Dual effects of synthetic phenolic antioxidants in type 2 diabetes mellitus: Mechanisms and advances

Table 1 The full name, abbreviation, CAS number, and primary uses of synthetic phenolic antioxidants

Name	Abbreviation	CAS	Primary uses
Butyl hydroxyanisole	BHA	121-00-6	Food preservative, antioxidant in fats/oils, cosmetics, pet food
Butylated hydroxytoluene	BHT	128-37-0	Food preservative, antioxidant in fats/oils, cosmetics, plastics, rubber, fuels
Tert-butylhydroquinone	TBHQ	1948-33-0	Food preservative (especially for vegetable oils), antioxidant

Table 2 Summary of the effects, mechanisms, and research characteristics of butylated hydroxyanisole, tert-butylhydroquinone, and butylated hydroxytoluene in regulating type 2 diabetes mellitus

Comparison dimension	BHA	TBHQ	BHT
Study type	In vitro (A549 cell cytotoxicity/genotoxicity, antioxidant), animal (mouse), cell (brown adipocytes)[15,19-22,30,45]	In vitro (BSA interaction, antioxidant), animal (rat/mouse), cell (kidney/pancreas/retina-related cells), transcriptomic analysis, molecular simulation[17,23-40,48]	In vitro (antioxidant, α-amylase inhibition, molecular docking), animal (rat/mouse), clinical observation[20,30,40-43,47]
Core effects (protective/adverse)	Protective: Antioxidant, free radical scavenging, α-glucosidase inhibition, anti-obesity[19,20,46]; Adverse: High-dose induces A549 cell apoptosis, DNA damage, associated with liver injury and carcinogenesis[15,20]	Protective: Inhibits T2DM-related oxidative stress/inflammation, protects pancreatic/renal/retinal cells, improves insulin resistance[23-40,48]; Potential risk: High-dose may cause DNA damage[33]; Others: Binds to BSA and alters its secondary structure[17]	Protective: Antioxidant, anti-inflammation, anti-diabetic, hepatoprotection, α-amylase inhibition[20,30,40,44]
Key experimental doses	In vitro: 30-100 μg/mL, 1 mmol/L; Cell: 100 μM; Animal: 7.5 g/kg (in feed)[15,19-22,30,45]	In vitro: Max TBHQ 155.9 μM (BSA experiment); Cell: 0.04-20 μM; Animal: 16.7-60 mg/kg, 1% in feed[17,23-40,48]	In vitro: 30 μg/mL, extraction content 4.75%-8.04%, pure compound for molecular docking[20,30,40-43,47]
Human exposure reference	0-0.5 mg/kg/day[47]	0-0.7 mg/kg/day[49]	0-0.125 mg/kg/day[48]
Exposure duration	In vitro: 10 minutes-72 hours; Cell: 1 hour-2 days; Animal: 4 weeks[15,19-22,30,45]	In vitro: 6 minutes (room temp incubation); Cell: 3 hours-4 days; Animal: 2 weeks-3 months, entire pregnancy[17,23-40,48]	In vitro: 30 minutes-3 days; Animal: 21 days-4 weeks; Clinical: Not specified[20,30,40-43,47]
Core mechanisms	Antioxidant: Free radical scavenging, iron/copper ion reduction[20]; Adverse: High-dose generates excessive ROS, induces DNA breakage and mitochondrial damage[15]	Antioxidant: Activates Nrf2 pathway, enhances SOD/GPx activity[23-40,48]; Anti-inflammation/anti-apoptosis: Inhibits NF-κB pathway, regulates Bax/Bcl-2[27,31,39]; Others: Binds to BSA, activates PI3K/Akt pathway[17,23-26,38]	Antioxidant: Free radical scavenging, enhances SOD/CAT activity[20,42-44,47]; Anti-inflammation/anti-diabetic: Inhibits NF-κB pathway, regulates blood glucose and insulin sensitivity[41-44,47]
Combined exposure with other pollutants		Synergistic with BMSC exosomes and resveratrol[33,34]
Food matrix effects
Genetic heterogeneity	More significant protective effect in IDH2 KO mice[19]	Involves Nrf2 knockout models, no definite effect of gene polymorphisms[23,29,31,34,35]

BHA: Butylated hydroxyanisole; TBHQ: Tert-butylhydroquinone; BHT: Butylated hydroxytoluene; BSA: Bovine serum albumin; T2DM: Type 2 diabetes mellitus; ROS: Reactive oxygen species; KO: Knockout; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; Nrf2: Nuclear factor erythroid 2-related factor 2; NF-κB: Nuclear factor kappa-B; Bcl-2: B-cell lymphoma 2; Bax: B-cell lymphoma 2-associated X protein; PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B; BMSC: Bone marrow mesenchymal stem cells; CAT: Catalase.