Insights on antioxidant therapeutic strategies in type 2 diabetes mellitus: A narrative review of randomized control trials

Table 1 Basic characteristics of included studies

No.	Study design	Setting	Population	Sample size	Intervention	Duration	Effect of treatment	Ref.
1	Randomized controlled trial	Primary Health Care Centre in Podgorica	T2DM patients	Total: n = 130; Group I: n = 65; Group II: n = 65	Group I: 14000 IU vitamin D + metformin; Group II: Metformin only	First for 3 mo and later on for 6 mo	Improves blood HbA1c and reduces advanced oxidation protein products	Cojic et al[22], 2021
2	Randomized controlled trial	Prince of Wales Hospital, the Teaching Hospital of The Chinese University of Hong Kong, Shatin, Hong Kong	T2DM patients	Total: n = 20; Group I: n = 10; Group II: n = 10	Group I: 1.4 g/d bilberry (Vaccinium myrtillus L.); Group II: Placebo	3 wk	Reduces serum HbA1c level by 4.6% and ascorbic acid by 14%	Chan et al[43], 2021
3	Randomized controlled trial	Department of Anesthesia, Isfahan University of Medical Sciences, Isfahan	T2DM patients	Total: n = 54; Group I: n = 27; Group II: n = 27	Group I: Three-gram citrulline daily; Group II: Placebo	2 mo	Reduces serum fasting blood glucose and MDA level by 16% and 25%, respectively; Increases serum levels of NOx, SOD, and GPx by 27%, 2%, and 2.2%, respectively	Azizi et al[45], 2021
4	Randomized controlled trial	Khon Kaen University, China	T2DM patients	Total: n = 24; Group I: n = 12: Group II: n = 12	Group I: 1000 mg vitamin C; Group II: Placebo daily	6 wk	Improves blood pressure regulation, increases NO release, and significantly lowers serum MDA and F2-IsoPs levels	Boonthongkaew et al[23], 2021
5	Randomized controlled trial	Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Hyderabad, India	T2DM patents	Total: n = 60 patients; Group I: n = 20; Group II: n = 20; Group III: n = 20	Group I: One capsule of T. chebula 250 mg twice daily; Group II: One capsule of T. chebula 500 mg twice daily; Group III: Placebo	12 wk	Improves serum NO level and reduces oxidative stress markers (GSH and MDA)	Pingali et al[31], 2020
6	Randomized controlled trial	Endocrinology and Metabolism Clinics of Golestan Hospital at Ahvaz Jundishapur University of Medical Science, Iran (IRCT registration number: IRCT20120704010181N12)	T2DM patients	Total: n = 42; Group I: n = 21; Group II: n = 21	Group I: One-gram Anethum graveolens (dill) powder; Group II: Placebo	8 wk	Decreases serum insulin, HOMA-IR, LDL-C, TC, and MDA and increases serum level of HDL and total antioxidant level	Haidari et al[33], 2020
7	Randomized controlled trial	Tan Tock Seng Hospital, Singapore (registration number: NCT02776397)	T2DM	Total: n = 187; Group I: Type 2 diabetes individuals with haptoglobin 2-2 (Hp 2-2); Group II: Type 2 diabetes individuals without haptoglobin 2-2 (Hp 2-2)	Group I: Total 400 IU of vitamin E daily; Group II: Placebo	24 wk	Increases reactive hyperaemia index, LDL, and ox-LDL concentrations	Dalan et al[24], 2020
8	Randomized controlled trial	Isfahan University Endocrine and Metabolism Research Centre, Isfahan, Iran (IRCT registration number: IRCT20180818040827N1	T2DM	Total: n = 80; Group I: n = 40; Group II: n = 40	Group I: 20 g wheat germ; Group II: Placebo	12 wk	Significant change in serum TC level	Mohammadi et al[47], 2020
9	Randomized controlled trial	Velayat Hospital of Qazvin University of Medical Sciences, Qazvin, Iran (IRCT registration number: IRCT2017041019669N4)	T2DM	Total: n = 62; Group I: n = 31; Group II: n = 31	Group I: 500 mg of propolis 3 times in a day; Group II: Placebo	8 wk	Decreases FBS, 2-hp, insulin, HbA1c, and HOMA-IR and upregulates TAC, SOD, and GSH	Afsharpour et al[40], 2019
10	Double-blind randomized, placebo-controlled clinical trial	Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Kermanshah University of Medical Sciences, Tehran, Iran (IRCT registration number: IRCT20140413017254N5)	T2DM	Total: n = 80; Group I: n = 40; Group II: n = 40	Group I: 80 mg Nano curcumin capsules once a day; Group II: Placebo	8 wk	Improves serum HbA1c, RBS, total neuropathy score, and total reflex score	Asadi et al[35], 2019
11	Double-blind, randomized, parallel, placebo-controlled trial	Yeh, Chung Shan Medical University Taiwan (registration number: NCT02622672)	T2DM	Total: n = 50; Group I: n = 25; Group II: n = 25	Group I: Liquid ubiquinol (100 mg/d); Group II: Placebo	12 wk	Reductions in blood HbA1c and fasting glucose, and increase in SOD activity	Yen et al[29], 2018
12	Single-blinded randomized controlled clinical trial	Medical Laboratories of the Central Blood Bank Society, and the Medical Relief Society, Gaza Strip, Palestine	T2DM	Total: n = 40 patients; Group I: n = 10; Group II: n = 10; Group III: n = 10; Group IV: n = 10	Group I: 500 mg of metformin + placebo twice daily; Group II: 500 mg of metformin + 500 mg of vitamin C twice daily; Group III: 500 mg of metformin + 400 mg of vitamin E twice daily; Group IV: 500 mg of metformin + 500 mg of vitamin C + 400 mg of vitamin E twice daily	90 d	Regulates FBS, HbA1c, HOMA-IR, and QISCI and improves GST, MDA, G6PD, GSH-PX, GSHE, and GSHW	El-Aal et al[25], 2018
13	Randomized double-blind placebo-controlled trial	Baqiyatallah University of Medical Sciences, Iran (IRCT registration number: IRCT201505301165N4)	T2DM	Total: n = 100; Group I: n = 50; Group II: n = 50	Group I: 500 mg curcumin + 5 mg piperine/day; Group II: Placebo	3 mo	Controls insulin, HbA1c, and HOMA-IR index	Panahi et al[36], 2018
14	Randomized, double blind, parallel group design	Clinics Hospital of Porto Alegre	T2DM	Total: n = 30; Group I: n = 15; Group II: n = 15	Group I: n-3 PUFAs (capsules containing 180 mg of eicosapentaenoic acid and 120 mg of docosahexaenoic acid; Group II: Placebo	8 wk	Reduces serum level of TBARS, F2-isoprostanes, and triglycerides	Fayh et al[27], 2018
15	Randomized double-blind placebo-controlled trial	Tehran University of Medical Sciences (IRCT registration number: IRCT2015072523336N1)	T2DM	Total: n = 48; Group I: n = 24; Group II: n = 24	Group I: 800 mg/d resveratrol daily; Group II: Placebo	2 mo	Decreases MDA and carbonyl protein and increases total thiol, NOS, and catalase	Seyyedebrahimi et al[49], 2018
16	Randomized double-blind placebo-controlled clinical trial	Diabetic Clinic of Golestan Hospital, Jundishapur University of Medical Science, in Ahvaz, Iran (IRCT registration number: IRCT2015081810181N6)	T2DM	Total: n = 64; Group I: n = 32; Group II: n = 32	Group I: 500 mg hesperidin/daily; Group II: Placebo	6 wk	Increases total antioxidant concentration and reduces serum concentrations of fructosamine, 8-OHDG, and MDA	Homayouni et al[38], 2017
17	Randomized double-blind placebo-controlled clinical trial	Toho University Medical Center	T2DM	Total: n = 50; Group I: n = 25; Group II: n = 25	Group I: Resveratrol oligo-stilbene 27.97 mg/100 mg/d; Group II: Placebo	12 wk	Decreases SBP and reactive oxygen metabolite significantly and also reduces risk of atherosclerosis in T2DM patients	Imamura et al[50], 2017

FBS: Fasting blood sugar; GST: Glutathione S-transferase; G6PD: Glucose 6-phosphate dehydrogenase; GSH: Glutathione; GSHE: Glorisa superba hydroalcoholic extract; HbA1c: Glycated hemoglobin; HDL: High density lipoprotein; HOMA-IR: Homeostasis model assessment of insulin resistance; IsoPs: Isoprostanes; LDL: Low-density lipoprotein; LDL-C: Low-density lipoprotein cholesterol; MDA: Malondialdehyde; n-3 PUFA: Polyunsaturated fatty acid; NO: Nitric oxide; NOS: Nitric oxide synthase; 8-OHDG: 8-hydroxy-2'-deoxyguanosine; ox-LDL: Oxidised low-density lipoprotein cholesterol; RBS: Random blood sugar; SBP: Systolic blood pressure; SOD: Superoxide dismutase; T2DM: Type 2 diabetes mellitus; TG: Triglyceride; TBARS: Thiobarbituric acid-reactive substances; TAC: Total antioxidant capacity; TC: Total cholesterol.