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.     

Circulating endothelium-enriched microRNA-126 as a potential biomarker for coronary artery disease in type 2 diabetes mellitus patients

Circulating microRNAs (miRNAs) have been shown as promising biomarkers for various diseases. We investigated the predictive potential of circulating endothelium-enriched miR-126 in type 2 diabetes patients (T2D) without chronic complications and T2D patients with coronary artery diseases (CAD). The expression levels of circulating miR-126, determined by quantitative real time PCR, were decrease in peripheral blood of T2D patients and T2D with CAD compared with healthy controls. MiR-126 strongly associated with T2D and CAD, negatively correlated with LDL in CAD patients and differentiated between T2D patients, T2D patients with CAD and healthy subjects. Circulating miR-126 may serve as a biomarker for predicting patients with T2D and diabetic CAD.     

浅析肠道菌群与2型糖尿病及冠心病的关系

糖尿病和冠心病是当前危害公共健康的最普遍的问题,它们的发病率逐年升高。由糖尿病引发的心脑血管、肾、周围神经、眼、足等并发症增加了患者致残或致死的风险。冠心病的常见并发症如心肌梗塞、心源性休克和心力衰竭等,严重时也会危及患者生命。研究表明,肠道菌群紊乱可通过诱发炎症反应、胰岛素抵抗、脂质代谢异常、提高血尿酸水平等途径,增加2型糖尿病和冠心病的发病率,从而影响这些疾病的发展及预后,其诱发2型糖尿病的机制含内毒素机制、短链脂肪酸机制和胆汁酸机制等。本文从肠道菌群失调的角度综述肠道菌群与2型糖尿病及冠心病的关系。     

2型糖尿病伴冠心病患者肠道菌群分布及其与糖、脂代谢指标的相关性

探讨2型糖尿病伴冠心病患者肠道菌群分布及其与糖、脂代谢指标的关系,为该类患者的治疗提供参考。

选取2021年1月至2021年12月我院收治的2型糖尿病伴冠心病患者50例作为试验组,选择50例同期在我院体检的健康人作为对照组,比较2组对象基本资料、肠道菌群分布（肠杆菌、肠球菌、双歧杆菌、拟杆菌、乳杆菌）、糖代谢指标[空腹血糖（FPG）、糖化血红蛋白（HbA1c）、空腹胰岛素（FINS）]水平、脂代谢指标[甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）]水平,分析肠道菌群分布与糖、脂代谢指标的相关性。

2组对象年龄、性别、体质量指数、收缩压、舒张压、吸烟史、高血压史比较差异均无统计学意义（均P＞0.05）。试验组患者肠道肠杆菌、肠球菌数量均高于对照组,双歧杆菌、拟杆菌、乳杆菌数量均低于对照组（均P＜0.05）。试验组患者FPG、FINS、血清HbA1c水平均高于对照组（均P＜0.05）。试验组患者血清TC、TG、LDL-C水平均高于对照组,而血清HDL-C水平低于对照组（均P＜0.05）。试验组患者肠道肠杆菌、肠球菌与FPG、HbA1c、FINS、TC、TG、LDL-C水平均呈正相关,与HDL-C均呈负相关（均P＜0.05）;而肠道双歧杆菌、拟杆菌、乳杆菌与FPG、HbA1c、FINS、TC、TG、LDL-C均呈负相关,与HDL-C均呈正相关（均P＜0.05）。

2型糖尿病伴冠心病患者肠道肠杆菌、肠球菌数量升高,双歧杆菌、拟杆菌、乳杆菌数量降低,且肠道菌群数量与糖、脂代谢指标具有显著相关性。

     

Simultaneously quantitative measurement of comprehensive profiles of esterified and non-esterified fatty acid in plasma of type 2 diabetic patients

Fatty acids, having intimate relationship with type 2 diabetes mellitus (DM2), are not only the main energy source as nutrients, but also signaling molecules in insulin secretion. In this work, we developed a two-step rapid method to comprehensive profiling of esterified fatty acid (EFA) and non-esterified fatty acid (NEFA) using KOH–CH₃OH to methylate EFA followed by H₂SO₄–CH₃OH to methylate NEFA. Its applications to fatty acids profiling of type 2 diabetic patients and health controls were also presented. The t-test results informed that 16 NEFAs and 7 EFAs had distinct differences between type 2 diabetes and health controls. Furthermore, quantitative alterations of fatty acids in plasma of type 2 diabetic patients treated with rosiglitazone were obtained by this method. Our research results indicated that the dynamic changes of NEFAs are various. Some decreased linearly, such as C18:0, C18:3n-6 and C22:6, and some changed nonlinearly, such as C18:3n-3 and C22:4. All results informed that fatty acid profiles could provide comprehensive and accurate information for not only discrimination between DM2 patients and health controls, but also evaluation alterations of fatty acids during therapeutic process.     

Research update on the association between SFRP5, an anti-inflammatory adipokine,with obesity,type 2 diabetes mellitus and coronary heart disease

Secreted frizzled-related protein 5 (SFRP5), an anti-inflammatory adipokine secreted by adipocytes, has been demonstrated to exert its anti-inflammatory effect via antagonizing the non-canonical wingless-type family member 5A (WNT5A) signalling pathways. The WNT5A protein, as a potent pro-inflammatory signalling molecule, is strongly involved in a variety of inflammatory disorders such as obesity, type 2 diabetes mellitus (T2DM) and atherosclerosis. In this review, we systematically outlined the current understanding on the roles of SFRP5 in the pathogenesis of three inflammatory diseases including obesity, T2DM and coronary heart disease (CHD). Our review might stimulate future research using SFRP5 as a promising novel therapeutic target for the treatment of obesity, T2DM and CHD.     

Landscape of the relationship between type 2 diabetes and coronary heart disease through an integrated gene network analysis

Type 2 diabetes (T2D) and coronary artery disease (CAD) are closely related chronic diseases with high prevalence and morbidity. However, a comprehensive comparison of the two diseases is lacking. Recent genome-wide association studies (GWAS) have identified a handful of single nucleotide polymorphisms (SNPs) that are significantly associated with the risk of T2D and CAD. These most significant findings may help interpret the pathogenesis of T2D and CAD. However, tremendous results from these GWAS are ignored. Here we revisited the raw datasets of these GWAS and performed an integrated gene network analysis to unveil the relationship between T2D and CAD by combining multiple datasets including protein–protein interaction (PPI) database, publication libraries, and pathway datasets. Our results showed that majority of genes were involved in the first module (1122 genes in T2D and 895 in CAD). Four pathways were found to be common in both T2D and CAD, including regulation of actin cytoskeleton, calcium signaling pathway, MAPK signaling pathway and focal adhesion (all P < 0.00001). MAX which was involved in small cell lung cancer pathway was a hub gene unique to T2D (OR = 1.2, P = 0.006) but not in CAD. In contrast, three hub genes including PLEKHG5 (T2D: OR = 1, P = 1; CAD: OR = 1.12, P = 0.006), TIAM1 (T2D: OR = 1, P = 1; CAD: OR = 1.48, P = 0.004) and AKAP13 (T2D: OR = 1, P = 1; CAD: OR = 1.38, P = 0.001) were hub genes unique to CAD. Moreover, for some hub genes (such as SMAD3) that were susceptible to both T2D and CAD, their associated polymorphisms were unique to each of the two diseases. Our findings might provide a landscape of the relationship between T2D and CAD.     

Changes and significance of serum angiopoietin-2 levels in patients with coronary heart disease

Coronary heart disease (CHD) is characterized by inflammatory process and endothelial dysfunction. To investigate angiopoietin-2 (Ang-2) profiles, we evaluated serum Ang-2 levels in different types of CHD in 166 subjects. Ang-2 was measured by enzyme-linked immunosorbent assay. Serum Ang-2 levels were significantly elevated in patients with CHD and gradually increased with advance of CHD. Ang-2 was positively correlated with Gensini scores and hs-CRP. Ang-2 might have potential implication in detecting and monitoring the progression of CHD.     

HPLC fingerprints combined with principal component analysis,hierarchical cluster analysis and linear discriminant analysis for the classification and differentiation of Peganum sp. indigenous to China

Introduction – Seeds of wild Peganum harmala Linn., P. multisectum (Maxim) Bobr., P. nigellastrum Bunge and a probable indeterminate species, herein referred to as P. variety, are commonly used in Chinese medicine. These seeds cannot be differentiated based on morphology. Objective – Seeds of P. harmala Linn., P. multisectum (Maxim) Bobr., P. nigellastrum Bunge and P. variety were collected in different provinces in China and their HPLC profiles were recorded for statistical analysis and pattern recognition. Methodology – HPLC chromatograms of seed extracts were recorded under the same conditions. Individual HPLC chromatograms for each species were evaluated against the mean chromatogram for the same species generated using a similarity evaluation computer program. Data from chromatographic fingerprints were also processed using principal component analysis (PCA), hierarchical cluster analysis (HCA) and linear discriminant analysis (LDA). Results – The Peganum sp. seed extracts had similar HPLC fingerprints but with some inter‐specific differences. The chromatographic fingerprints combined with PCA, HCA and LDA could distinguish the seeds of the different species of Peganum investigated. Conclusion – HPLC fingerprints can be used to authenticate and differentiate the seeds of three different species of genus Peganum indigenous to China. The results indicated that the unidentified P. variety might indeed be a new species or variety. Copyright © 2009 John Wiley & Sons, Ltd.     

2型糖尿病与糖尿病肾病患者微炎症及肠道微生物多样性分析

目的 分析2型糖尿病(T2DM)及糖尿病肾病(DKD)患者微炎症情况和肠道微生物多样性。 方法 将2016年4月至2019年7月在我院进行治疗的68例T2DM患者(T2DM组)和57例DKD患者(DKD组)纳入研究,选择同期于我院进行健康体检的36例志愿者作为对照组。收集3组对象一般资料、血液标本和粪便标本,测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDLC)、糖化血红蛋白(HbAlc)、空腹血糖(FBG)、超敏C反应蛋白(hsCRP)、白细胞介素6(IL6)水平,并对肠道细菌进行16S rDNA序列测序。比较3组对象一般资料,血液指标,肠道菌群门水平构成情况,肠道菌群多样性,肠道菌属差异性,并对患者炎性指标与菌群种类进行相关性分析。 结果 DKD组患者糖尿病病程长于T2DM组(P结论 2型糖尿病患者普遍存在微炎症和肠道菌群失衡,微炎症程度与肾脏病变和肠道菌群数量密切相关。T2DM与DKD患者在肠道菌群结构上具有一致性和差异性,肠道菌群检测有可能成为预测T2DM患者发生肾脏病变的风险指标。     

血浆miRNA-1、miRNA-21对冠心病合并糖尿病患者PCI术后支架内再狭窄的影响

目的：观察血浆miRNA-1、miRNA-21在冠心病（CHD）与无冠脉病变患者中含量的差异,探讨其在CHD合并糖尿病（DM）患者的经皮冠状动脉介入治疗（PCI）后发生支架内再狭窄（ISR）与非支架内再狭窄（NISR）患者的含量差异及其对ISR的预测价值。方法：入选CHD支架置入术后患者（CHD组,n=187）、无冠脉病变患者（对照组,n=195）。根据指南,将对照组分为正常对照组（n=150）、单纯DM组（n=45）;将CHD组分为单纯CHD组（n=119）、CHD合并DM组（n=68）,又将CHD组分为ISR组（n=48）及NISR组（n=139）;再将ISR组分为单纯ISR组（n=26）和ISR合并DM组（n=22）。收集各组患者血浆,提取总miRNA,检测miRNA-1、miRNA-21含量并分析各组的含量差异。结果：与对照组比较,CHD组miRNA-1、miRNA-21含量均升高（P<0.05）;与NISR组比较,ISR组miRNA-1、miRNA-21含量均升高（P<0.05）。与单纯CHD组比较,CHD合并DM组ISR发生率明显升高;而且与单纯ISR组比较,ISR合并DM组miRNA-21含量升高（P<0.05）,而单纯ISR组与ISR合并DM组miRNA-1含量无明显差异（P<0.05）。Logistics分析表明,与CHD患者相关危险因素DM、miRNA-1、miRNA-21的OR值分别为2.132,3.066,1.924（P<0.05,P<0.01）;ISR患者相关危险因素DM、miRNA-21的OR值分别为3.091,5.654（P<0.05,P<0.01）;CHD合并DM患者PCI术后发生ISR相关危险因素miRNA-21的OR值为9.148（P<0.01）。ROC曲线评价表明,miRNA-1,miRNA-21与CHD患者发生ISR的AUC分别为0.854,0.857;miRNA 21与CHD合并DM患者发生ISR的AUC为0.783。结论：血浆miRNA-1、miRNA-21对诊断CHD患者支架置入术后ISR发生有重要临床意义,miRNA-21对诊断CHD合并DM患者支架置入术后ISR发生尤其有重要临床意义。     

Determination of metabolic equivalents during low- and high-intensity resistance exercise in healthy young subjects and patients with type 2 diabetes

The purpose of this study was to quantify the metabolic equivalents (METs) of resistance exercise in obese patients with type 2 diabetes (T2DM) and healthy young subjects and to evaluate whether there were differences between sessions executed at low- versus high-intensity resistance exercise. Twenty obese patients with T2DM (62.9±6.1 years) and 22 young subjects (22.6±1.9 years) performed two training sessions: one at vigorous intensity (80% of 1-repetition maximum (1RM)) and one at moderate intensity (60% of 1RM). Both groups carried out three strength exercises with a 2-day recovery between sessions. Oxygen consumption was continuously measured 15 min before, during and after each training session. Obese T2DM patients showed lower METs values compared with young healthy participants at the baseline phase (F= 2043.86; P<0.01), during training (F=1140.59; P<0.01) and in the post-exercise phase (F=1012.71; P<0.01). No effects were detected in the group x intensity analysis of covariance. In this study, at both light-moderate and vigorous resistance exercise intensities, the METs value that best represented both sessions was 3 METs for the obese elderly T2DM patients and 5 METs for young subjects.     

Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

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The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound 11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.     

The DrugPattern tool for drug set enrichment analysis and its prediction for beneficial effects of oxLDL on type 2 diabetes

Enrichment analysis methods, e.g., gene set enrichment analysis, represent one class of important bioinformatical resources for mining patterns in biomedical datasets. However, tools for inferring patterns and rules of a list of drugs are limited. In this study, we developed a web-based tool, DrugPattern, for drug set enrichment analysis. We first collected and curated 7019 drug sets, including indications, adverse reactions, targets, pathways, etc. from public databases. For a list of interested drugs, DrugPattern then evaluates the significance of the enrichment of these drugs in each of the 7019 drug sets. To validate DrugPattern, we employed it for the prediction of the effects of oxidized low-density lipoprotein (oxLDL), a factor expected to be deleterious. We predicted that oxLDL has beneficial effects on some diseases, most of which were supported by evidence in the literature. Because DrugPattern predicted the potential beneficial effects of oxLDL in type 2 diabetes (T2D), animal experiments were then performed to further verify this prediction. As a result, the experimental evidences validated the DrugPattern prediction that oxLDL indeed has beneficial effects on T2D in the case of energy restriction. These data confirmed the prediction accuracy of our approach and revealed unexpected protective roles for oxLDL in various diseases. This study provides a tool to infer patterns and rules in biomedical datasets based on drug set enrichment analysis. DrugPattern is available at http://www.cuilab.cn/drugpattern.     

Assessment of serum tenascin-C and growth differentiation factor-15 among type 2 diabetes mellitus patients with and without acute coronary syndrome

BackgroundHigh prevalence of type 2 diabetes mellitus (T2DM) is associated with a higher prevalence of acute coronary syndrome (ACS). Inflammation is one of the important contributors to the pathogenesis and complications of coronary atherosclerotic plaque. Growth Differentiation Factor-15 (GDF-15) and Tenascin-C (TNC) play an important role in the initiation of atherosclerotic plaque as well as its rupture. The aim of the study was to evaluate the association between serum GDF-15, TNC, and the risk of ACS among T2DM patients.MethodsAnthropometric parameters, routine biochemical investigations like liver and renal function tests, lipid profile, and Creatine Kinase-Total (CK-T), Creatine Kinase-MB (CK-MB) were measured in 42 T2DM patients with ACS and 42 T2DM patients. Serum GDF-15 and TNC were measured by Human Sandwich-ELISA kits.ResultsSerum GDF-15 and TNC levels were significantly higher in T2DM patients with ACS as compared to T2DM patients. Serum GDF-15 was significantly correlated with waist circumference, diastolic blood pressure, pulse, serum CK-T, and CK-MB. Serum TNC was significantly correlated with the pulse, serum CK-T, CK-MB, high-density lipoprotein-cholesterol, and blood urea nitro GEN. Multivariate linear regression analysis showed that waist circumference was independently positively associated with serum GDF-15.ConclusionsT2DM patients with higher serum GDF-15 and TNC levels were at higher risk of acute coronary syndrome independent of other cardiovascular risk factors.     

Dual targeting of PTP1B and glucosidases with new bifunctional iminosugar inhibitors to address type 2 diabetes

The diffusion of type 2 diabetes (T2D) throughout the world represents one of the most important health problems of this century. Patients suffering from this disease can currently be treated with numerous oral anti-hyperglycaemic drugs, but none is capable of reproducing the physiological action of insulin and, in several cases, they induce severe side effects. Developing new anti-diabetic drugs remains one of the most urgent challenges of the pharmaceutical industry. Multi-target drugs could offer new therapeutic opportunities for the treatment of T2D, and the reported data on type 2 diabetic mice models indicate that these drugs could be more effective and have fewer side effects than mono-target drugs. α-Glucosidases and Protein Tyrosine Phosphatase 1B (PTP1B) are considered important targets for the treatment of T2D: the first digest oligo- and disaccharides in the gut, while the latter regulates the insulin-signaling pathway. With the aim of generating new drugs able to target both enzymes, we synthesized a series of bifunctional compounds bearing both a nitro aromatic group and an iminosugar moiety. The results of tests carried out both in vitro and in a cell-based model, show that these bifunctional compounds maintain activity on both target enzymes and, more importantly, show a good insulin-mimetic activity, increasing phosphorylation levels of Akt in the absence of insulin stimulation. These compounds could be used to develop a new generation of anti-hyperglycemic drugs useful for the treatment of patients affected by T2D.