A Descriptive Review of the Action Mechanisms of Berberine, Quercetin and Silymarin on Insulin Resistance/Hyperinsulinemia and Cardiovascular Prevention

Abstract

Insulin resistance (IR) and the associated hyperinsulinemia are early pathophysiological changes which, if not well treated, can lead to type 2 diabetes, endothelial dysfunction and cardiovascular disease. While diabetes care is fairly well standardized, the prevention and treatment of IR lacks a single pharmaceutical approach and many lifestyle and dietary interventions have been proposed, including a wide range of food supplements. Among the most interesting and well-known natural remedies, alkaloid berberine and the flavonol quercetin have particular relevance in the literature, while silymarin-the active principle of the Silybum marianum thistle-was traditionally used for lipid metabolism disorders and to sustain liver function. This review describes the major defects of insulin signaling leading to IR and the main properties of the three mentioned natural substances, their molecular targets and synergistic action mechanisms. The actions of berberine, quercetin and silymarin are partially superimposable as remedies against reactive oxygen intermediates generated by a high-lipid diet and by NADPH oxidase, which is triggered by phagocyte activation. Furthermore, these compounds inhibit the secretion of a battery of pro-inflammatory cytokines, modulate intestinal microbiota and are especially able to control the various disorders of the insulin receptor and post-receptor signaling systems. Although most of the evidence on the effects of berberine, quercetin and silymarin in modulating insulin resistance and preventing cardiovascular disease derive from experimental studies on animals, the amount of pre-clinical knowledge strongly suggests the need to investigate the therapeutic potential of these substances in human pathology.

Keywords: berberine; diabetes; flavonoids; food supplements; insulin resistance; insulin signaling; oxidative stress; quercetin; silymarin.

Figure 1

Dynamic relationships between insulin resistance and hyperinsulinemia and their consequences on the cardiovascular system. LPS: Lipopolysaccharide; VSMC: Vascular Smooth Muscle Cells.

Figure 2

Mechanisms of insulin resistance indicating some targets of the action of the polyphenols described in the text (green asterisks). Legend: INSR: Insulin receptor; IRS-1: Insulin receptor substrate-1; PTP1B: Protein tyrosine phosphatase 1B; Akt: Ak mouse thymoma; PKB: Protein Kinase B; HFD: high-fat diet; NOX1: NADPH oxidase-1; SOCS3: suppressor of cytokine signaling 3; CRP: C-reactive protein; LPS: lipopolysaccharide; PI3K: phosphatidyl-inositol 3 kinase; METTL3: Methyltransferase Like 3; RAC1: Rac family small GTPase 1; GSK3β: Glycogen synthase kinase-3β; ERK: extracellular signal-regulated kinases; PRKD2: Protein Kinase D2; SREBP-1c: sterol regulatory element binding transcription factor 1; GlyS: glycogen synthetase; GSV: GLUT4 storage vesicle; AMPK: AMP-activated protein kinase; TNF-α: Tumor necrosis factor-α; The letters after the green asterisk are referred in the text of the manuscript.

Figure 3

Molecular structures of Quercetin, Berberine and Silibinin and some foods and plants that contain particularly important doses. A: Capes (Capparis spinosa); B: Blueberry (various plants of Vaccinium genus); C: Red onions (Allium cepa); D: Barberry (Berberis vulgaris) berries; E: Coptis chinensis (used with its dried roots); F: Silybum marianum.