Table 1.

Effects and Mechanisms of Action of Flavonoids on Chronic Complications of DM. In vivo and in vitro Experiments.

In vivo Studies
Disease	Animal	DM	Model	Treatment	Results	Effect	PMID
Diabetic Nephropathy	Rat	T1D	STZ	Hesperidin 100 mg/kg/day 2 weeks	↓FGF-23; ↑α-Klotho	Anti-toxic in liver/kidney	30551370
	Rat	T1D	Alloxan	Ramipril 5 mg/kg + Rutin 50 mg/kg/day 6 weeks	Prevented podocyte injury, ↓TGF-β ↓ GRP78 and CHOP (ER stress markers)	Anti-oxidant and anti-fibrotic	30372836
	Rat	T1D	STZ	Resveratrol 5 mg/kg/day 45/90 days	↓Renal hypertrophy and structural changes. ↓AGEs accumulation; ↓oxidative stress	Renoprotective, anti-fibrotic and anti-oxidant	29229234
	Rat	T1D	STZ	Naringin 20–80 mg/kg/day 12 weeks	↓ROS: ↑SOD and ↓NOX4	Renoprotective and anti-oxidant	28395989
	Rat	T2D	HFD/STZ	Pyrrosiae folium 50–200 mg/kg/day 12 weeks	↓ renal IL-6, TNF-α and IL-1β	Renoprotective and anti-inflammatory	29945390
	Rat	T2D	HFD/STZ	Formononetin 10–40 mg/kg/day. 16 weeks	↑ creatinine clearance; ↑SIRT1; ↑SOD; ↑catalase	Renoprotective, anti-diabetic and anti-oxidant	30641085
	Mouse	T1D	STZ	Diosmetin 25–100 mg/kg/day 8 weeks	Reduced serum FBG, BUN and creatinine and albuminuria.↓ Akt and NF-κB expression. ↑ iNOS	Renoprotective, anti-diabetic, anti-inflammatory and anti-oxidant	30278036
	Mouse	T2D	db/db mouse	Chrysin 10 mg/kg/day 10 weeks	↓ Collagen fiber accumulation ↓ AGEs accumulation	Anti-fibrotic	29987200
Diabetic Retinopathy	Rat	T1D	STZ	Catechin 50–200 mg/kg/day 8 weeks	Modulation NF-κB pathway ↓ IL-1β, IL-6, and TNF-α	Anti-inflammatory	30373863
	Rat	T1D	STZ	Biochanin A 10–15 mg/kg/day. 6 weeks	↓ TNFα, IL-1β and VEGF	Anti-inflammatory and anti-angiogenic	30054234
	Rat	T1D	STZ	Trans-Resveratrol 5 mg/kg/day. 2–4 weeks	↑ Cyp26b1 and Cyp3a9 transcription levels	Anti-oxidant	30030988
	Rat	T1D	STZ	Morus alba extract 100 mg/kg/day 16 weeks	↓ Caspase-3, Bax and ↑ Bcl2; ↓TNF-α and IL-1β; ↑CAT, SOD and GPx. ↓VEGF	Anti-apoptotic, anti-oxidant, anti-inflammatory and anti-angiogenic	27059477
	Rat	T1D	STZ	Naringenin 50 mg/kg/day 5 weeks	↑GSH; ↓Caspase-3, Bax and ↑ Bcl2; ↓pro-BDNF and ↑BDNF	Neuroprotective, anti-oxidant and anti-apoptotic	29064407
	Mouse	T1D	STZ	Galangin 10 mg/kg/day 30 days	↑Occludin and claudin1; ↓Iba-1 ↓ TNFα, IL-1β and IL-6 ↓p65, IκB and IKK phosphorylation	Neuroprotective and anti-inflammatory	30597356
	Mouse	T2D	db/db mouse	Chrysin 10 mg/kg/day 10 weeks	Increasing retinoid binding proteins (RPE65, LRAT, RDH5, and rhodopsin)	Anti-oxidant	30096827
Diabetic Neuropathy	Rat	T1D	STZ	Catechin 25/50 mg/kg/day 4 weeks	↑SOD and CAT ↓MDA and lymphocyte infiltration	Neuroprotective and antioxidant	30372853
	Rat	T1D	STZ	Deguelin 4–8 mg/kg/day 2 weeks	↑Nrf2; ↓ caspase-3 in neurons ↑ (Na+-K+) ATPase activity	Neuroprotective, anti-oxidant and anti-inflammatory	30045011
	Rat	T1D	STZ	Resveratrol 10 mg/kg/day 120 days	↑ SOD and GSH; ↓ nitrosative stress and MPO	Anti-oxidant and anti-inflammatory effect	29906751
	Rat	T1D	STZ	Phloretin 25–50 mg/kg/day 4 weeks	↑ SOD and GSH ↓ IL-6 and TNF-α; ↓ MDA	Neuroprotective, anti-oxidant and anti-inflammatory	29635891
Cardiovascular complications	Rat	T2D	HGI	Rutin 25–50 mg/kg/day 12 weeks	↓ inflammasome pathway in aortic tissue; ↓ROS generation	Anti-inflammatory and anti-oxidant	27936392
	Rat	T2D	HFD/STZ	Resveratrol 10 mg/kg/day 8 weeks	↓ TLR4/MyD88/NF-κB signaling pathway.	Cardioprotective and anti-inflammatory	30658350
	Rat	T1D	STZ	Apigenin 100 mg/kg/day 7 months	↓ cardiomyocyte enlargement; ↑SOD and GPx ↓ NF-κB/p65 signaling pathway activation ↓ Col-I, Col-III, CTGF, TGFβ	Cardioprotective, anti-oxidant, anti-inflammatory and anti-fibrotic	28176247
	Rat	T1D	STZ + IRIA	Resveratrol 5 mg/kg/day + Glibenclamide 5 mg/kg/day 6 weeks	↑ Kir6.2 expression (subunit of KATP channel)	Anti-arrhythmic	28176247
	Rat	T1D	STZ	Heracleum Persicum 100 mg/kg/day; 8 weeks	↓MDA; ↑GSH, CAT and SOD	Anti-oxidant	29726706
	Rat	T1D	STZ	Isoquecertin 40 mg/kg/day 45 days	↓ TG, PPL and FFA	Anti-hyperlipidemic	30817903
	Rat	T1D	STZ	Galangin 40 mg/kg 45 days	↓ TG, PPL, total cholesterol and FFA	Anti-hyperlipidemic	29952676
	Mouse	T2D	db/db mouse	Scutellarin 25–100 mg/kg 8 weeks	↑ high-density lipoprotein cholesterol ↓ TG and cholesterol	Anti-hyperlipidemic	30881587
	Mouse	T2D	HFI	Liquiritigenin 4–16 mg/kg/day	↓NF-κB signaling pathway ↓α-SMA, Col-I, Col-II, TGF-β1	Anti- inflammatory and anti-fibrotic	28039849
	Mouse	T2D	HFI	Liquiritin 10/20 mg/kg/day	↓α-SMA, Col I and Col II	Anti-fibrotic	27810791
In vitro Studies
Disease	Cell type		Stimulus	Treatment	Results	Effect	PMID
Diabetic Nephropathy	Human embryonic kidney cells		HG	Combretum micranthum 10–25 µg/mL	Hydrogen peroxide and nitric oxide scavenging activity	Anti-oxidant	30976670
	Rat mesangial cells		HG	Marein 100–400 µM	Regulating AMPK, TGF-β1/Smads pathway ↓ NF-κB signaling pathway	Anti-inflammatory and anti-fibrotic	30630477
	Rat/human renal tubular epithelial cells		HG	Kaempferol 5–50 μM	↓ RhoA/Rho Kinase signaling	Anti-inflammatory, anti-oxidant and anti-fibrotic	30551415
	Mesangial cells		HG	Corn silkextract 200 µg/mL	↓ α-glucosidase and α-amylase, IL-6, AGEs, Col IV and fibronectin	Anti-inflammatory, anti-oxidant and anti-fibrotic	30530231
	Rat mesangial cells		AGEs	Kaempferitrin 10–35 µM	↑SOD activity ↓MDA, Col IV and TGF-β1	Anti-oxidant and anti-fibrotic	30373106
	Rat mesangial cells		HG	Liquiritigenin 20–40 µM	↓ NOX4 and ↑SOD Decrease collagen IV fibronectin, Il-6 and IL-1β	Anti-oxidant, anti-inflammatory and anti-fibrotic	30119269
	Human proximal tubular epithelial cells		HG	Astilbin 10–20 µM	Modulating PI3K/Akt pathway	Anti-proliferative	30119185
	Mouse podocyte cell line		HG	Genistein 20 µM	Inactivating mTOR signaling	Autophagia	29999001
	Human mesangial cells		HG	Chrysin 1–20 µM	↓ Collagens, α-SMA, fibroblast-specific protein-1, MMPs	Anti-fibrotic	29987200
	Rat mesangial cells		HG	Naringin 5–80 μmol/L	Modulating NLRP3 signaling pathway ↓IL-1β, IL-18 and caspase-1	Anti-inflammatory and anti-apoptotic	29929501
	Rat mesangial cells		AGEs	Kaempferitrin 10–35 μM	↓MDA levels; ↑SOD and ROS generation. ↓ Collagen IV and TGF-β1	Anti-oxidant and anti-fibrotic	30373106
	Human mesangial cells		AGEs	Chrysin 1–20 µM	↓ Collagens, α-SMA, fibroblast-specific protein-1, MMPs	Anti-fibrotic	29987200
Diabetic Retinopathy	Human retinal pigment epithelial cell line		Glucose oxidase	Myricetin 40 μg/mL	Activation of Nrf2 ↑ SOD ↓ NOS2	Anti-oxidant	30820141
	Human retinal pigment epithelial/endothelial cells		HG	Baicalin 2.5–100 μM	Inhibition of NF-κB and p38 MAPK pathways	Anti-apoptotic and anti-inflammatory	30625293
	Human retinal pigment epithelial cell line		H2O2	Kaempferol 20–100 nM	Modulation Bax/Bcl-2/caspase-3 pathway; ↑ SOD and ↓VEGF	Anti-apoptotic, anti-oxidant, and anti-angiogenic	30584457
	Human retinal pigment epithelium cells		HG	Chrysin 1–20 µM	↓VEGF and PDGF, AGEs and ER stress	Anti-angiogenic	30096827
	Human retinal capillary endothelial cells		HG	Blueberry Anthocyanin 10 μg/mL	↑CAT, SOD, ↓ Nox4 and eNOS levels ↓ICAM-1 and NF-κB; ↓VEGF	Anti-oxidant, anti-inflammatory and anti-angiogenic	29682153
	Rat retinal ganglial cells		HG	Eriodictyol 5–20 μM	↓ROS and ↑ SOD, GPx, catalase ↓ TNFα, IL-8	Anti-oxidant and anti-inflammatory	30317656
	Mice microglia retinal cells		HG	Galangin 20/50 µM	↓IL-1β, TNFα;↓ NF-κB activation	Anti-inflammatory	30597356
Diabetic Neuropathy	Rat dorsal root ganglion neurons		HG	Quercetin 10 mmol/L + other flavonoids	↑ Nrf-2/HO-1 pathway; scavenging ROS ↓NF-κB activation	Anti-oxidant and anti-inflammatory	28861887
	Schwann cells		HG	Puerarin 10 µmol/L	↓Caspase-3; ↓ROS production and mitochondria depolarization	Anti-apoptotic and anti-oxidant	28181078
	Rat dorsal root ganglion neurons		HG	Quercetin 2.5–10 mmol/L	↑ Nrf-2/HO-1; ↓ NF-κB inhibition	Anti-oxidant and anti-inflammatory	23770986
Cardiovascular complications	Human aortic endothelial cells		Palmitic acid	Blueberry Anthocyanins 12–16 nmol	↓Nox-mediated ROS production	Anti-oxidant	29024402
	Human umbilical vein endothelial cells		HG	Rutin 30–100 µM	↓Nox2 and Nox4	Anti-oxidant	27936392
	Human aortic endothelial cells		Palmitic acid	Resveratrol 50–100 µM	↓ ROS production via AMPK-mTOR pathway	Autophagia and anti-oxidant	30421395