1Nutrition and Foods Program, School of Family and Consumer Sciences, Texas State University, San Marcos, TX, USA
2Institute for Translational Epidemiology & Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Department of Mathematics, Texas State University, San Marcos, TX, USA
4Department of Obstetrics and Gynecology, Vagelos College of Physician and Surgeons, Columbia University, New York, NY, USA
5Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Copyright © 2024 Korean Diabetes Association
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
Ka Kahe is an international editorial board member of the Diabetes & Metabolism Journal. He was not involved in the review process of this review. Otherwise, there is no conflict of interest.
FUNDING
Ka Kahe is partially supported by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases Grant (grant number R01DK116603). Jie Zhu is supported by the 2022 Multidisciplinary Internal Research Grant, Translational Health Research Center/Community Health and Economic Resilience Research (THRC/CHERR) Faculty Fellowship Funding, and the Research Enhancement Program at Texas State University. Xiaotao Zhang is supported by Icahn School of Medicine at Mount Sinai Institute Start-Up Grant.
Study | Year | Location | Study population | Design | Exposure | Follow-up | Outcomes/Major results |
---|---|---|---|---|---|---|---|
Al-Maskari et al. [10] | 2012 | Oman | 100 Omani adults aged 42.92–59.33 years (n=50 diabetic cases, n=50 healthy controls) | Case-control | Dietary intakes and serum levels of folate and vitamin B12 | NA | Bothe dietary intakes and serum levels of folate and vitamin B12 were lower in patients with T2DM than those in the healthy controls (all P<0.05). |
Hong et al. [11] | 2017 | South Korea | 7,333 Adults aged ≥40 years | Prospective | Dietary folate intake (not including folate intake from supplements) | 4.06 years | Dietary folate intake was inversely associated with risk of T2DM for women (RR in the highest vs. the lowest quartile was 0.64 [95% CI, 0.43–0.95; Ptrend =0.0244]). |
Eshak et al. [12] | 2019 | Japan | 19,168 Healthy adults aged 40–79 years | Prospective | Intake of water-soluble vitamins | 5 years | Higher dietary intakes of folate and vitamin B2 were associated with lower risk of T2DM in Japanese women (OR in the highest vs. the lowest quartile of intakes were 0.70 [95% CI, 0.46–0.98; Ptrend =0.03] for folate and 0.56 [95% CI, 0.34–0.93; Ptrend =0.03] for vitamin B2). |
Zhu et al. [13] | 2020 | USA | 4,704 White and Black adults aged 18–30 years | Prospective | Total intake of folate, vitamin B6, and vitamin B12 | 30 years | Intake of folate, but not vitamin B6, or vitamin B12, was inversely associated with DM incidence (HR in the highest vs. the lowest quartile of folate intake was 0.70 [95% CI, 0.51–0.97; Ptrend =0.02]). |
Virtanen et al. [14] | 2020 | Finland | 2,332 Men aged 42–60 years | Prospective | Choline intake | 19.3 years | Higher choline intake was associated with lower risk of T2DM among men in eastern Finland (HR in the highest vs. the lowest quartile of choline intake was 0.75 [95% CI, 0.57–0.98; Ptrend =0.02]). |
Dibaba et al. [15] | 2020 | USA | 13,440 Men and women aged 45–64 years | Prospective | Intake of choline and betaine | 9 years | Overall and among male participants, neither dietary choline nor betaine intake was associated with risk of T2DM. |
Among women, there was a trend for a modestly higher T2DM risk (HR in the highest vs. the lowest quartile of choline intake was 1.54 [95% CI, 1.06–2.25; Pinteraction for sex=0.07]). | |||||||
Greenberg et al. [16] | 2021 | USA | 46,263 Postmenopausal women aged 50–79 years | Prospective | Intake of choline and betaine | 13.3 years | Higher choline intake was associated with increase in DM risk (HR in the highest vs. the lowest quartile of choline intake was 1.30 [95% CI, 1.15–1.47; Ptrend <0.0001]). |
There was a significant linear trend but no significant association between betaine intake and risk of DM (HR in the highest vs. the lowest quartile of betaine intake was 0.90 [95% CI, 0.81–1.002; Ptrend =0.04]). | |||||||
Lu et al. [17] | 2022 | China | 1,565 Chinese adults aged 40–75 years | Prospective | Serum betaine | 8.9 years | Higher serum betaine was associated with lower risk of T2DM (HR in the highest vs. the lowest quartile was 0.46 [95% CI, 0.31–0.69; Ptrend <0.001]). |
Gao et al. [18] | 2019 | Canada | 1,081 Canadian adults aged 28–56 years | Cross-sectional | Serum choline and betaine levels | NA | Serum choline level was negatively correlated with serum fasting glucose levels in males (R=–0.121, P=0.006). |
Serum betaine level was negatively associated with insulin levels (R=−0.081, P=0.043), and HOMA-IR index (R=−0.086, P=0.021) in males. In females, serum betaine level was negatively associated with insulin levels (R=−0.104, P=0.016), and with HOMA-IR index (R=−0.092, P=0.034). | |||||||
Nie et al. [19] | 2022 | China | 188 Chinese adults aged 57–72 years (n=94 diabetic cases, n=94 healthy controls) | Case-control | Plasma metal levels | NA | Plasma Zn level was positively correlated with elevated DM risk (OR in the highest vs. the lowest quartile of plasma Zn levels was 2.37 [95% CI, 1.47–3.81; P<0.001]). |
Cheng et al. [20] | 2022 | China | 772 Adults aged 43–82 years (n=370 T2DM cases, n=402 controls) | Cross-sectional | Serum folate | NA | Higher serum folate level was associated with lower risk of T2DM (OR in the highest vs. the lowest quartile of serum folate levels was 0.909 [95% CI, 0.840–0.983; Ptrend =0.0177]). |
Ding et al. [21] | 2022 | China | 901 Participants (n=417 males, n=484 females) aged 18–75 years | Cross-sectional | Dietary intake of betaine, total choline, methionine, folate, vitamins B6 and B12 | NA | Higher dietary intakes of total choline and vitamin B6 were associated with a lower incidence of hyperglycemia (OR in the highest vs. the lowest quartile were 0.601 [95% CI, 0.365–0.988; Ptrend =0.365–0.988] for total choline; 0.575 [95% CI, 0.346–0.956; Ptrend =0.038] for vitamin B6). |
There were null associations of dietary intakes of folate, vitamin B12, methionine, and betaine with risk of hyperglycemia. | |||||||
Sun et al. [22] | 2023 | China | 12,489 Chinese adults aged ≥20 years | Cross-sectional | Methionine intake | NA | Higher intake of dietary methionine was associated with higher risk of DM (OR in the highest vs. the lowest quartile was 1.49 [95% CI, 1.12– 1.98; Ptrend =0.009]). |
Study | Year | Location | Study population | Design | Intervention | Duration | Outcomes/Major results |
---|---|---|---|---|---|---|---|
DM risk | |||||||
Song et al. [7] | 2009 | USA | 5,442 Female health professionals aged 54–72 years with history of CVD or ≥3 CVD risk factors | Double-blind RCT | Treatment group: daily intake of a combination pill containing 2.5 mg FA, 50 mg vitamin B6, and 1 mg vitamin B12 (n=2,132) | 7.3 years | No significant effect on risk of DM |
Placebo group: a matching placebo pill daily (n=2,120) | ↓Blood Hcy | ||||||
Qin et al. [8] | 2016 | China | 20,702 Hypertensive patients aged 52.3–57.5 years | Double-blind RCT | Daily treatment with tablets containing: (1) 10 mg enalapril and 0.8 mg FA (n=10,348); or (2) 10 mg enalapril alone (n=10,354) | 4.5 years | No significant effect on FPG and risk of DM |
Ranasinghe et al. [9] | 2018 | Sri Lanka | 200 Participants with prediabetes aged 44–59.4 years | Double-blind RCT | Treatment group: capsules containing 20 mg zinc daily (n=100) | 12 months | ↓FPG, ↓2-hour glucose after the OGTT, ↓HOMA-IR, ↓T2DM development |
Placebo group: capsules containing inactive ingredients (n=100) | ↑HOMA-β | ||||||
Glucose metabolism index | |||||||
Aarsand et al. [37] | 1998 | Norway | 28 Diabetic patients with metformin treatment for more than 1 year, aged 53.9–64.1 years | Double-blind RCT | Treatment group: tablets containing 0.25 mg folate+60 mg Fe2+ daily (n=14) | 12 weeks | No significant effect on FSG and HbA1c |
↓Serum Hcy | |||||||
Placebo group: tablets containing 60 mg Fe2+ daily (n=14) | ↑Serum vitamin B12 and folate | ||||||
Doshi et al. [23] | 2001 | UK | 50 Patients with coronary artery disease, aged 46–65 years | A randomized, double-blind, placebo-controlled crossover trial | Treatment group: 5 mg FA supplement per day | Two 6-week treatments separated by a washout period of 4 months | No significant effect on FPG |
Placebo group: matched placebo | ↑Plasma folate | ||||||
↓Plasma Hcy | |||||||
Doshi et al. [24] | 2002 | UK | 33 Patients with coronary artery disease, aged 46–65 years | Double-blind RCT | Treatment group: 5 mg FA supplement per day (n=16) | 6 weeks | No significant effect on FPG |
Placebo group: matched placebo (n=17) | ↑Plasma folate | ||||||
↓Plasma Hcy | |||||||
Setola et al. [38] | 2004 | Italy | 50 Patients with metabolic syndrome+hyperinsulinemia, aged 66.1–68.5 years | Double-blind, parallel, identical placebo-drug RCT | Group 1: treated with diet+placebo for 2 months | 2 months | ↓Insulin levels, ↓HOMA-IR, ↓Hcy levels |
Group 2: treated with diet+placebo (1 month) then diet+FA (5 mg/day)+vitamin B12 (500 µg/day) for 2nd month | No significant effect on fasting glucose | ||||||
Kilicdag et al. [48] | 2005 | Turkey | 49 Female patients with PCOS (group 1, 17.22–31.06 years; group 2, 18.27–25.73 years; group 3, 18.27–31.61 years) | RCT | Group 1 received metformin (850 mg twice daily) (n=20) | 12 weeks | No significant effect on HOMA-IR |
Group 2 received metformin (850 mg twice daily)+B-group vitamins (vitamin B1 250 mg, vitamin B6 250 mg, vitamin B12 1,000 µg twice daily) (n=20) | ↓Serum Hcy (groups 1 & 2) | ||||||
Group 3 received metformin (850 mg twice daily)+FA (174 µg), vitamin D (1,200 µg) and calcium (666.670 mg) twice daily (n=20) | ↑Plasma FA (group 3), ↑plasma vitamin B12 (group 2) | ||||||
Mangoni et al. [25] | 2005 | Australia | 26 T2DM patients aged 46–65 years | Double-blind, parallel-group RCT | Treatment group: 5 mg FA supplement per day (n=13) | 4 weeks | No significant effect on plasma glucose, HbA1c, and serum vitamin B12 |
Placebo group: matched placebo (n=13) | ↓Plasma Hcy, ↑serum folate | ||||||
Sheu et al. [26] | 2005 | Taiwan | 84 Obese women who were 20% over their ideal weight | Double-blind RCT | Treatment group: 5 mg FA supplement per day (n=36) | 12 weeks | ↓HOMA-IR, ↓fasting plasma insulin, ↓serum Hcy |
Placebo group: matched placebo (n=38) | No significant effect on FPG and fasting serum vitamin B12 and folate | ||||||
This program also included caloric restriction and light exercises to promote weight loss. | |||||||
Villa et al. [27] | 2005 | Italy | 20 Healthy postmenopausal women aged 48–61 years | RCT | Treatment group: 7.5 mg FA supplement per day (n=10) | 8 weeks | No significant effect on fasting glucose and insulin, and vitamin B12, methionine |
Placebo group: commercial calcium capsule (n=10) | ↓Hcy levels | ||||||
Moat et al. [28] | 2006 | USA | 128 Patients with angiographically proven CAD aged 53–68 years | Double-blind, parallel, RCT | 84 Patients were randomly divided into 3 groups for FA study (placebo, n=29; low-dose FA 400 µg/day, n=30; and high-dose FA 5 mg/day, n=25). Parallelly 44 patients were randomly divided into 2 groups for betaine study (Placebo, n=23 or betaine, 100 mg/kg/day, n=21). | 6 weeks | ↓Total plasma Hcy levels, ↑plasma folate, and no significant difference in blood glucose and serum vitamin B12 for FA study |
↓Plasma folate but no significant difference in blood glucose, serum vitamin B12, or plasma Hcy for betaine study | |||||||
Solini et al. [29] | 2006 | Italy | 60 Healthy overweight adults aged 29–61 years | Unmasked randomized, placebo-controlled trial | All patients were put on a hypocaloric diet and were randomly assigned to either a placebo or FA (2.5 mg/day) group. | 12 weeks | ↓Fasting plasma insulin, ↓HOMA-IR, ↑serum folate |
No significant difference in serum vitamin B12, Hcy, or FPG | |||||||
Title et al. [30] | 2006 | Canada | 19 T2DM patients aged 35–65 years | Randomized, double-blind, placebo-controlled, crossover trial | Patients were randomly assigned to receive either oral FA (10 mg/day) or a matching placebo for 2 weeks. This was followed by 8 weeks of washout period and then patients were crossed over to receive alternate treatment for another 2 weeks. | 2 weeks+8 weeks washout+2 weeks | No significant effect on plasma Hcy and plasma glucose |
↑Serum folate | |||||||
Moens et al. [31] | 2007 | Belgium | 40 Patients with acute myocardial infarction, aged 42–70 years | Randomized, double-blind, placebo-controlled crossover trial | Patients were randomly divided into 2 groups: Group A (n=20) received FA (10 mg/day) for initial 6 weeks then a placebo for another 6 weeks. For group B (n=20), the order was reversed. There was a washout of 2 weeks between the treatments. | 6 weeks+2 weeks washout+6 weeks | No significant difference in plasma vitamin B12, and FPG |
↑Plasma and RBC folate, ↓plasma Hcy | |||||||
Mao et al. [50] | 2008 | China | 443 Patients with mild to moderate hypertension, aged 27–75 years | Double-blind RCT | Participants were randomly assigned to 3 groups: control (10 mg of enalapril, n=149); low-FA group (10 mg enalapril+0.4 mg of FA, n=146); high-FA group (10 mg enalapril+0.8 mg of FA, n=148). | 8 weeks | ↓FPG in low-FA and high-FA groups |
↑Serum folate | |||||||
Mashavi et al. [42] | 2008 | Israel | 57 T2DM patients aged 54.1–66.1 years | Double-blind RCT | Group 1: 1,500 mg metformin+folate (1,000 µg), vitamin B12 (400 µg), and vitamin B6 (10 mg) daily (n=28) | 4 months | No significant difference in HOMA-IR and FPG |
↑Serum FA, ↑serum vitamin B12 | |||||||
Group 2: 1,500 mg metformin+placebo daily (n=29) | ↓Serum Hcy | ||||||
Potter et al. [39] | 2008 | Australia | 162 Patients with history of stroke, aged 52–80 years | Double-blind RCT | Treatment group: a single daily tablet containing FA (2 mg), vitamin B6 (25 mg), and vitamin B12 (500 µg) (n=83) | 104 weeks | No significant difference in FGB and HbA1c |
↓Blood Hcy | |||||||
Placebo group: matched placebo (n=79) | ↑Serum B6, ↑serum vitamin B12, ↑RBC folate | ||||||
Cagnacci et al. [32] | 2009 | Italy | 30 Healthy White postmenopausal women aged 48–58 years | Double-blind RCT | Treatment group: 15 mg/day 5-methyltetrahy-drofolate (n=15) | 3 weeks | ↓HOMA-IR, ↓blood insulin, ↓blood Hcy |
Placebo group: matched placebo (n=15) | No significant effect on FBP | ||||||
Palomba et al. [41] | 2010 | Italy | 47 Females with PCOS, aged 23.6–30 years | Non-randomized placebo-controlled double-blind trial | Experimental group: 1,700 mg metformin+400 µg FA daily (n=25) | 25 weeks | ↓Fasting serum insulin, ↓HOMA-IR |
Control group: 1,700 mg metformin+a placebo daily (n=25) | ↑Serum Hcy | ||||||
No significant difference in serum folate, vitamin B12, or FBG | |||||||
Kurt et al. [40] | 2010 | Turkey | 44 Adults aged >65 years with vitamin B12 deficiency | Double-blind RCT | Treatment group: FA (5 mg)+vitamin B12 (500 µg) daily (n=24) | 8 weeks | ↓HOMA-IR, ↓serum Hcy |
Placebo group: matched placebo (n=20) | ↑Serum folate, ↑serum vitamin B12 | ||||||
No significant difference in FPG | |||||||
Gargari et al. [33] | 2011 | Iran | 48 Overweight and obese men with T2DM and under metformin treatment, aged 46.9–67.7 years | Double-blind RCT | Treatment group: FA (5 mg) supplementation daily (n=24) | 8 weeks | ↓HOMA-IR, ↓serum HbA1c, ↓serum insulin |
Placebo group: matched placebo (n=24) | ↑Serum folate, ↑serum vitamin B12 | ||||||
No significant difference in FBG | |||||||
Grigoletti et al. [34] | 2013 | Brazil | 30 HIV-infected individuals aged 43–47 years | Double-blind RCT | Treatment group: FA (5 mg) supplementation daily (n=15) | 4 weeks | No significant difference in FSG |
Placebo group: matched placebo (n=15) | ↑Serum vitamin B12, ↑serum folate | ||||||
↓Plasma Hcy | |||||||
Asemi et al. [35] | 2014 | Iran | 81 Overweight or obese women with PCOS aged 18–40 years | Double-blind RCT | Group 1: 1 mg FA daily (n=27) | 8 weeks | ↓Serum insulin, ↓HOMA-IR, ↓plasma Hcy |
Group 2: 5 mg FA daily (n=27) | No significant difference in FPG | ||||||
Group 3: matched placebo (n=27) | |||||||
Karamali et al. [45] | 2015 | Iran | 58 Females with GDM aged 18–40 years | Double-blind RCT | Treatment group: 233 mg zinc gluconate daily (n=29) | 6 weeks | ↓FPG, ↓serum insulin, ↓HOMA-IR, ↓HOMA-β |
Placebo group: matched placebo (n=29) | ↑QUICKI, ↑serum zinc | ||||||
Asemi et al. [49] | 2016 | Iran | 58 Females with cervical intraepithelial neoplasia grade 1, aged 18–55 years | Double-blinded RCT | Treatment group: 5 mg FA daily (n=29) | 6 weeks | ↓Serum insulin levels, ↓HOMA-β, ↓plasma Hcy |
Placebo group: matched placebo (n=29) | |||||||
Hashemi et al. [36] | 2016 | Iran | 79 Pregnant women with preeclampsia, aged 21–41 years | Randomized, triple-blind, clinical trial | Treatment group: 5 mg FA daily | 8 weeks | No significant difference in FBG |
Placebo group: matched placebo | |||||||
Talari et al. [43] | 2016 | Iran | 60 Patients with metabolic syndrome, aged 40–85 years | Double-blind RCT | Treatment group: tablets containing 5 mg FA daily (n=30) | 12 weeks | ↓FPG, ↓serum insulin, ↓HOMA-IR, ↓plasma Hcy |
Placebo group: daily placebo tablets (n=30) | No significant difference in HOMA-β | ||||||
Bahmani et al. [44] | 2018 | Iran | 60 Women with endometrial hyperplasia | Double-blind RCT | Treatment group: 5 mg FA daily (n=30) | 12 weeks | ↓FPG, ↓serum insulin, ↓HOMA-IR, ↑QUICKI |
Placebo group: matched placebo (n=30) | |||||||
Attia et al. [46] | 2022 | Australia | 98 Prediabetic participants aged 40–70 years | Double-blind RCT | Treatment group: a daily capsule containing 30 mg elemental zinc gluconate (n=48) | 12 months | No significant difference in FBG, HbA1c, and HOMA-β |
Placebo group: a daily capsule containing cellulose (n=50) |
DM, diabetes mellitus; CVD, cardiovascular diseases; RCT, a randomized placebo-controlled trial; FA, folic acid; Hcy, homocysteine; FBG, fasting blood glucose; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; HOMA-IR, homeostasis model assessment of insulin resistance; T2DM, type 2 diabetes mellitus; HOMA-β, homeostatic model assessment of β-cell function; FSG, fasting serum glucose; HbA1c, glycosylated hemoglobin; PCOS, polycystic ovarian syndrome; CAD, coronary artery disease; RBC, red blood cell; FGB, fibrinogen beta chain; FBP, folate-binding protein; HIV, human immunodeficiency virus; GDM, gestational diabetes mellitus; QUICKI, quantitative insulin sensitivity check index.
Study | Year | Location | Study population | Design | Exposure | Follow-up | Outcomes/Major results |
---|---|---|---|---|---|---|---|
Al-Maskari et al. [10] | 2012 | Oman | 100 Omani adults aged 42.92–59.33 years (n=50 diabetic cases, n=50 healthy controls) | Case-control | Dietary intakes and serum levels of folate and vitamin B12 | NA | Bothe dietary intakes and serum levels of folate and vitamin B12 were lower in patients with T2DM than those in the healthy controls (all P<0.05). |
Hong et al. [11] | 2017 | South Korea | 7,333 Adults aged ≥40 years | Prospective | Dietary folate intake (not including folate intake from supplements) | 4.06 years | Dietary folate intake was inversely associated with risk of T2DM for women (RR in the highest vs. the lowest quartile was 0.64 [95% CI, 0.43–0.95; Ptrend =0.0244]). |
Eshak et al. [12] | 2019 | Japan | 19,168 Healthy adults aged 40–79 years | Prospective | Intake of water-soluble vitamins | 5 years | Higher dietary intakes of folate and vitamin B2 were associated with lower risk of T2DM in Japanese women (OR in the highest vs. the lowest quartile of intakes were 0.70 [95% CI, 0.46–0.98; Ptrend =0.03] for folate and 0.56 [95% CI, 0.34–0.93; Ptrend =0.03] for vitamin B2). |
Zhu et al. [13] | 2020 | USA | 4,704 White and Black adults aged 18–30 years | Prospective | Total intake of folate, vitamin B6, and vitamin B12 | 30 years | Intake of folate, but not vitamin B6, or vitamin B12, was inversely associated with DM incidence (HR in the highest vs. the lowest quartile of folate intake was 0.70 [95% CI, 0.51–0.97; Ptrend =0.02]). |
Virtanen et al. [14] | 2020 | Finland | 2,332 Men aged 42–60 years | Prospective | Choline intake | 19.3 years | Higher choline intake was associated with lower risk of T2DM among men in eastern Finland (HR in the highest vs. the lowest quartile of choline intake was 0.75 [95% CI, 0.57–0.98; Ptrend =0.02]). |
Dibaba et al. [15] | 2020 | USA | 13,440 Men and women aged 45–64 years | Prospective | Intake of choline and betaine | 9 years | Overall and among male participants, neither dietary choline nor betaine intake was associated with risk of T2DM. |
Among women, there was a trend for a modestly higher T2DM risk (HR in the highest vs. the lowest quartile of choline intake was 1.54 [95% CI, 1.06–2.25; Pinteraction for sex=0.07]). | |||||||
Greenberg et al. [16] | 2021 | USA | 46,263 Postmenopausal women aged 50–79 years | Prospective | Intake of choline and betaine | 13.3 years | Higher choline intake was associated with increase in DM risk (HR in the highest vs. the lowest quartile of choline intake was 1.30 [95% CI, 1.15–1.47; Ptrend <0.0001]). |
There was a significant linear trend but no significant association between betaine intake and risk of DM (HR in the highest vs. the lowest quartile of betaine intake was 0.90 [95% CI, 0.81–1.002; Ptrend =0.04]). | |||||||
Lu et al. [17] | 2022 | China | 1,565 Chinese adults aged 40–75 years | Prospective | Serum betaine | 8.9 years | Higher serum betaine was associated with lower risk of T2DM (HR in the highest vs. the lowest quartile was 0.46 [95% CI, 0.31–0.69; Ptrend <0.001]). |
Gao et al. [18] | 2019 | Canada | 1,081 Canadian adults aged 28–56 years | Cross-sectional | Serum choline and betaine levels | NA | Serum choline level was negatively correlated with serum fasting glucose levels in males (R=–0.121, P=0.006). |
Serum betaine level was negatively associated with insulin levels (R=−0.081, P=0.043), and HOMA-IR index (R=−0.086, P=0.021) in males. In females, serum betaine level was negatively associated with insulin levels (R=−0.104, P=0.016), and with HOMA-IR index (R=−0.092, P=0.034). | |||||||
Nie et al. [19] | 2022 | China | 188 Chinese adults aged 57–72 years (n=94 diabetic cases, n=94 healthy controls) | Case-control | Plasma metal levels | NA | Plasma Zn level was positively correlated with elevated DM risk (OR in the highest vs. the lowest quartile of plasma Zn levels was 2.37 [95% CI, 1.47–3.81; P<0.001]). |
Cheng et al. [20] | 2022 | China | 772 Adults aged 43–82 years (n=370 T2DM cases, n=402 controls) | Cross-sectional | Serum folate | NA | Higher serum folate level was associated with lower risk of T2DM (OR in the highest vs. the lowest quartile of serum folate levels was 0.909 [95% CI, 0.840–0.983; Ptrend =0.0177]). |
Ding et al. [21] | 2022 | China | 901 Participants (n=417 males, n=484 females) aged 18–75 years | Cross-sectional | Dietary intake of betaine, total choline, methionine, folate, vitamins B6 and B12 | NA | Higher dietary intakes of total choline and vitamin B6 were associated with a lower incidence of hyperglycemia (OR in the highest vs. the lowest quartile were 0.601 [95% CI, 0.365–0.988; Ptrend =0.365–0.988] for total choline; 0.575 [95% CI, 0.346–0.956; Ptrend =0.038] for vitamin B6). |
There were null associations of dietary intakes of folate, vitamin B12, methionine, and betaine with risk of hyperglycemia. | |||||||
Sun et al. [22] | 2023 | China | 12,489 Chinese adults aged ≥20 years | Cross-sectional | Methionine intake | NA | Higher intake of dietary methionine was associated with higher risk of DM (OR in the highest vs. the lowest quartile was 1.49 [95% CI, 1.12– 1.98; Ptrend =0.009]). |
Study | Year | Location | Study population | Design | Intervention | Duration | Outcomes/Major results |
---|---|---|---|---|---|---|---|
DM risk | |||||||
Song et al. [7] | 2009 | USA | 5,442 Female health professionals aged 54–72 years with history of CVD or ≥3 CVD risk factors | Double-blind RCT | Treatment group: daily intake of a combination pill containing 2.5 mg FA, 50 mg vitamin B6, and 1 mg vitamin B12 (n=2,132) | 7.3 years | No significant effect on risk of DM |
Placebo group: a matching placebo pill daily (n=2,120) | ↓Blood Hcy | ||||||
Qin et al. [8] | 2016 | China | 20,702 Hypertensive patients aged 52.3–57.5 years | Double-blind RCT | Daily treatment with tablets containing: (1) 10 mg enalapril and 0.8 mg FA (n=10,348); or (2) 10 mg enalapril alone (n=10,354) | 4.5 years | No significant effect on FPG and risk of DM |
Ranasinghe et al. [9] | 2018 | Sri Lanka | 200 Participants with prediabetes aged 44–59.4 years | Double-blind RCT | Treatment group: capsules containing 20 mg zinc daily (n=100) | 12 months | ↓FPG, ↓2-hour glucose after the OGTT, ↓HOMA-IR, ↓T2DM development |
Placebo group: capsules containing inactive ingredients (n=100) | ↑HOMA-β | ||||||
Glucose metabolism index | |||||||
Aarsand et al. [37] | 1998 | Norway | 28 Diabetic patients with metformin treatment for more than 1 year, aged 53.9–64.1 years | Double-blind RCT | Treatment group: tablets containing 0.25 mg folate+60 mg Fe2+ daily (n=14) | 12 weeks | No significant effect on FSG and HbA1c |
↓Serum Hcy | |||||||
Placebo group: tablets containing 60 mg Fe2+ daily (n=14) | ↑Serum vitamin B12 and folate | ||||||
Doshi et al. [23] | 2001 | UK | 50 Patients with coronary artery disease, aged 46–65 years | A randomized, double-blind, placebo-controlled crossover trial | Treatment group: 5 mg FA supplement per day | Two 6-week treatments separated by a washout period of 4 months | No significant effect on FPG |
Placebo group: matched placebo | ↑Plasma folate | ||||||
↓Plasma Hcy | |||||||
Doshi et al. [24] | 2002 | UK | 33 Patients with coronary artery disease, aged 46–65 years | Double-blind RCT | Treatment group: 5 mg FA supplement per day (n=16) | 6 weeks | No significant effect on FPG |
Placebo group: matched placebo (n=17) | ↑Plasma folate | ||||||
↓Plasma Hcy | |||||||
Setola et al. [38] | 2004 | Italy | 50 Patients with metabolic syndrome+hyperinsulinemia, aged 66.1–68.5 years | Double-blind, parallel, identical placebo-drug RCT | Group 1: treated with diet+placebo for 2 months | 2 months | ↓Insulin levels, ↓HOMA-IR, ↓Hcy levels |
Group 2: treated with diet+placebo (1 month) then diet+FA (5 mg/day)+vitamin B12 (500 µg/day) for 2nd month | No significant effect on fasting glucose | ||||||
Kilicdag et al. [48] | 2005 | Turkey | 49 Female patients with PCOS (group 1, 17.22–31.06 years; group 2, 18.27–25.73 years; group 3, 18.27–31.61 years) | RCT | Group 1 received metformin (850 mg twice daily) (n=20) | 12 weeks | No significant effect on HOMA-IR |
Group 2 received metformin (850 mg twice daily)+B-group vitamins (vitamin B1 250 mg, vitamin B6 250 mg, vitamin B12 1,000 µg twice daily) (n=20) | ↓Serum Hcy (groups 1 & 2) | ||||||
Group 3 received metformin (850 mg twice daily)+FA (174 µg), vitamin D (1,200 µg) and calcium (666.670 mg) twice daily (n=20) | ↑Plasma FA (group 3), ↑plasma vitamin B12 (group 2) | ||||||
Mangoni et al. [25] | 2005 | Australia | 26 T2DM patients aged 46–65 years | Double-blind, parallel-group RCT | Treatment group: 5 mg FA supplement per day (n=13) | 4 weeks | No significant effect on plasma glucose, HbA1c, and serum vitamin B12 |
Placebo group: matched placebo (n=13) | ↓Plasma Hcy, ↑serum folate | ||||||
Sheu et al. [26] | 2005 | Taiwan | 84 Obese women who were 20% over their ideal weight | Double-blind RCT | Treatment group: 5 mg FA supplement per day (n=36) | 12 weeks | ↓HOMA-IR, ↓fasting plasma insulin, ↓serum Hcy |
Placebo group: matched placebo (n=38) | No significant effect on FPG and fasting serum vitamin B12 and folate | ||||||
This program also included caloric restriction and light exercises to promote weight loss. | |||||||
Villa et al. [27] | 2005 | Italy | 20 Healthy postmenopausal women aged 48–61 years | RCT | Treatment group: 7.5 mg FA supplement per day (n=10) | 8 weeks | No significant effect on fasting glucose and insulin, and vitamin B12, methionine |
Placebo group: commercial calcium capsule (n=10) | ↓Hcy levels | ||||||
Moat et al. [28] | 2006 | USA | 128 Patients with angiographically proven CAD aged 53–68 years | Double-blind, parallel, RCT | 84 Patients were randomly divided into 3 groups for FA study (placebo, n=29; low-dose FA 400 µg/day, n=30; and high-dose FA 5 mg/day, n=25). Parallelly 44 patients were randomly divided into 2 groups for betaine study (Placebo, n=23 or betaine, 100 mg/kg/day, n=21). | 6 weeks | ↓Total plasma Hcy levels, ↑plasma folate, and no significant difference in blood glucose and serum vitamin B12 for FA study |
↓Plasma folate but no significant difference in blood glucose, serum vitamin B12, or plasma Hcy for betaine study | |||||||
Solini et al. [29] | 2006 | Italy | 60 Healthy overweight adults aged 29–61 years | Unmasked randomized, placebo-controlled trial | All patients were put on a hypocaloric diet and were randomly assigned to either a placebo or FA (2.5 mg/day) group. | 12 weeks | ↓Fasting plasma insulin, ↓HOMA-IR, ↑serum folate |
No significant difference in serum vitamin B12, Hcy, or FPG | |||||||
Title et al. [30] | 2006 | Canada | 19 T2DM patients aged 35–65 years | Randomized, double-blind, placebo-controlled, crossover trial | Patients were randomly assigned to receive either oral FA (10 mg/day) or a matching placebo for 2 weeks. This was followed by 8 weeks of washout period and then patients were crossed over to receive alternate treatment for another 2 weeks. | 2 weeks+8 weeks washout+2 weeks | No significant effect on plasma Hcy and plasma glucose |
↑Serum folate | |||||||
Moens et al. [31] | 2007 | Belgium | 40 Patients with acute myocardial infarction, aged 42–70 years | Randomized, double-blind, placebo-controlled crossover trial | Patients were randomly divided into 2 groups: Group A (n=20) received FA (10 mg/day) for initial 6 weeks then a placebo for another 6 weeks. For group B (n=20), the order was reversed. There was a washout of 2 weeks between the treatments. | 6 weeks+2 weeks washout+6 weeks | No significant difference in plasma vitamin B12, and FPG |
↑Plasma and RBC folate, ↓plasma Hcy | |||||||
Mao et al. [50] | 2008 | China | 443 Patients with mild to moderate hypertension, aged 27–75 years | Double-blind RCT | Participants were randomly assigned to 3 groups: control (10 mg of enalapril, n=149); low-FA group (10 mg enalapril+0.4 mg of FA, n=146); high-FA group (10 mg enalapril+0.8 mg of FA, n=148). | 8 weeks | ↓FPG in low-FA and high-FA groups |
↑Serum folate | |||||||
Mashavi et al. [42] | 2008 | Israel | 57 T2DM patients aged 54.1–66.1 years | Double-blind RCT | Group 1: 1,500 mg metformin+folate (1,000 µg), vitamin B12 (400 µg), and vitamin B6 (10 mg) daily (n=28) | 4 months | No significant difference in HOMA-IR and FPG |
↑Serum FA, ↑serum vitamin B12 | |||||||
Group 2: 1,500 mg metformin+placebo daily (n=29) | ↓Serum Hcy | ||||||
Potter et al. [39] | 2008 | Australia | 162 Patients with history of stroke, aged 52–80 years | Double-blind RCT | Treatment group: a single daily tablet containing FA (2 mg), vitamin B6 (25 mg), and vitamin B12 (500 µg) (n=83) | 104 weeks | No significant difference in FGB and HbA1c |
↓Blood Hcy | |||||||
Placebo group: matched placebo (n=79) | ↑Serum B6, ↑serum vitamin B12, ↑RBC folate | ||||||
Cagnacci et al. [32] | 2009 | Italy | 30 Healthy White postmenopausal women aged 48–58 years | Double-blind RCT | Treatment group: 15 mg/day 5-methyltetrahy-drofolate (n=15) | 3 weeks | ↓HOMA-IR, ↓blood insulin, ↓blood Hcy |
Placebo group: matched placebo (n=15) | No significant effect on FBP | ||||||
Palomba et al. [41] | 2010 | Italy | 47 Females with PCOS, aged 23.6–30 years | Non-randomized placebo-controlled double-blind trial | Experimental group: 1,700 mg metformin+400 µg FA daily (n=25) | 25 weeks | ↓Fasting serum insulin, ↓HOMA-IR |
Control group: 1,700 mg metformin+a placebo daily (n=25) | ↑Serum Hcy | ||||||
No significant difference in serum folate, vitamin B12, or FBG | |||||||
Kurt et al. [40] | 2010 | Turkey | 44 Adults aged >65 years with vitamin B12 deficiency | Double-blind RCT | Treatment group: FA (5 mg)+vitamin B12 (500 µg) daily (n=24) | 8 weeks | ↓HOMA-IR, ↓serum Hcy |
Placebo group: matched placebo (n=20) | ↑Serum folate, ↑serum vitamin B12 | ||||||
No significant difference in FPG | |||||||
Gargari et al. [33] | 2011 | Iran | 48 Overweight and obese men with T2DM and under metformin treatment, aged 46.9–67.7 years | Double-blind RCT | Treatment group: FA (5 mg) supplementation daily (n=24) | 8 weeks | ↓HOMA-IR, ↓serum HbA1c, ↓serum insulin |
Placebo group: matched placebo (n=24) | ↑Serum folate, ↑serum vitamin B12 | ||||||
No significant difference in FBG | |||||||
Grigoletti et al. [34] | 2013 | Brazil | 30 HIV-infected individuals aged 43–47 years | Double-blind RCT | Treatment group: FA (5 mg) supplementation daily (n=15) | 4 weeks | No significant difference in FSG |
Placebo group: matched placebo (n=15) | ↑Serum vitamin B12, ↑serum folate | ||||||
↓Plasma Hcy | |||||||
Asemi et al. [35] | 2014 | Iran | 81 Overweight or obese women with PCOS aged 18–40 years | Double-blind RCT | Group 1: 1 mg FA daily (n=27) | 8 weeks | ↓Serum insulin, ↓HOMA-IR, ↓plasma Hcy |
Group 2: 5 mg FA daily (n=27) | No significant difference in FPG | ||||||
Group 3: matched placebo (n=27) | |||||||
Karamali et al. [45] | 2015 | Iran | 58 Females with GDM aged 18–40 years | Double-blind RCT | Treatment group: 233 mg zinc gluconate daily (n=29) | 6 weeks | ↓FPG, ↓serum insulin, ↓HOMA-IR, ↓HOMA-β |
Placebo group: matched placebo (n=29) | ↑QUICKI, ↑serum zinc | ||||||
Asemi et al. [49] | 2016 | Iran | 58 Females with cervical intraepithelial neoplasia grade 1, aged 18–55 years | Double-blinded RCT | Treatment group: 5 mg FA daily (n=29) | 6 weeks | ↓Serum insulin levels, ↓HOMA-β, ↓plasma Hcy |
Placebo group: matched placebo (n=29) | |||||||
Hashemi et al. [36] | 2016 | Iran | 79 Pregnant women with preeclampsia, aged 21–41 years | Randomized, triple-blind, clinical trial | Treatment group: 5 mg FA daily | 8 weeks | No significant difference in FBG |
Placebo group: matched placebo | |||||||
Talari et al. [43] | 2016 | Iran | 60 Patients with metabolic syndrome, aged 40–85 years | Double-blind RCT | Treatment group: tablets containing 5 mg FA daily (n=30) | 12 weeks | ↓FPG, ↓serum insulin, ↓HOMA-IR, ↓plasma Hcy |
Placebo group: daily placebo tablets (n=30) | No significant difference in HOMA-β | ||||||
Bahmani et al. [44] | 2018 | Iran | 60 Women with endometrial hyperplasia | Double-blind RCT | Treatment group: 5 mg FA daily (n=30) | 12 weeks | ↓FPG, ↓serum insulin, ↓HOMA-IR, ↑QUICKI |
Placebo group: matched placebo (n=30) | |||||||
Attia et al. [46] | 2022 | Australia | 98 Prediabetic participants aged 40–70 years | Double-blind RCT | Treatment group: a daily capsule containing 30 mg elemental zinc gluconate (n=48) | 12 months | No significant difference in FBG, HbA1c, and HOMA-β |
Placebo group: a daily capsule containing cellulose (n=50) |
DM, diabetes mellitus; NA, not applicable; T2DM, type 2 diabetes mellitus; RR, risk ratio; CI, confidence interval; OR, odds ratio; HR, hazard ratio; HOMA-IR, homeostasis model assessment of insulin resistance; Zn, zinc.
DM, diabetes mellitus; CVD, cardiovascular diseases; RCT, a randomized placebo-controlled trial; FA, folic acid; Hcy, homocysteine; FBG, fasting blood glucose; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; HOMA-IR, homeostasis model assessment of insulin resistance; T2DM, type 2 diabetes mellitus; HOMA-β, homeostatic model assessment of β-cell function; FSG, fasting serum glucose; HbA1c, glycosylated hemoglobin; PCOS, polycystic ovarian syndrome; CAD, coronary artery disease; RBC, red blood cell; FGB, fibrinogen beta chain; FBP, folate-binding protein; HIV, human immunodeficiency virus; GDM, gestational diabetes mellitus; QUICKI, quantitative insulin sensitivity check index.