The Nrf2/Keap1/ARE Pathway and Oxidative Stress as a Therapeutic Target in Type II Diabetes Mellitus

Table 2

Small molecule activators of Nrf2 in TIIDM.

Molecule	Source	Mechanism of Nrf2 activation	Evidence
Sulforaphane (SFN)	Natural (cruciferous vegetables such as broccoli, brussel sprouts, and cabbage)	Modification of Keap1 cysteine residues	(i) Pancreatic β-cell protection [45]
			(ii) Prevented cardiac oxidative damage, inflammation, and hyperglycemic-induced fibrosis [139]
			(iii) Renal protection in db mice [110]
Curcumin (CUR)	Natural (turmeric)	Modification of Keap1 cysteine residues	(i) Reduced number of prediabetic individuals who progressed to type II DM [140]
			(ii) Activates liver enzymes involved in glycolysis, gluconeogenesis, and lipid metabolism [141]
Bardoxolone methyl (CDDO-Me/RTA 402)	Synthetic (derivative of oleanolic acid)	Modification of Keap1 cysteine residues	(i) Efficacy in short-term clinical trials in patients with type II DM and CKD [107]
			(ii) Did not reduce risk of end-stage renal disease (ESRD) or death from cardiovascular failure in patients with DM and stage IV CKD and was terminated early due to side effects [106]
Tert-butylhydroquinone (tBHQ)	Synthetic (preservative in unsaturated vegetable oils and edible animal fats)	Modification of Keap1 cysteine residues/activation of upstream kinases	(i) Prevented glucose-induced impairments in diabetic retinopathy [142]
Cinnamic aldehyde (CA)	Natural (found in bark of cinnamon tree)	Activation of upstream kinases	(i) Lowered blood glucose, total cholesterol, triglycerides, and increased HDL in diabetic rats and mice [143]
			(ii) Prevented development of hypertension in conditions of insulin resistance [144]
			(iii) Improved renal and glomerular function [110]
Resveratrol (RES)	Natural (polyphenol, found in the skin of red grapes, peanuts, and berries)	Activation of upstream kinases	(i) Reduced blood glucose and HbA1c levels [145]
			(ii) Restored secretory function of β-cells in response to toxicity [146]
			(iii) Renoprotective effects in DM [147]
Magnesium lithospermate B (MLB)	Natural (active polyphenol acid of Radix Salviae miltiorrhizae herb)	Activation of upstream kinases	(i) Suppressed progression of renal injury in diabetic rats [148]
			(ii) Protection against DM-related atherosclerosis [149]
MG132	Synthetic peptide aldehyde	Proteosome inhibitor	(i) Renoprotective against DM-induced oxidative damage, inflammation, and fibrosis [113]
Pterostilbene	Natural (blueberries, grapes)	Mechanism unclear	(i) Protective against β-cell apoptosis [150]
Catechins	Natural (flavenols, found in red wine, berries, grapes)	Likely activation of upstream kinases	(i) Reduced hepatic glucose production and enhanced pancreatic function [151, 152]
			(ii) Decreased cytokine-induced β-cell damage in vitro [153]
			(iii) Prevented reduction in islet mass in vivo [154]
			(iv) Protected against nephrotoxicity [155]

HDL: high-density lipoprotein; HbA1c: a marker of chronic hyperglycemia.