine (median[IQR]): −0.04 [−0.24; 0.01] nmol/mmol, p = 0.02). A sevelamer-mediated reduction in interleukin-2 (p = 0.04) and a trend towards reduction in interleukin-6 (p = 0.053) were found in patients with T2D.ConclusionsThis study reveals a potential effect of sevelamer treatment on inflammation and possible oxidative RNA modifications. The potential protective effects of sevelamer in terms of cardiovascular disease in patients with T2D need further investigation.     

Changes in diabetes distress among people with type 2 diabetes during a risk screening programme for diabetic kidney disease – Longitudinal observations of the PRIORITY study

AimsTo investigate levels and changes in diabetes distress over the course of the PRIORITY (Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In people with TYpe 2 diabetes and normoalbuminuria) randomised controlled trial of screening for diabetic kidney disease (DKD) risk among people with type 2 diabetes (T2D) at a specialist diabetes clinic in Denmark.MethodsOf 436 trial participants with T2D, 216 were invited to complete the 17-item diabetes distress scale at the time of screening (T1, n = 180), immediately after receiving the screening results at 6–8 weeks (T2, n = 169), and at 12 months follow up (T3, n = 107). Linear mixed models were used to explore changes in diabetes distress.ResultsNo significant changes in diabetes distress were observed between the time of screening, receiving results, and at 12 months. Changes in diabetes distress were not influenced by diabetes empowerment, sense of coherence, or perceived support for diabetes self-management.ConclusionsIn contrast to previous studies demonstrating that screening programmes can have negative psychological consequences, our findings indicate that participating in this screening programme for DKD does not influence emotional burden or physician-related distress among people with T2D.