Table 2.
Characteristics of antioxidative micronutrients’ effects on type 2 diabetes mellitus and its complications in meta-analysis of clinical trials
| Author | Type of antioxidant/ Control | meta-analyzed studies (n)/ Disorders | Participants | Intervention | Outcome measures | Significant results | Effective dose | Quality assessment | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Sample size (n) | Age (yr) | Sex | Dose/ Frequency | Duration | |||||||
| Chromium | |||||||||||
| Asbaghi et al. 2021 [15] | Chr/ Placebo | 24/ T2DM | 1418 | 35–73 | Both | 42–1000 µg/d | 6-25w | Lipid profiles | ↓TGs, ↓TC, ↑HDL-C | > 200 µg/d for TGs, TC, ≤ 200 µg/d for LDL-C | Yes |
| Zhao et al. 2021 [56] | Chr (Different formulations)/ Placebo | 10/ T2DM | 509 | 35–68 | Both | 42–1000 µg/d | 90–175 d | HbA1c, FBS, Lipid profile | ↓HbA1c | NO | Yes |
| Asbaghi et al. 2020 [57] | Chr/ Placebo | 23/ T2DM | 732 | 28–68 | Both | 50–1000 µg/d | 4-25w | FBS, Insulin, HbA1c, HOMA | ↓ FBS, ↓HbA1c, ↓HOMA, ↓Insulin | for all: > 200 and ≤ 200 mg/d | Yes |
| Yin et al. 2015 [58] | Chr (Different formulations)/ Placebo | 14/ T2DM | 875 | 30–83 | Both | 23.2–1000 µg/d | 8-24w | HbA1c, FBS | Subgroup analysis: ↓FBS | No | Yes |
| Suksomboon et al. 2014 [16] | Mono Chr or mixed with VC, VE, or biotin/ Placebo | 25/ T2DM, NIDDM, Healthy | 1641 | > 18–83 | Both | 1.28–1000 µg/d | 3–24 w | FPG, HbA1c, Lipid profile | ↓FPG, ↓HbA1c, ↓TGs | > 200 µg/d | Yes |
| Patal et al. 2010 [17] | Chr/ Placebo | 6/ T2DM | 671 | UN | UN | 200–1000 ug/d | 3-7 m | FBS, FI, HbA1c, 2hpp-Bs, lipid profile | Totally: NO, Subgroup analysis: ↓FBS, ↓HbA1c | NO | Yes |
| Balk et al. 2007 [59] | Chr (Different formulations)/ Placebo | 41/ T2DM, NGT, IGT | 1198 | UN | UN | 1.28–1000 µg/d | 3w-8 m | FBS, HbA1c, Bs2hpp, lipid profile, IS | In T2DM: ↓FBS ↓HbA1c | For FBS: 1000 µg/d, For HbA1c: 200 µg/d | Yes |
| Althuis et al. 2002 [60] | Chr (Different formulations)/ Placebo | 15/ T2DM, IGT, Healthy | 618 | 18–93 | Both | 10.8–1000 µg/d | 28d-16 m | FBS, Glucose at 120 min, HbA1c, FI, Insulin at 120 min | NO | NO | Yes |
| Zinc | |||||||||||
| Jayawardena et al. 2021 [61] | Zn with-without other micronutrients/ Placebo | 3/Pre-diabetes | 265 | UN | Both | 20–30 mg/d | 6-12 m | FBS, BS2hpp, HbA1c, HOMA, CRP, lipid profiles | ↓FBS, ↓BS2hpp, ↓TC, ↓HDL-C, ↓HOMA, ↑zinc serum | No | Yes |
| Pompano et al. 2021 [62] | Zn/ Placebo | 27/ T2DM, CVD, obese, healthy | 2016 | 20–70 | Both | 9.8–75 mg/d | 4-50w | FBS, HbA1c, HOMA, lipid profile | Low dose (< 25 mg/d): ↓FBS, ↓TC, ↓TGs, ↓LDL-C High dose (≥ 25 mg/d): ↓HbA1c, ↓HOMA | < 25 mg/d and ≥ 12 w | Yes |
| Asbaghi et al. 2020 [63] | Zn/ Placebo | 9/T2DM | 427 | 48–66 | Both | 30–660 mg/d | 6-52w | Lipid profiles | Totally: ↓TGs, ↓TC Subgroup analyses: ↓HDL-C | For TGs, LDL-C: < 100 mg/d, For TC, HDL-C each doses | Yes |
| Wang et al. 2019 [64] | Zn formulations/ Placebo | 32/ T2DM, Obese | 1700 | 18–75 | Both | 5-660 mg/d | 1-12 m | FBS, BS2hpp, HbA1c, FI, HOMA, hs-CRP | Totally: ↓FBS, ↓Bs2hpp, ↓FI, ↓HOMA, ↓HbA1c, ↓hs-CRP Subgroup analysis: ↓FBS in T2DM vs. others, ↓FBS by inorganic Zn vs. organic Zn | NO | Yes |
| Capdor et al. 2013 [65] | Zn formulations/ Placebo | 14/ T2DM, non-DM | 3978 | Infants-68 | Both | 3-240 mg/d | 1.4–390 w | FBS, HbA1c, Serum insulin, serum Zn | Totally: ↓FBS, ↓HbA1c, ↑serum Zn, Subgroup analysis: ↓FBS in T2DM and high risk for DM vs. healthy | NA | NO |
| Jayawardena et al. 2012 [66] | Zn formulation with-without other antioxidants/ Placebo | 25/ T1DM, T2DM | 1317 | Mean: 4.1–72.0 | UN | 7.5–660 mg/d | 3w-5 yr | FBS, BS2hpp, HbA1c, lipid profiles, BP | ↓FBS, ↓HbA1c, ↓TC, ↓LDL-C, ↓SBP, ↓DBP | NO | UN |
| Coenzyme Q10 | |||||||||||
| Dludla et al. 2020 [67] | CoQ10/ Placebo | 12/T2DM or MetS | 650 | 46 -63 | Both | 20–400 mg/d | 8-24w | FBS, insulin, HbA1c, Lipid profile, BMI | ↓LDL-C, ↓TC | No | Yes |
| Suksomboon et al. 2015 [68] | CoQ10 or CoQ10 + fenofibrate/ Placebo | 7/ DM | 356 | UN | UN | 100 mg/ twice daily or 200 mg/d | 3-6 m | FBS, HbA1c, lipid profile, BP | ↓TGs by CoQ10 or CoQ10 + Fenofibrate, ↓TC by CoQ10 + Fenofibrate | NA | Yes |
| Moradi et al. 2016 [69] | CoQ10/ UN | 14/ T2DM, non-DM | 920 | 35–70 | Both | 100–300 mg/d | 4-25w | FBS, HbA1c, FI | Totally: ↓FBS, Subgroup analysis: ↓FBS in duration < 20w, < 200 mg/d | < 200 mg/d | UN |
| Alpha lipoic acid | |||||||||||
| Ebada et al. 2019 [70] | ALA/Placebo | 10/ T1DM, T2DM | 553 | 46–72 | Both | 300–600 mg/d | 3-24w | HbA1c, FBS, Lipid profile, HOMA, GPx | ↑GPx | No | Yes |
| Rahimlou et al. 2019 [71] | ALA/ Placebo | 41/ T2DM, T1DM, Overweight, MetS, | 2564 | 15–74 | Both | 300–1200 mg/d | 2-192w | HbA1c, FBS, TNF-α, IL- 6, CRP, insulin, HOMA | ↓HbA1c, ↓FBS, ↓TNF-α, ↓IL-6, ↓CRP | < 600 and ≥ 600 mg/d for FBS, HbA1C, CRP, IL-6 | Yes |
| Akbari et al. 2018 [72] | ALA alone or plus nutrients/ Placebo | 24/ T2DM, non-DM | 1537 | 16–92 | UN | 200–1800 mg/d | 2-51w | FBS, FI, HbA1c, HOMA, lipid profile | Totally: ↓FBS, ↓FI, ↓HbA1c, ↓HOMA, ↓TGs, ↓TC, ↓LDL-C, Subgroup analysis: ↓FBS: in T2DM, by 600 mg/d, ↓FI: in non-DM, > 12w treatment, ↓HbA1c: by > 600 mg/d, > 12w treatment, by ALA with/ without nutrients, ↓HOMA: in T2DM, non-DM, by ≤ 600 mg/d, > 12w treatment, ↓TGs: in T2DM, by 600 mg/d, > 12w treatment, by combination, ↓TC: in T2DM, in non-DM, ≤ 600 mg/d, > 12w treatment, by sole ALA, ↓LDL-C: in T2DM, by 600 mg/d, < 8w treatment, by sole ALA | varied | Yes |
| Amato Nesbit et al. 2018 [73] | ALA/ Placebo | 6/ DPN | 1614 | UN | UN | 600–1800 mg/d | 3w-4 yr | DPN symptoms | ↓ Pain | NO | Yes |
| Wang et al. 2018 [74] | ALA + Epalrestat/ Epalrestat | 12/DPN | 813 | 40–87 | UN |
ALA:300 or 600 mg/d Epalrestat: 50 mg/tid |
14-28d | MNCV, SNCV, TSS, TCSS | Totally: effective, Subgroup analysis: After 14, 21, 28d by 300, or 600 mg ALA: ↑Median & peroneal MNCV, ↑median & peroneal SNCV, After 21d by 600 mg ALA: ↓TCSS, ↓TSS | 600 mg/dALA after 14d, 28d | Yes |
| Cakici et al. 2016 [75] | ALA/ Placebo | 6/ DPN (T1DM, T2DM) | 885 | 56–60 | UN | 100–1800 mg/d | 30 min IV-6 m oral | TSS | ↓TSS | 600 mg/d oral or IV | Yes |
| Snedecore et al. 2013 [76] | ALA, non-ALA/ Placebo, other treatments | 58/ painful DPN | 1183 | Mean: 53–71 | Both | Varied (ALA: 600–1800 mg/d) | 4-27w | Pain reduction | NO (for ALA) | NA | Yes |
| Han et al. 2012 [77] | ALA/ non-ALA | 15/ DPN | 1058 | Mean: 43.9–66.0 | UN | 300–600 mg/d | 14-28d | Efficacy treatment, MNCV, SNCV | ↑efficacy,↑MNCV, ↑SNCV | 300–600 mg/d for 2-4w | Yes |
| Mijnhout et al. 2012 [78] | ALA/ Placebo | 4/ DPN | 653 | 18–74 | UN | 100–1800 mg/d | 3-5w | TSS | ↓TSS | 600 mg/d for 3w | Yes |
| Ziegler et al. 2004 [79] | ALA/ Placebo | 4/ DPN | 1258 | 48–65 | Both | 600 mg/d IV | > 3w | TSS, NISLL | ↓TSS, ↓NISLL | 600 mg/d IV > 3w | Yes |
Legend: Chr Chromium; VC Vitamin C; VE Vitamin E; T2DM Type 2 diabetes mellitus; NIDDM Non-insulin dependent; W Week; FPG Fasting plasma glucose; HbA1c Glycosylated hemoglobin; TGs Triglycerides; NGT Normal glucose tolerance; IGT Impaired glucose tolerance; UN Unknown; m Month; FBS Fasting blood sugar; BS2hpp Blood sugar 2 h post prandial; IS Insulin sensitivity; D Day; FI Fasting insulin; IU International unit; HOMA Homeostasis model assessment index; Yr Year; IR Insulin resistance; CoQ10 Coenzyme Q10; BP Blood pressure; NA Not applicable; CAD Coronary artery diseases; DBP Diastolic blood pressure; GPx Glutathione peroxidase, MDA Malondialdehyde; TBARS Thiobarbituric acid reactive substances; TAC Total antioxidant capacity; SOD Superoxide dismutase; Zn Zinc; ALA Alpha lipoic acid; Sel Selenium; DPN Diabetic peripheral neuropathy; MNCV Motor nerve conduction velocity; SNCV Sensory nerve conduction velocity; TCSS Toronto clinical scoring system; TSS Total symptom score; LDL-C Low density lipoprotein cholesterol; CRP C-reactive protein; IL-6 Interleukin-6; NISLL Neuropathy impairment score lower limbs; GPx Glutathione peroxidase; TNF-α Tumor necrosis factor alpha.