Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis

Background

Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs.

Methods

MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events.

Results

Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily. Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped.

Conclusions

GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.     

Structural modulation of gut microbiota during alleviation of type 2 diabetes with a Chinese herbal formula

The gut microbiota is hypothesized to have a critical role in metabolic diseases, including type 2 diabetes (T2D). A traditional Chinese herbal formula, Gegen Qinlian Decoction (GQD), can alleviate T2D. To find out whether GQD modulates the composition of the gut microbiota during T2D treatment, 187 T2D patients were randomly allocated to receive high (HD, n=44), moderate (MD, n=52), low dose GQD (LD, n=50) or the placebo (n=41) for 12 weeks in a double-blinded trial. Patients who received the HD or MD demonstrated significant reductions in adjusted mean changes from baseline of fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) compared with the placebo and LD groups. Pyrosequencing of the V3 regions of 16S rRNA genes revealed a dose-dependent deviation of gut microbiota in response to GQD treatment. This deviation occurred before significant improvement of T2D symptoms was observed. Redundancy analysis identified 47 GQD-enriched species level phylotypes, 17 of which were negatively correlated with FBG and 9 with HbA1c. Real-time quantitative PCR confirmed that GQD significantly enriched Faecalibacterium prausnitzii, which was negatively correlated with FBG, HbA1c and 2-h postprandial blood glucose levels and positively correlated with homeostasis model assessment of β-cell function. Therefore, these data indicate that structural changes of gut microbiota are induced by Chinese herbal formula GQD. Specifically, GQD treatment may enrich the amounts of beneficial bacteria, such as Faecalibacterium spp. In conclusion, changes in the gut microbiota are associated with the anti-diabetic effects of GQD.     

肠道菌群与2型糖尿病相关性的研究进展

摘要：糖尿病是一种常见的代谢性疾病,发病率高,易引起严重的微血管、大血管并发症,造成多重器官损伤;缺乏有效的治疗手段,患者生存质量普遍偏低,致残率、致死率走高;发病机制异常复杂,目前仍未能完全阐明。近年来,大量报道显示,肠道菌群作为人体不可分割的部分,参与了宿主的健康维持和疾病发生,与2型糖尿病的发生、发展有着直接的关系。本文就肠道菌群与2型糖尿病的相关性研究进展进行简要综述,为肠道菌群及2型糖尿病的相关研究提供参考。     

肠道菌群与2型糖尿病相关性的研究进展

肠道菌群是人体肠道微生态的重要组成部分,以多种途径影响宿主的代谢与生理功能,通过调节肠道菌群结构与多样性,改善慢性疾病的发生发展已成为国内外的研究热点。本研究归纳总结了近年来肠道菌群影响2型糖尿病的主要途径,为阐明肠道菌群与2型糖尿病的相关性以及基于肠道菌群靶点的药物研制和临床治疗提供新的思路。     

从肠道菌群及色氨酸代谢角度探讨中药在三阴性乳腺癌中作用的研究进展

三阴性乳腺癌属于免疫原性较强的乳腺癌亚型,由于缺乏有效的治疗靶点,仍属于难以治疗的乳腺癌类型。越来越多的研究表明,肠道菌群可通过干预宿主或微生物的色氨酸代谢,重塑肿瘤免疫微环境,从而影响三阴性乳腺癌的发生、发展及免疫治疗疗效。中药在以往的研究中已被证实可以有效调节肠道稳态,抑制炎症反应,促进肿瘤细胞的凋亡等。然而,肠道菌群及其代谢物与三阴性乳腺癌之间的中医机制尚不明确。因此,本文在中医辨证乳腺癌基础理论的基础上,回顾以往的文献,从肠道菌群和色氨酸代谢的角度出发,梳理中药对肠道菌群及其代谢物质的干预作用,探索其抗肿瘤的机制,以期能为中西医结合治疗三阴性乳腺癌提供新的思路和方法。

     

肠道微生物与1型糖尿病的相关性研究

1型糖尿病(type 1 diabetes, T1D)是一种自身免疫性疾病,越来越多的证据支持肠道菌群是T1D发病的重要因素。在T1D发生前,观察到肠道通透性发生改变,使抗原透过肠黏膜进而攻击胰岛β细胞。患有T1D宿主体内的肠道微生物也与健康宿主的微生物有别,其调节性T细胞、Toll样受体(toll-like receptor, TLR)、丁酸、粘蛋白、胰高血糖素样肽-1(glucagon-likepeptide1,GLP-1)等可能与T1D有关。尽管通过细菌定植促进自身免疫的机制在糖尿病动物模型中虽已发现,但有些问题目前尚不清楚。现就肠道黏膜通透性与T1D的关系、宿主体内微生物组成的变化、肠道微生物与T1D的相关性作一阐述。     

Effects of chromium supplementation on lipid profile in patients with type 2 diabetes: A systematic review and dose-response meta-analysis of randomized controlled trials

BackgroundThe purpose of this study was to determine the influence of chromium supplementation on lipid profile in patients with type 2 diabetes mellitus (T2DM).MethodsA systematic search was performed in Scopus, Embase, Web of Science, the Cochrane library and PubMed databases to find randomized controlled trials (RCTs) related to the effect of chromium supplementation on lipid profile in patients with T2DM, up to June 2020. Meta-analyses were performed using the random-effects model, and I² index was used to evaluate heterogeneity.ResultsThe primary search yielded 725 publications. 24 RCTs (with 28 effect size) were eligible. Our meta-analysis indicated that chromium supplementation resulted in a significant decrease in serum levels of triglyceride (TG) (MD: -6.54 mg/dl, 95 % CI: -13.08 to -0.00, P = 0.050) and total cholesterol (TC) (WMD: -7.77 mg/dl, 95 % CI: -11.35 to -4.18, P < 0.001). Furthermore, chromium significantly increases high-density lipoprotein (HDL) (WMD: 2.23 mg/dl, 95 % CI: 0.07–4.40, P = 0.043) level. However, chromium supplementation did not have significant effects on low-density lipoprotein (LDL) (WMD: -8.54 mg/dl, 95 % CI: -19.58 to 2.49, P = 0.129) level.ConclusionChromium supplementation may significantly improve lipid profile in patients with T2DM by decreasing TG and TC and increasing HDL. However, based on our analysis, chromium failed to affect LDL. It should be noted that the lipid-lowering properties of chromium supplementation were small and may not reach clinical importance.     

Effects of sodium glucose cotransporter-2 inhibitors on serum uric acid in type 2 diabetes mellitus: A systematic review with an indirect comparison meta-analysis

To describe the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). PubMed, EMBASE, and CENTRAL were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to Aug 10, 2017, without language or date restrictions. Thirty-one studies totaling 13,650 patients were included. SGLT2 inhibitors significantly decreased SUA levels compared with placebo, canagliflozin WMD –37.02?μmol/L, 95% CI [–38.41, –35.63], dapagliflozin WMD –38.05?μmol/L, 95% CI [–44.47, –31.62], empagliflozin WMD –42.07?μmol/L, 95% CI [–46.27, –37.86]. The drug class effect of SUA reduction suggesting SGLT2 inhibitors might be beneficial for diabetic patients with hyperuricemia.     

Glycosylated hemoglobin in relationship to cardiovascular outcomes and death in patients with type 2 diabetes: a systematic review and meta-analysis

Background

Chronic hyperglycemia in type 2 diabetes increases the risk of microvascular events. However, there is continuing uncertainty about its effect on macrovascular outcomes and death. We conducted a meta-analysis of prospective studies to estimate the association of glycosylated hemoglobin level with the risk of all-cause mortality and cardiovascular outcomes among patients with type 2 diabetes.

Methodology/Principal Findings

We systematically searched the MEDLINE database through April 2011 by using Medical Subject Heading search terms and a standardized protocol. We included prospective cohort studies that reported data of glycosylated hemoglobin level on the risk of incident cardiovascular events and all-cause mortality. Relative risk estimates (continuous and categorical variables) were derived or abstracted from each cohort study. Twenty six studies were included in this analysis with a mean follow-up rang of 2.2–16 years. The pooled relative risk associated with a 1% increase in glycosylated hemoglobin level among patients with type 2 diabetes was 1.15 (95% CI, 1.11 to 1.20) for all-cause mortality, 1.17 (95% CI, 1.12 to 1.23) for cardiovascular disease, 1.15 (95% CI, 1.10 to 1.20) for coronary heart disease, 1.11 (95% CI, 1.05 to 1.18) for heart failure, 1.11 (95% CI, 1.06 to 1.17) for stroke, and 1.29 (95% CI, 1.18 to 1.40) for peripheral arterial disease, respectively. In addition, a positive dose-response trend existed between glycosylated hemoglobin level and cardiovascular outcomes.

Conclusions/Significance

Chronic hyperglycemia is associated with an increased risk for cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes, likely independently from other conventional risk factors.     

肠道菌群在中药代谢中的作用

近年来,中药在疾病防治方面所发挥的巨大作用受到了广泛认可。科学合理地解释中药的作用机制将有助于提高其利用价值。越来越多的证据表明肠道菌群在中药治疗中起着至关重要的作用,是打开我国中医药宝库的一把钥匙。肠道菌群在中药成分代谢过程中发挥着复杂的作用：一方面,人类肠道菌群通过编码多种活性酶,促进了中药组分中的非碳水化合物小分子与碳水化合物在肠道中的代谢过程;另一方面,经肠道菌群代谢转化后产生的中药产物具有多种药理作用。因此,在未来中药研究中应更多地考虑肠道微生态因素,这有助于为中药的药理作用机制研究奠定新的科学基础。     

中国人群肠道微生物鸟枪法宏基因组测序研究进展

肠道微生物与人类健康的相关性研究仍然是当前生命科学研究领域的前沿热点之一。不依赖培养的16Sr RNA基因高通量测序是当前的主要研究手段。但随着测序成本的降低和数据分析方法的日渐成熟,宏基因组鸟枪法测序因具有信息量更大、更全等优势,将逐渐成为今后一段时间内研究肠道微生物组的重要手段。美国在人类微生物组计划的资助下,对30 805份样品进行了肠道微生物宏基因测序分析。通过NCBI Pub Med和SRA数据库检索,共发现72项研究收集了约10000份中国人的肠道样品用于宏基因组测序。但到目前为止,仅56项研究进行了公开发表,其中与代谢性疾病相关的文献16篇,与感染和免疫性疾病相关的文献16篇,与心脑血管疾病相关的文献12篇。由于采样地点以北京、广州、上海等大城市为主,测序平台和测序分析方法均存在较大差异,且大部分研究仍以相关性分析为主,相关研究成果在临床疾病诊疗中所发挥的作用仍非常有限。规范采样方法、标准化测序平台和数据分析流程,开展多中心平行研究将有助于数据整合和比较分析。同时,结合使用转录组、蛋白质组和培养组学等多组学方法开展功能验证和分子作用机制研究,将有利于更好地将肠道微生物研究...     

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。

     

Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies

Objective

Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

Research Design and Methods

Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

Results

The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10⁻¹⁸). Substantial heterogeneity was present (I² = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10⁻⁴), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10⁻¹³), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10⁻⁵). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

Conclusions

A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.     

Body iron stores and heme-iron intake in relation to risk of type 2 diabetes: a systematic review and meta-analysis

Background and Objective

Emerging evidence from biological and epidemiological studies has suggested that body iron stores and heme-iron intake may be related to the risk of type 2 diabetes (T2D). We aimed to examine the association of body iron stores and heme-iron intake with T2D risk by conducting a systematic review and meta-analysis of previously published studies.

Research Design and Methods

Systematic review and subsequent meta-analysis were conducted by searching MEDLINE database up to June 22, 2012 to identify studies that analyzed the association of body iron stores or dietary heme-iron intake with T2D risk. The meta-analysis was performed using the effect estimates and 95% confidence intervals (CIs) to calculate the pooled risk estimates, while the heterogeneity among studies was examined using the I² and Q statistic.

Results

The meta-analysis included 16 high-quality studies: 12 studies analyzed ferritin levels (4,366 T2D patients and 41,091 controls) and 4 measured heme-iron intake (9,246 T2D patients and 179,689 controls). The combined relative risk (RR) comparing the highest and lowest category of ferritin levels was 1.66 (95% CI: 1.15–2.39) for prospective studies, 2.29 (95% CI: 1.48–3.54) for cross-sectional studies with heterogeneity (Q = 14.84, p = 0.01, I² = 66.3%; Q = 44.16, p<0.001, I² = 88.7%). The combined RR comparing the highest and lowest category of heme-iron intake was 1.31 (95% CI: 1.21–1.43) with heterogeneity (Q = 1.39, p = 0.71, I² = 0%). No publication bias was found. Additional 15 studies that were of good quality, had significant results, and analyzed the association between body iron stores and T2D risk were qualitatively included in the systematic review.

Conclusions

The meta-analysis and systematic review suggest that increased ferritin levels and heme-iron intake are both associated with higher risk of T2D.     

营养干预对肝硬化代偿期合并糖尿病患者肠道菌群的影响

探讨营养干预对肝硬化代偿期合并糖尿病患者肠道微生物的影响。

收集2022年9月—2023年9月本院收治的80名肝硬化代偿期合并糖尿病患者,随机分为对照组和观察组,每组40例。对照组使用常规降糖药物治疗,观察组在对照组基础上,进行营养干预,根据1.5 g/kg的体重剂量摄入乳清蛋白质粉,接受常规饮食咨询和营养建议。每4周收集空腹血清样本,在干预前和营养干预后12周收集粪便样本,使用全自动生化分析仪、ELISA法检测血清葡萄糖、总胆固醇、高密度脂蛋白（HDL-c）胆固醇和低密度脂蛋白胆固醇（LDL-c）胆固醇水平等临床参数。使用Illumina Nova Seq平台对粪便基因组DNA测序。

对照组患者12周后临床各项指标与基线比较,差异均无统计学意义（P＞0.05）。观察组患者营养干预后空腹血糖（t=2.862,P=0.005）、空腹胰岛素（t=5.926,P＜0.001）、HOMA-IR（t=2.680,P=0.009）、hs-CRP（t=3.386,P=0.001）、蛋白质氧化率（t=7.762,P=0.001）均显著降低,呼吸商显著增加（t=2.958,P=0.004）。营养干预后6个菌种的相对丰度发生了显著变化,分别属于厚壁菌门、拟杆菌门和变形菌门。属于拟杆菌属和梭菌目的菌种在营养干预后产生了显著的菌株基因组变化。基于HOMA-IR的相对改善,将观察组患者分为响应者（R）亚组和非响应者（NR）亚组。两个亚组之间肠道微生物群的动态变化差异有统计学意义（P=0.008）。

肠道微生物群在营养干预对肝硬化代偿期合并糖尿病患者胰岛素敏感性影响中发挥重要作用,可能有助于临床实施个体化生活方式干预。

     

Association between shift work and risk of type 2 diabetes mellitus: a systematic review and dose-response meta-analysis of observational studies

ABSTRACT

To evaluate the association between shift work and risk of type 2 diabetes mellitus, we searched PubMed, EMBASE and Web of Science from their inception to June 8, 2019. Observational studies examining the relationship between shift work and type 2 diabetes were included. Subgroup analyses were conducted to explore whether specific characteristics would affect the relationship. A dose-response relationship was estimated by using generalized least squares trend regression. Finally, twelve cohort studies and nine cross-sectional studies were included (inter-rater agreement, k = 0.96). The result of meta-analysis indicated that shift work was associated with an increased risk of type 2 diabetes (relative risk = 1.10, 95% confidence interval = 1.05–1.14). Subgroup analyses demonstrated that female shift workers have increased risk of type 2 diabetes while male not observed, health care workers showed the highest risk compared with civil servants and manual workers, and night shift and rotating shift were associated with an increased risk of type 2 diabetes. Dose-response meta-analysis based on three cohorts among female workers indicated that there might be a positive association between duration of shift work and the risk of type 2 diabetes. In conclusion, shift work is positively associated with an increased risk of type 2 diabetes. Among female workers, with the years of exposure to shift work prolonged, the risk of type 2 diabetes might increase accordingly. In the future, more studies are needed to confirm the results of dose-response analysis.     

Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease ultimately leading to destruction of insulin secreting β-cells in the pancreas. Genetic susceptibility plays an important role in T1D etiology, but even mono-zygotic twins only have a concordance rate of around 50%, underlining that other factors than purely genetic are involved in disease development. Here we review the influence of dietary and environmental factors on T1D development in humans as well as animal models. Even though data are still inconclusive, there are strong indications that gut microbiota dysbiosis plays an important role in T1D development and evidence from animal models suggests that gut microbiota manipulation might prove valuable in future prevention of T1D in genetically susceptible individuals.     

Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults

Background

Previous studies have demonstrated that fetuin-A is related to insulin resistance among subjects with normal glucose tolerance but not patients with type 2 diabetes. There are limited data available concerning fetuin-A and insulin resistance in Chinese. We aimed to study the association of feuin-A with insulin resistance among participants with or without type 2 diabetes in a large sample size of adults aged 40 and older.

Methodology and Principal Findings

A community-based cross-sectional study was performed among 5,227 Chinese adults. The average age of our study was 61.5±9.9 years. Serum fetuin-A concentrations were not significantly different between male and female (296.9 vs. 292.9 mg/l, p = 0.11). Compared with the lowest quartile, the highest quartile of serum fetuin-A revealed a significant higher proportion of type 2 diabetic patients (34.8% vs. 27.3%, p<0.0001). In the multinomial logit models, the risk of type 2 diabetes was associated with each one quartile increase of serum fetuin-A concentrations when referenced not only to normal glucose tolerance (OR 1.24, 95% CI 1.07–1.43, p = 0.004) but also to impaired glucose regulation (OR 1.25, 95% CI 1.08–1.44, p = 0.003, respectively), after adjustment for age, sex, community, current smoking, and current drinking. The logistic regression analysis showed that fetuin-A were associated with elevated HOMA-IR and fasting serum insulin both among the participants with or without type 2 diabetes in the full adjusted analysis. There was no significant association between elevated serum fetuin-A concentrations and impaired glucose regulation (all p≥0.12).

Conclusions and Significance

Higher fetuin-A concentrations were associated with type 2 diabetes and insulin resistance in middle aged and elderly Chinese.