Flavonoids and Insulin-Resistance: From Molecular Evidences to Clinical Trials

Abstract

Insulin-resistance is one of the main factors responsible for the onset and progression of Metabolic Syndrome (MetS). Among all polyphenols, the effects of flavonoids and their main food sources on insulin sensitivity have been widely evaluated in molecular and clinical studies. The aim of this review is to analyse the data observed in vitro, in vivo and in clinical trials concerning the effects of flavonoids on insulin resistance and to determine the molecular mechanisms with which flavonoids interact with insulin signaling.

Keywords: flavonoids; insulin-resistance; metabolic syndrome.

Figure 1

Normal insulin signaling. Insulin binds to the insulin receptor (IR) inducing a conformational change and a rapid autophosphorylation of IR leading to the recruitment and phosphorylation of receptor substrates such as insulin receptor substrate (IRS) and Shc proteins. Shc proteins activate the Ras/mitogen-activated protein kinase (MAPK), whereas IRS proteins mostly activates the phosphoinositide 3-kinase (PI3K)/Akt pathway by recruiting and activating PI3K. In the skeletal muscle and adipose tissue, the PI3K/Akt pathway induces AMP-activated protein kinase (AMPK) phosphorylation and the expression of the glucose transporter type 4 (GLUT4) and its translocation from intracellular vesicles to the cell membrane promoting the uptake of glucose. In the liver, the PI3K/Akt pathway inhibits the expression of phosphoenol pyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6P) suppresses gluconeogenesis and activates glucokinase (GK) and glycogen synthase kinase (GSK), promoting glycogen synthesis. Arrow stimulates, T bar inhibits

Figure 2

Impaired Insulin signaling. Insulin resistance impairs the activation of PI3K/Akt of the skeletal muscle and adipose tissue leading to a decreased GLUT4 expression and translocation, resulting in impaired glucose uptake. Deficits in hepatic insulin signaling release FOXO1 back to the nucleus to promote the expression of PEPCK and G6P genes promoting gluconeogenesis and decrease GK and GSK activation suppressing glycogen synthesis. Arrow with red X: impaired stimulation, T bar with red X: impaired inhibition

Figure 3

Effects of flavonoids on impaired insulin signaling. Flavonoids induce IR and IRS phosphorylation and activate PI3K/Akt pathway and AMPK, promoting GLUT4 translocation in skeletal muscle and adipose tissues. In the liver, the PI3K/Akt pathway activated by flavonoids decreases PEPCK and G6P expression, suppressing gluconeogenesis and increasing GK and GSK expression, promoting glycogen synthesis.