The Flavonoid Silibinin Decreases Glucose-6-Phosphate Hydrolysis in Perifused Rat Hepatocytes by an Inhibitory Effect on Glucose-6-Phosphatase

Abstract

Background/Aims: The flavonoid silibinin has been reported to be beneficial in several hepatic disorders. Recent evidence also suggests that silibinin could be beneficial in the treatment of type 2 diabetes, owing to its anti-hyperglycemic properties. However, the mechanism(s) underlying these metabolic effects remains unknown. Methods: The effects of silibinin on liver gluconeogenesis were studied by titrating hepatocytes from starved rats with sub-saturating concentrations of various exogenous substrates in a perifusion system. Hepatocytes from fed rats were also used to investigate glycogenolysis from endogenous glycogen. The effect of silibinin on glucose-6-phosphatase kinetics was determined in intact and permeabilized rat liver microsomes. Results: Silibinin induced a dose-dependent inhibition of gluconeogenesis associated with a potent decrease in glucose-6-phosphate hydrolysis. This effect was demonstrated whatever the gluconeogenic substrates used, i.e. dihydroxyacetone, lactate/pyruvate, glycerol and fructose. In addition, silibinin decreased the glucagon-induced stimulation of both gluconeogenesis and glycogenolysis, this being associated with a reduction of glucose-6-phosphate hydrolysis. Silibinin inhibits glucose-6-phosphatase in rat liver microsomes in a concentration-dependent manner that could explain the decrease in glucose-6-phosphate hydrolysis seen in intact cells. Conclusion: The inhibitory effect of silibinin on both hepatic glucose-6-phosphatase and gluconeogenesis suggests that its use may be interesting in treatment of type 2 diabetes.

The Effects of Oral Administration of Different Doses of Hydroalcoholic Extract of Silymarin on Status of Serum Trace Elements

“…The mechanism of action of silymarin may have an effect on the kinetics of glucose-6 phosphatase and inhibition of gluconeogenesis, increase insulin and improve pancreatic function, in addition to reducing hydroxy-3-methylglutaryl-CoA reductase and improving liver function. Silymarin acts by inhibiting hepatic glucose-6-phosphatase hydrolysis in perfused rat hepatocytes by an inhibitory effect on glucose-6-phosphatase and gluconeogenesis (Guigas et al, 2007). Silymarin recovers pancreatic function to increase insulin level.…”

Silibinin: A novel inhibitor of Aβ aggregation

“…Silibinin, a flavonoid isolated from milk thistle (Silybum marianum) and has been used clinically for thousands of years in China and Europe as an anti-hepatotoxic agent to treat liver diseases, especially alcoholic liver disease (Brandon-Warner et al, 2010; Guigas et al, 2007). Recent studies have shown that silibinin has a strong antioxidant activity, increases cellular glutathione content, induces superoxide dismutase (SOD), antagonizes manganese-induced neurotoxicity in adult mice, and inhibits lipid peroxidation (Schumann et al, 2003).…”

The Therapeutic Potential of Milk Thistle in Diabetes

“…Thus, silibin inhibits gluconeogenesis in perifused hepatocytes independently of the gluconeogenic substrate. Furthermore, silibin inhibits glucose-6-phosphate hydrolysis in a variable manner, independently of the carbohydrate source, but it does not seem to have significant effects in the fructose cycle [7].…”