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.

Clinically Effective Molecules of Natural Origin for Obesity Prevention or Treatment

“…Silymarin has various beneficial metabolic effects, including serving as a PPAR-gamma agonist, improving the sensitivity of the insulin receptor type 1 substrate, increasing the activity of PI3K, Nrf2, and Akt, increasing the expression of GLUT4 on the cell surface and inhibiting HMG-CoA reductase [ 195 , 196 ]. Silymarin has demonstrated choleretic activity by generating upregulation of the bile salt export pump [ 197 , 198 ].…”

Insulin resistance/hyperinsulinemia: an important cardiovascular risk factor that has long been underestimated

“…It is contained in many plants including Coptis Chinensis. There is a large amount of scientific literature that supports the fact that berberine has favorable effects on cardiovascular risk factors such as hypercholesterolemia, hyperglycemia, arterial hypertension and insulin resistance ( 62 – 65 ).…”

The Negative Impact of Insulin Resistance/Hyperinsulinemia on Chronic Heart Failure and the Potential Benefits of Its Screening and Treatment

“…In the RELAX study, it was shown that subjects with HFpEF and DM had similar levels of NT-ProBNP compared with nondiabetics, but markedly higher levels of the vasoconstrictor endothelin-1 (ET-1), of markers of inflammation such as uric acid and C-reactive protein, and of profibrotic markers such as valectin-3 and carboxy-terminal telopeptide of collagen type 1 [34]. It is well known that the alterations of these parameters are also characteristic of IR/Hyperin states [35]. Echocardiographically, patients with HF and DM had a significantly abnormal LV diastolic function as shown by higher E/e' ratio, with increased LVM and reduced exercise tolerance compared with subjects with HF without DM [36].…”

“…From the analysis of experimental in vitro and in vivo studies, it clearly appears that these three substances reduce IR and consequent circulating elevated insulin levels. Therefore, these substances could protect the evolution toward overt type 2 diabetes and the development of cardiovascular abnormalities [35]. Both quercetin and silymarin have extensive literature that support their efficacy in counteracting IR/Hyperins and LVH development, and in preventing cardiovascular alterations [57][58][59][60][61][62][63][64][65].…”