2型糖尿病肠道菌群研究进展

2型糖尿病是一种常见的慢性消耗性疾病,其发病机制十分复杂,流行病学研究表明,肥胖、高热量饮食、体力活动不足及年龄增大是2型糖尿病最主要的环境因素。它是一种以胰岛素抵抗和胰岛素分泌不足为特征的代谢性疾病。肠道菌群作为进入人体的一个重要环境因素,肠道微生物的菌群变化影响宿主能量物质的吸收,调节肠道的分泌功能和非特异性免疫功能,从营养、代谢、疾病等各方面与我们生命活动相关。肠道菌群已成为我们身体的一部分,影响宿主的免疫,在肥胖、糖尿病、代谢综合征等疾病中都具有非常重要的作用。     

内脂素与2型糖尿病关系的研究进展

内脂素是新近被发现的主要由内脏脂肪合成的一种脂肪细胞因子,它具有类胰岛素样作用,能降低血糖和促进脂肪组织的分化与合成。内脂素还可以调节血管平滑肌的成熟和影响胰岛细胞的胰岛素的分泌,亦具有调节炎症反应和免疫功能的作用。随着研究的发展,人们对内脂素的结构特性、分布、表达调控及其生物学功能有了更加深入的认识。2型糖尿病是以胰岛素抵抗和糖代谢紊乱为特征的代谢性疾病,研究发现内脂素与2型糖尿病密切相关,其中与肥胖、胰岛素抵抗及胰岛素分泌方面的关系尤为显著,深入研究内脂素的生理和病理生理作用将会有力地促进对2型糖尿病的进一步认识、治疗与预防。     

c-Jun N-terminal kinase pathways in diabetes

Type 2 diabetes develops from insulin resistance and has become a worldwide epidemic. The c-Jun N-terminal kinases have been considered as signaling molecules linking inflammation and insulin resistance. Genetic disruption of c-Jun N-terminal kinase-1 gene prevents the development of insulin resistance in obese and diabetic mice. Inhibition of c-Jun N-terminal kinases by a small cell-permeable peptide improves insulin sensitivity in mice. Hepatic inhibition of c-Jun N-terminal kinases using a dominant-negative protein or knockdown of c-Jun N-terminal kinase-1 gene by RNA interference reduces blood glucose and insulin levels and enhances hepatic insulin signaling in mice. Recent evidence demonstrates that the hepatic c-Jun N-terminal kinase pathway plays an important role in lipid and lipoprotein homeostasis in mice. This review discusses recent advances in our understanding of the role of c-Jun N-terminal kinase pathway in metabolic control and its potential as a target for the treatment of type 2 diabetes.     

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA₁c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA_IR score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA_IR, proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.     

Plasma fatty acid metabolic profiling and biomarkers of type 2 diabetes mellitus based on GC/MS and PLS-LDA

Metabolic profiling has increasingly been used as a probe in disease diagnosis and pharmacological analysis. Herein, plasma fatty acid metabolic profiling including non-esterified fatty acid (NEFA) and esterified fatty acid (EFA) was investigated using gas chromatography/mass spectrometry (GC/MS) followed by multivariate statistical analysis. Partial least squares-linear discrimination analysis (PLS-LDA) model was established and validated to pattern discrimination between type 2 diabetic mellitus (DM-2) patients and health controls, and to extract novel biomarker information. Furthermore, the PLS-LDA model visually represented the alterations of NEFA metabolic profiles of diabetic patients with abdominal obesity in the treated process with rosiglitazone. The GC/MS-PLS-LDA analysis allowed comprehensive detection of plasma fatty acid, enabling fatty acid metabolic characterization of DM-2 patients, which included biomarkers different from health controls and dynamic change of NEFA profiles of patients after treated with medicine. This method might be a complement or an alternative to pathogenesis and pharmacodynamics research.     

Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes

Mitochondrial dysfunction has been reported in skeletal muscle of obese subjects and of type 2 diabetic patients. Reduced mitochondrial mass and defective activity have been proposed to explain this dysfunction. Alterations in mitochondrial function may be crucial to explain the metabolic changes and insulin resistance that characterize both obesity and type 2 diabetes. Consequently, the identification of the primary mechanisms involved is of great relevance.Mitochondrial dynamics refers to the movement of mitochondria along the cytoskeleton and also to the regulation of mitochondrial morphology and distribution, which depend on fusion and fission events. In recent years, some of the proteins that participate in mitochondrial fusion and fission have been identified in mammalian cells. Recent evidence indicates that proteins participating in these processes are also involved in metabolism. The mitochondrial fusion protein mitofusin 2 stimulates respiration, substrate oxidation and the expression of subunits that participate in respiratory complexes in cultured cells. In this regard, skeletal muscle of obese subjects and of type 2 diabetic patients shows reduced mitofusin 2 expression. Therefore, alterations in the activity of the proteins involved in mitochondrial dynamics, and particularly mitofusin 2, may participate in the reduced mitochondrial function present in skeletal muscle in obesity and in type 2 diabetes.     

Therapeutic potential of human embryonic stem cells in type 2 diabetes mellitus

AIM:To evaluate the safety and efficacy of human embryonic stem cells(h ESCs)for the management of type 2 diabetes mellitus(T2DM).METHODS:Patients with a previous history of diabetes and its associated complications were enrolled and injected with hE SC lines as per the defined protocol.The patients were assessed using Nutech functional score(NFS),a numeric scoring scale to evaluate the patients for 11 diagnostic parameters.Patients were evaluated at baseline and at the end of treatment period 1(T1).All the parameters were graded on the NFS scale from 1to 5.Highest possible grade(HPG)of 5 was considered as the grade of best improvement.RESULTS:Overall,94.8%of the patients showed improvement by at least one grade of NFS at the end of T1.For all the 11 parameters evaluated,54%of patients achieved HPG after treatment.The four essential parameters(improvement in glycated hemoglobin(HbA 1c)and insulin level,and fall in number of other oral hypoglycemic drugs with and without insulin)are presented in detail.For Hb A1c,72.6%of patients at the end of T1 met the World Health Organization cut off value,i.e.,6.5%of HbA 1c.For insulin level,65.9%of patients at the end of T1 were able to achieve HPG.After treatment,the improvement was seen in 16.3%of patients who required no more than two medications along with insulin.Similarly,21.5%of patients were improved as their dosage regimen for using oral drugs was reduced to 1-2 from 5.CONCLUSION:hE SC therapy is beneficial in patients with diabetes and helps in reducing their dependence on insulin and other medicines.     

黄连素调节肠道菌群治疗2型糖尿病的机制研究进展

2型糖尿病（type 2 diabetes mellitus,T2DM）主要由胰岛素分泌的相对和/或绝对缺乏引起,因其高发病率、高致残率已成为全球公共卫生领域面临的共同难题。由肥胖、氧化应激和慢性炎症等原因引起的胰岛素抵抗是其主要的发病机制之一。黄连素是一种安全性高、不良反应低、具有多种药理作用的天然的五环异喹啉类生物碱。然而黄连素在动物模型中的口服生物利用度极低,提示肠道菌群可能是其发挥多重药理作用的靶点。肠道菌群被称为“第二基因组”,通过调节代谢物、微生物－肠－脑轴、炎症反应、肠道激素和氧化应激影响T2DM。本文以综述的形式分析了黄连素调节肠道菌群在T2DM治疗中的作用机制,以期为T2DM及其他代谢性疾病的治疗提供新的思路。

     

Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance

Type 2 diabetes is characterized by cellular and extracellular Mg depletion. Epidemiologic studies showed a high prevalence of hypomagnesaemia and lower intracellular Mg concentrations in diabetic subjects. Insulin and glucose are important regulators of Mg metabolism. Intracellular Mg plays a key role in regulating insulin action, insulin-mediated-glucose uptake and vascular tone. Reduced intracellular Mg concentrations result in a defective tyrosine-kinase activity, post-receptorial impairment in insulin action, and worsening of insulin resistance in diabetic patients. Mg deficit has been proposed as a possible underlying common mechanism of the "insulin resistance" of different metabolic conditions. Low dietary Mg intake is also related to the development of type 2 diabetes. Benefits of Mg supplementation on metabolic profile in diabetic subjects have been found in most, but not all clinical studies, and larger prospective studies are needed to support the potential role of dietary Mg supplementation as a possible public health strategy in diabetes risk.     

Relationship between pancreatic vesicular monoamine transporter 2 (VMAT2) and insulin expression in human pancreas

Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of beta cell mass in vivo. We questioned, (1) What proportion of beta cells express VMAT2? (2) Is VMAT2 expressed by other pancreatic endocrine or non-endocrine cells? (3) Is the relationship between VMAT2 and insulin expression disturbed in type 1 (T1DM) or type 2 diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained for insulin, VMAT2 and other pancreatic hormones. Most beta cells expressed VMAT2. VMAT2 expression was not changed by the presence of diabetes. In tail of pancreas VMAT2 immunostaining closely correlated with insulin staining. However, VMAT2 was also expressed in some pancreatic polypeptide (PP) cells. Although VMAT2 was not excluded as a target for beta cell mass measurement, expression of VMAT2 in PP cells predicts residual VMAT2 expression in human pancreas even in the absence of beta cells.     

Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes

Recently, vaspin was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose tissue in a rat model of type 2 diabetes. In this study, we examined whether vaspin mRNA expression is a marker of visceral obesity and correlates with anthropometric and metabolic parameters in paired samples of visceral and subcutaneous adipose tissue from 196 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. Vaspin mRNA expression was only detectable in 23% of the visceral and in 15% of the subcutaneous (SC) adipose tissue samples. Vaspin mRNA expression was not detectable in lean subjects (BMI<25) and was more frequently detected in patients with type 2 diabetes. No significant correlations were found between visceral vaspin gene expression and visceral fat area or SC vaspin expression. However, visceral vaspin expression significantly correlates with BMI, % body fat, and 2 h OGTT plasma glucose. Subcutaneous vaspin mRNA expression is significantly correlated with WHR, fasting plasma insulin concentration, and glucose infusion rate during steady state of an euglycemic-hyperinsulinemic clamp. Multivariate linear regression analysis revealed % body fat as strongest predictor of visceral vaspin and insulin sensitivity as strongest determinant of SC vaspin mRNA expression. In conclusion, our data indicate that induction of human vaspin mRNA expression in adipose tissue is regulated in a fat depot-specific manner and could be associated with parameters of obesity, insulin resistance, and glucose metabolism.     

肠道梭菌属与2型糖尿病的相关性研究进展

摘要：随着经济社会的发展和人类生活水平的提高,2型糖尿病及其慢性并发症不仅严重影响了患者自身的生活质量,而且也给其家庭和社会带来了沉重的负担,已逐渐成为全球突出的社会问题。如果人体内肠道菌群的结构和功能发生紊乱,则可能引起2型糖尿病的发生,因此肠道菌群成为备受关注的研究对象。相关文献指出肠道菌群中的梭菌属与肠黏膜完整性、内脏脂肪、免疫稳态、能量代谢、肠蠕动有关。本文总结了梭菌属的生物学特性、在机体内的生理功能及与2型糖尿病之间的相关性,旨在为进一步研究肠道梭菌属与2型糖尿病间的关系提供参考。     

肠道短链脂肪酸与2型糖尿病相关性研究进展

2型糖尿病(type 2 diabetes,T2DM)是一种以高血糖为特征的代谢性疾病.随着经济的发展,人们的生活方式发生了巨大的变化,T2DM患者数量不断增加.T2DM的发病机制复杂,与遗传、环境、年龄、种族及生活方式等密切相关.近年来,许多研究表明肠道菌群通过多种途径参与T2DM的发生,其中短链脂肪酸起着主要作用....     

MicroRNAs and type 2 diabetes/obesity

MicroRNAs belong to a newly identified class of small non-coding RNAs that have been widely implicated in the fine-tuning of many physiological processes such as the pathogenesis of type 2 diabetes(T2D) and obesity.Microarray studies have highlighted an altered profile of miRNA expression in insulin target tissues in diabetic and obese models.Emerging evidences suggest that miRNAs play significant roles in insulin production,secretion and actions,as well as in diverse aspects of glucose homeostasis and adipocyte differentiation. The identification of tissue-specific miRNAs implicated in T2D and obesity might be useful for the future development of effective strategies for early diagnosis and therapeutic intervention of obesity-related medical complications.     

Association of the -112A>C polymorphism of the uncoupling protein 1 gene with insulin resistance in Japanese individuals with type 2 diabetes

The -112A>C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) has been associated with type 2 diabetes mellitus in Japanese individuals. The aim of the present study was to investigate the effects of this polymorphism, as well as the well-known -3826A>G polymorphism (rs1800592), on clinical characteristics of type 2 diabetes. We determined the genotypes of the two polymorphisms in 93 Japanese patients with type 2 diabetes. Intramyocellular lipid content and hepatic lipid content (HLC) were measured by magnetic resonance spectroscopy. No significant differences in age, sex, BMI, or HbA1c level were detected between type 2 diabetic patients with the -112C allele and those without it. However, homeostasis model assessment for insulin resistance (p=0.0089) and HLC (p=0.012) was significantly greater in patients with the -112C allele. We did not detect an association of the -3826A>G polymorphism (rs1800592) of UCP1 gene with any measured parameters. These results suggest that insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes.     

Adiponectin,TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis

AimsThere has been growing evidence that adiponectin, tumor necrosis factor-α (TNF-α) and inflammatory cytokines involved in insulin resistance and may be attractive candidates for assessing risk of the incident type 2 diabetes (T2DM). A systematic review and meta-analysis of prospective studies was conducted to assess the associations of levels of serum adiponectin, TNF-α and inflammatory markers (Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Interleukin-18 (IL-18), C-reactive protein (CRP)) with risk of T2DM.Materials/methodsWe searched PubMed, ISI Web of Knowledge, EMBASE, and Cochrane Library databases up until February 1, 2016 for eligible studies which were matched to search subjects. Either fixed-effects or random-effects models were used to estimate the summary risk incorporated between study variations.Results19 studies comprising a total of 39,136 participants and 7924 cases were included in the meta-analysis. Our findings showed that an obvious association of elevated CRP levels with T2DM risk (relative risk [RR] 1.48 [95% CI 1.26–1.71]), with the absence of publication bias. For IL-6, the meta-analysis involved 16 cohorts with a total of 24,929 participants and 4751 cases. Using data from all trials, a strong positive correlation (1.32 [1.14, 1.51]) was observed between basal plasma IL-6 and T2DM, whereas relatively lower relation between TNF-α (1.16 [0.87, 1.45]), IL-18 (1.45 [1.16, 1.73]), IL-1β (0.87, [0.59, 1.15]) and independently increased risk to occurrence of T2DM. Conversely, we also found that the level of adiponectin decreased significantly in patients with T2DM. Sensitivity analyses further supported the associations.ConclusionsThis meta-analysis indicates that T2DM risk as whole was strongly associated with elevated levels of inflammatory cytokines (IL-1β, IL-6, IL-18, CRP), TNF-α and low levels of adiponectin. Despite an overall detectable association in the meta-analysis, considerable heterogeneity existed between studies. Further work is needed, it seems clear that a complex interplay of inflammation and the development of DM. Moreover, these biomarkers are predictors of T2DM subjects and should take more attention to measure levels of these as well as to target therapy/interventions.     

胰岛素受体基因多态性与2 型糖尿病的相关性

目的：探讨胰岛素受体基因（INSR）的第8外显子NaiⅠ多态性与湖北汉族人群2型糖尿痛的相关性;方法：采用同胞对（家系内对照）和随机病例-对照两种实验设计,并结合聚合酶链反应-限制性片断长度多态性（PCR—RFLP）技术分析了224个样本的INSR基因第8外显子NsiⅠ多态性,并洲定了身高、体重、腰围、臀围、血压和空腹血糖等生理指标;结果：两种实验设计中对照组与病例组的基因型和基因频率均无显著差异;结论：INSR基因在湖北汉族人群2型糖屎病的发生发展中可能不起主要作用。