Research progress on flavonoids in the prevention and treatment of diabetic microvascular complications

doi:10.12092/j.issn.1009-2501.2026.06.004

Abstract

Abstract:

Diabetes mellitus is a common metabolic disease characterized by chronic hyperglycemia. Prolonged elevated blood glucose levels damage microvasculature throughout the body (including those in the retina, renal glomeruli, vasa nervorum, and intramyocardial small coronary arteries). This leads to clinical manifestations such as diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic cardiomyopathy, all of which significantly impair the patient's quality of life and can even pose fatal risks. The pathogenesis of diabetic microvascular complications is closely associated with pathological changes induced by hyperglycemia, including the abnormal activation of multiple metabolic pathways, oxidative stress, and inflammatory responses, among other factors. These processes ultimately lead to pathological alterations, including microvascular endothelial dysfunction, basement membrane thickening, and microcirculatory disturbances. Flavonoids, a broad class of naturally occurring compounds ubiquitous in plants, possess a wide range of biological activities, such as anti-inflammatory, antioxidant, and endothelium-protective effects, which render them highly promising for preventing and treating diabetic microvascular complications. This review summarizes recent advances in the study of flavonoids for preventing and treating diabetic microvascular complications. Furthermore, it discusses the current challenges and future directions for the clinical use of flavonoids, aiming to provide a comprehensive reference for their continued development and applications.

Key words: flavonoids, diabetes mellitus, microvascular complications

CLC Number:

Su GUO, Xiaojiang QIN, Xuelu JIANG, Mengwei FANG, Zhi MAN, Xin MENG, Zhifa ZHENG, Liangyuan ZHAO, Yiwei SHI, Xiaomin HOU. Research progress on flavonoids in the prevention and treatment of diabetic microvascular complications[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(6): 752-763.

Figures/Tables 4

References 67

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Classification	Flavonoids	Sources	Mechanisms	Ref
Flavonols	Quercetin	Vegetables, tea, nuts, seed, fruits, red wine	(DR):↑ganglion cell number and retinal thickness, ↓ BRB breakdown, VEGF, ICAM-1 level, ↓ vascular permeability and leakage (DKD): ↓ EGFR/Erk1/2 signaling pathway → ↓ podocyte apoptosis,↑ Nrf2/HO-1 pathway → ↓ iron-driven lipid peroxidation (DN):↑Slit-2, Netrin-1 expression, ↓ Rho/ROCK signaling pathway overactivation →↑ nerve axon growth and regeneration,↑ nerve conduction ↑AMPK/PGC-1α pathway → ↓ mitochondrial morphology and dysfunction, ↓ ROS generation → protection of Schwann cells (DMC):↑ Nrf2 pathway → ↓ ROS level, cardiomyocyte apoptosis,↑ AMPK signaling pathway →↑ eNOS activity, microvascular density, blood flow	[29] [34-35] [41-42] [48-49]
	Rutin	Buckwheat, tobacco, citrus fruits, tea, asparagus	(DN): ↓ NLRP3 inflammasome activity → ↓ IL-1β, IL-18 secretion,↑ blood perfusion (DCM):↑ capillary density, permeability →↑ myocardial perfusion ↓ MMP/TGF-β1 imbalance →↑ myocardial function, ↓cardiac remodeling	[45] [52]
	Kaempferol	Broccoli, apples, grapes, onions, herbs	(DR): ↓ERRα activity, ↓ cell proliferation, migration, tube formation, ↓ VEGF expression,↑TSP-1,ADAMTS-1 level→↓angiogenic effects (DKD): ↓RhoA/Rho kinase activity → ↓smooth muscle cell contraction and ECM hyperplasia,↑ hemodynamic disturbance	[28] [36]
Flavanones	Hesperetin	Lemons, limes, Oranges, grapefruits, citrus	(DR):↑capillary resilience, maintain structural integrity, ↓fragility, and hemorrhage risk	[26]
	Naringenin naringin	Pomelos, lemons, limes, oranges, grapefruits, citrus	(DR):↑GTPCH1/eNOS pathway →↑eNOS activity and NO generation, retinal endothelial cells (DKD): ↓AGEs-RAGE, IL-1β, TNF-α levels → ↓ inflammatory cell adhesion and infiltration (DMC): ↓Bax/Caspase-3 expression → ↓ myocardial fibrosis, basement membrane thickness ↑ Nrf2 signaling, ↓ NF-κB signaling, ↓ ROS generation, and inflammatory cells →↑ cardiomyocytes, endothelial cells (DMC): induce ERK1/2, PKCδ, Akt phosphorylation →↑ Nrf2 nuclear translocation, antioxidant gene expression → ↓ apoptosis ↓ ROS level → ↓ mitochondrial membrane potential depolarization, Caspase-3 activity	[27] [37] [50] [51]
Flavones	Luteolin	Lonicera japonica, peppermint, carrots, capsicum annuum, celery	(DR): modulation of the NLRP3/NOX4 signaling pathway→↓NLRP3,NOX4,TXNIP,NLRP1 expression,↓retinal cell apoptosis,↑integrity of the microvascular structure (DKD):↓ type IV collagen deposition，TGF-β1 level→↑basement membrane abnormalities (DN):↑Nrf2/HO-1 signaling pathway→↓MDA level,↑SOD activity,↓oxidative stress→↑nerve blood flow induction GAP-43 expression→neurite growth	[30] [33] [43]
	Baicalein baicalin	Scutellaria baicalensis	(DR):↓pVEGF-R2 level→↓NOX2 activity and ROS generation→↓oxidative damage of endothelial cells, ↓GFAP and VEGF expression in Müller cells, ↓vascular abnormality, and ganglion cell loss (DKD)↑Nrf2 signaling pathway,↑HO-1, NQO-1 expression→↓MDA,↑SOD,CAT level,↓Erk1/2, JNK,P38 phosphorylation→↓pro-inflammatory cytokines (IL-1β, IL-6, MCP-1, and TNF-α level)	[31] [38]
Flavanols	Catechin	Tea, cocoa, grapes, apples, legumes	(DN):↑NO level, ↓ET-1level→↓nerve injury,↑nutritional support	[46]
	Epigallocatechin-3-gallate	Camellia sinensis	(DMC):↑AMPK/mTOR signaling pathway→↑cardiomyocyte,pericyte autophagy in microvessels ↓TGF-β1/MMPs signaling →↓myocardial interstitial deposition→↑microvascular function	[53]
Isoflavones	Genistein puerarin	Soybeans and other plants, Pueraria lobata	(DKD):↑SIRT1expression, AMPK/mTOR pathway→↑podocyte autophagy→↓urinary protein,renal injury (DN):↓oxidative stress, endothelial dysfunction ↑NGF level,microvascular dysfunction	[39] [44]

Classification	Flavonoids	Sources	Mechanisms	Ref
Flavonols	Quercetin	Vegetables, tea, nuts, seed, fruits, red wine	(DR):↑ganglion cell number and retinal thickness, ↓ BRB breakdown, VEGF, ICAM-1 level, ↓ vascular permeability and leakage (DKD): ↓ EGFR/Erk1/2 signaling pathway → ↓ podocyte apoptosis,↑ Nrf2/HO-1 pathway → ↓ iron-driven lipid peroxidation (DN):↑Slit-2, Netrin-1 expression, ↓ Rho/ROCK signaling pathway overactivation →↑ nerve axon growth and regeneration,↑ nerve conduction ↑AMPK/PGC-1α pathway → ↓ mitochondrial morphology and dysfunction, ↓ ROS generation → protection of Schwann cells (DMC):↑ Nrf2 pathway → ↓ ROS level, cardiomyocyte apoptosis,↑ AMPK signaling pathway →↑ eNOS activity, microvascular density, blood flow	[29] [34-35] [41-42] [48-49]
	Rutin	Buckwheat, tobacco, citrus fruits, tea, asparagus	(DN): ↓ NLRP3 inflammasome activity → ↓ IL-1β, IL-18 secretion,↑ blood perfusion (DCM):↑ capillary density, permeability →↑ myocardial perfusion ↓ MMP/TGF-β1 imbalance →↑ myocardial function, ↓cardiac remodeling	[45] [52]
	Kaempferol	Broccoli, apples, grapes, onions, herbs	(DR): ↓ERRα activity, ↓ cell proliferation, migration, tube formation, ↓ VEGF expression,↑TSP-1,ADAMTS-1 level→↓angiogenic effects (DKD): ↓RhoA/Rho kinase activity → ↓smooth muscle cell contraction and ECM hyperplasia,↑ hemodynamic disturbance	[28] [36]
Flavanones	Hesperetin	Lemons, limes, Oranges, grapefruits, citrus	(DR):↑capillary resilience, maintain structural integrity, ↓fragility, and hemorrhage risk	[26]
	Naringenin naringin	Pomelos, lemons, limes, oranges, grapefruits, citrus	(DR):↑GTPCH1/eNOS pathway →↑eNOS activity and NO generation, retinal endothelial cells (DKD): ↓AGEs-RAGE, IL-1β, TNF-α levels → ↓ inflammatory cell adhesion and infiltration (DMC): ↓Bax/Caspase-3 expression → ↓ myocardial fibrosis, basement membrane thickness ↑ Nrf2 signaling, ↓ NF-κB signaling, ↓ ROS generation, and inflammatory cells →↑ cardiomyocytes, endothelial cells (DMC): induce ERK1/2, PKCδ, Akt phosphorylation →↑ Nrf2 nuclear translocation, antioxidant gene expression → ↓ apoptosis ↓ ROS level → ↓ mitochondrial membrane potential depolarization, Caspase-3 activity	[27] [37] [50] [51]
Flavones	Luteolin	Lonicera japonica, peppermint, carrots, capsicum annuum, celery	(DR): modulation of the NLRP3/NOX4 signaling pathway→↓NLRP3,NOX4,TXNIP,NLRP1 expression,↓retinal cell apoptosis,↑integrity of the microvascular structure (DKD):↓ type IV collagen deposition，TGF-β1 level→↑basement membrane abnormalities (DN):↑Nrf2/HO-1 signaling pathway→↓MDA level,↑SOD activity,↓oxidative stress→↑nerve blood flow induction GAP-43 expression→neurite growth	[30] [33] [43]
	Baicalein baicalin	Scutellaria baicalensis	(DR):↓pVEGF-R2 level→↓NOX2 activity and ROS generation→↓oxidative damage of endothelial cells, ↓GFAP and VEGF expression in Müller cells, ↓vascular abnormality, and ganglion cell loss (DKD)↑Nrf2 signaling pathway,↑HO-1, NQO-1 expression→↓MDA,↑SOD,CAT level,↓Erk1/2, JNK,P38 phosphorylation→↓pro-inflammatory cytokines (IL-1β, IL-6, MCP-1, and TNF-α level)	[31] [38]
Flavanols	Catechin	Tea, cocoa, grapes, apples, legumes	(DN):↑NO level, ↓ET-1level→↓nerve injury,↑nutritional support	[46]
	Epigallocatechin-3-gallate	Camellia sinensis	(DMC):↑AMPK/mTOR signaling pathway→↑cardiomyocyte,pericyte autophagy in microvessels ↓TGF-β1/MMPs signaling →↓myocardial interstitial deposition→↑microvascular function	[53]
Isoflavones	Genistein puerarin	Soybeans and other plants, Pueraria lobata	(DKD):↑SIRT1expression, AMPK/mTOR pathway→↑podocyte autophagy→↓urinary protein,renal injury (DN):↓oxidative stress, endothelial dysfunction ↑NGF level,microvascular dysfunction	[39] [44]

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