The Coming Age of Flavonoids in the Treatment of Diabetic Complications

Abstract

Diabetes mellitus (DM), and its micro and macrovascular complications, is one of the biggest challenges for world public health. Despite overall improvement in prevention, diagnosis and treatment, its incidence is expected to continue increasing over the next years. Nowadays, finding therapies to prevent or retard the progression of diabetic complications remains an unmet need due to the complexity of mechanisms involved, which include inflammation, oxidative stress and angiogenesis, among others. Flavonoids are natural antioxidant compounds that have been shown to possess anti-diabetic properties. Moreover, increasing scientific evidence has demonstrated their potential anti-inflammatory and anti-oxidant effects. Consequently, the use of these compounds as anti-diabetic drugs has generated growing interest, as is reflected in the numerous in vitro and in vivo studies related to this field. Therefore, the aim of this review is to assess the recent pre-clinical and clinical research about the potential effect of flavonoids in the amelioration of diabetic complications. In brief, we provide updated information concerning the discrepancy between the numerous experimental studies supporting the efficacy of flavonoids on diabetic complications and the lack of appropriate and well-designed clinical trials. Due to the well-described beneficial effects on different mechanisms involved in diabetic complications, the excellent tolerability and low cost, future randomized controlled studies with compounds that have adequate bioavailability should be evaluated as add-on therapy on well-established anti-diabetic drugs.

Keywords: cardiovascular disease; diabetes; diabetic nephropathy; flavonoids; inflammation; microvascular complications; oxidative stress; therapeutics.

Figure 1

(A) Common chemical structure of flavonoids. (B) Chemical structure of flavonoid subtypes described in the literature.

Figure 2

Effect of flavonoids on glucose metabolism. The main effect of flavonoids on skeletal muscle and adipose tissue is the enhancement of glucose uptake mediated by the translocation of GLUT4 to the plasmatic membrane. Conversely, in the liver, flavonoids act in a different way. They try to reduce glucose blood levels both by reducing gluconeogenic genes (such as G6Pase and PEPCK) and therefore glucose production and GLUT2, and therefore preventing the release of glucose from liver to the bloodstream. The production of glucose is also prevented in the intestine by blocking the digestion of complex carbohydrates. In the pancreas, flavonoids predominantly reduce oxidative stress improving the viability of β-cell, consequently ameliorating insulin secretion. WAT: White adipose tissue; AMPK: AMP-activated protein kinase; GLUT4: glucose transporter type 4, GLUT 2: glucose transporter type 2, G6Pase: glucose-6-phosphatase, PEPCK: phosphoenolypyruvate carboxykinase.

Figure 3

Potential beneficial effects of flavonoids in specific target organ of DM complications. AGEs, advanced glication end products; AMPK, activated protein kinase; Bax, Bcl-2 associated X; Bcl-2; B-cell lymphoma 2; CTGF, connective tissue growth factor; FFA, free fatty acid; GLUT4, glucose transporter type 4; HDL Cholesterol, High Density Lipoprotein Cholesterol; Hmox-1, Heme oxygenase (decycling) 1; MAPK, mitogen-activated protein kinases; mTOR, mammalian Target of Rapamycin; NF-Kβ, Nuclear factor kappa beta; NRF2, Nuclear Factor Erythroid 2-related Factor 2; PDGF, Platelet Derived Growth Factor; Rho, Ras homologous; RhoA, Ras homolog family member A; ROS, reactive oxygen species; SIRT1, sirtuin 1; TGFβ1, transforming growth factor beta 1; TLRs, toll like receptors; VEGF, vascular endothelial growth factor.