Genistein represses PEPCK‐C expression in an insulin‐independent manner in HepG2 cells and in alloxan‐induced diabetic mice

Abstract

Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to different concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK-C) and the signaling pathways was studied. Further, the biological relevance of the in vitro study was tested in alloxan-induced diabetic mice. Genistein lowered PEPCK-C expression and glucose production in HepG2 cells accompanied with increased in phosphorylation states of AMPK, MEK½, ERK½, and CRTC2. Treatment with the AMPK inhibitor (compound C) enhanced genistein-induced MEK½ and ERK½ activity indicating a potential cross-talk between the two signaling pathways. In vivo, genistein also reduced fasting glucose levels accompanied with reduced PEPCK-C expression and increased in AMPK and ERK½ phosphorylation states in the liver of genistein-treated alloxan-induced diabetic mice. Genistein fulfills the criteria of a suitable anti-diabetic agent by reducing glucose production and inhibiting PEPCK-C expression in HepG2 cells and also in alloxan-induced diabetic mice. These results indicate that genistein is an effective candidate for preventing T2DM through the modulation of AMPK-CRTC2 and MEK/ERK signaling pathways, which may allow a novel approach to modulate dysfunction in hepatic gluconeogenesis in T2DM.

Mulberry leaf extract displays antidiabetic activity in db/db mice via Akt and AMP-activated protein kinase phosphorylation

“…Our LC-MS analysis shows that in addition to DNJ, MLE contains genistein glycoside, kaempferol glycosides, and caffeoylquinic acid derivatives. Previous studies have shown that genistein is responsible for suppressed hepatic gluconeogenesis and increased insulin secretion ( 16 , 17 ), kaempferol stimulates insulin secretion and exerts insulinotropic effects ( 18 , 19 ), and caffeoylquinic acid is effective in stimulating glucose transport in muscle cells by activating AMPK and Akt ( 20 ). These results suggest that the antidiabetic effects of MLE in db/db mice may be mediated by not only DNJ but also a combination of several constituents of MLE.…”

Is Chickpea a Potential Substitute for Soybean? Phenolic Bioactives and Potential Health Benefits

“…Phosphoenolpyruvate carboxykinase (PEPCK) activity regulate normal blood glucose levels and has been shown to be increased in diabetic animal models. Dkhar et al [284] investigated the effect of genistein on the expression of PEPCK and glucose production in alloxan-induced diabetic mice. Genistein (50 mg/kg body weight) reduced fasting glucose levels, PEPCK-C expression and increased AMPK and ERK 1/2 phosphorylation states in the liver of the genistein-treated alloxan-induced diabetic mice [284].…”

“…Dkhar et al [284] investigated the effect of genistein on the expression of PEPCK and glucose production in alloxan-induced diabetic mice. Genistein (50 mg/kg body weight) reduced fasting glucose levels, PEPCK-C expression and increased AMPK and ERK 1/2 phosphorylation states in the liver of the genistein-treated alloxan-induced diabetic mice [284]. The same study also showed that glucose production in HepG2 cells was reduced by about 50% in cells treated with genistein (30 µM).…”

Effects and Underlying Mechanisms of Bioactive Compounds on Type 2 Diabetes Mellitus and Alzheimer’s Disease

“…Therefore, genistein may exert an antidiabetic role in T2DM by improving the lipid and glucose metabolism. Furthermore, Dkhar et al [77] reported that genistein reduced fasting glucose, inhibited cytosolic phosphoenolpyruvate carboxykinase (PEPCK), and activated AMPK and ERK1/2 pathway in alloxan-induced diabetic mice, which may in turn improve dysfunction in hepatic gluconeogenesis in T2DM. Furthermore, recent studies have shown that genistein might also be a prospective therapeutic approach for the management of T2DM complications [78, 79].…”

“…(8) Some bioactive compounds reduce NFT levels by inhibiting tau hyperphosphorylation. References: [46, 47, 50, 54, 55, 59, 61, 62, 64, 72, 75, 77, 81, 89, 93, 98, 101, 103, 108, 110, 116, 117, 121, 123, 126, 132, 133, 139, 140, 147, 149, 151, 152, 159, 162, 169, 175, 180, 183, 186, 189, 194–196, 200, 204, 215, 217, 227, 231, 234].…”