Department of Nutrition, Exercise, and Sports, Faculty of Science, University of Copenhagen, Frederiksberg, Denmark.
Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
Am J Clin Nutr. 2019 Jan 1;109(1):29-42. doi: 10.1093/ajcn/nqy234.
Various mechanisms link higher total homocysteine to higher insulin resistance (IR) and risk of type 2 diabetes (T2D). Folate supplementation is recognized as a way to lower homocysteine. However, randomized controlled trials (RCTs) show inconsistent results on IR and T2D outcomes.
The aim of this study was to examine the effect of folate supplementation on IR and T2D outcomes.
We conducted a systematic literature search in PubMed, Web of Science, and EMBASE and prior systematic reviews and meta-analyses and identified 29 RCTs (22,250 participants) that assessed the effect of placebo-controlled folate supplementation alone or in combination with other B vitamins on fasting glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), or risk of T2D. The meta-analysis was conducted using both random- and fixed-effects models to calculate weighted mean differences (WMDs) or risk ratios with 95% CIs. Subgroup analyses were conducted based on intervention type (folate alone or in combination with other B vitamins), as well as analysis based on population characteristics, duration, dose, and change in homocysteine.
When compared with placebo, folate supplementation lowered fasting insulin (WMD: -13.47 pmol/L; 95% CI: -21.41, -5.53 pmol/L; P < 0.001) and HOMA-IR (WMD: -0.57 units; 95% CI: -0.76, -0.37 units; P < 0.0001), but no overall effects were observed for fasting glucose or HbA1c. Heterogeneity was low in all meta-analyses, and subgroup analysis showed no signs of effect modification except for change in homocysteine, with the most pronounced effects in trials with a change of >2.5 µmol/L. Changes in homocysteine after folate supplementation correlated with changes in fasting glucose (β = 0.07; 95% CI: 0.01, 0.14; P = 0.025) and HbA1c (β = 0.46; 95% CI: 0.06, 0.85; P = 0.02). Only 2 studies examined folate supplementation on risk of T2D, and they found no change in RR (pooled RR: 0.91; 95% CI: 0.80, 1.04; P = 0.16).
Folate supplementation might be beneficial for glucose homeostasis and lowering IR, but at present there are insufficient data to conclusively determine the effect on development of T2D. This trial was registered on the Prospero database as CRD42016048254.
多种机制将较高的总同型半胱氨酸与较高的胰岛素抵抗（IR）和 2 型糖尿病（T2D）风险联系起来。叶酸补充被认为是降低同型半胱氨酸的一种方法。然而，随机对照试验（RCT）在 IR 和 T2D 结果方面显示出不一致的结果。
本研究旨在探讨叶酸补充对 IR 和 T2D 结局的影响。
我们在 PubMed、Web of Science 和 EMBASE 以及先前的系统评价和荟萃分析中进行了系统文献检索，确定了 29 项 RCT（22250 名参与者），评估了单独或联合使用其他 B 族维生素的安慰剂对照叶酸补充对空腹血糖、胰岛素、稳态模型评估的胰岛素抵抗（HOMA-IR）、糖化血红蛋白（HbA1c）或 T2D 风险的影响。使用随机和固定效应模型计算加权均数差值（WMD）或风险比，并计算 95%置信区间（CI）。根据干预类型（叶酸单独或与其他 B 族维生素联合使用）进行亚组分析，以及根据人群特征、持续时间、剂量和同型半胱氨酸变化进行分析。
与安慰剂相比，叶酸补充降低了空腹胰岛素（WMD：-13.47 pmol/L；95%CI：-21.41，-5.53 pmol/L；P<0.001）和 HOMA-IR（WMD：-0.57 单位；95%CI：-0.76，-0.37 单位；P<0.0001），但空腹血糖或 HbA1c 无总体影响。所有荟萃分析的异质性均较低，除同型半胱氨酸变化外，亚组分析未显示出效应修饰的迹象，而在同型半胱氨酸变化>2.5µmol/L的试验中，效果最明显。叶酸补充后同型半胱氨酸的变化与空腹血糖（β=0.07；95%CI：0.01，0.14；P=0.025）和 HbA1c（β=0.46；95%CI：0.06，0.85；P=0.02）的变化相关。只有 2 项研究检查了叶酸补充对 T2D 风险的影响，他们发现 RR 没有变化（合并 RR：0.91；95%CI：0.80，1.04；P=0.16）。
叶酸补充可能有益于葡萄糖稳态和降低 IR，但目前尚无足够数据确定其对 T2D 发展的影响。本试验在 Prospéro 数据库中注册，注册号为 CRD42016048254。
