Quercetin Preservesβ-Cell Mass and Function in Fructose-Induced Hyperinsulinemia through Modulating Pancreatic Akt/FoxO1 Activation

Abstract

Fructose-induced hyperinsulinemia is associated with insulin compensative secretion and predicts the onset of type 2 diabetes. In this study, we investigated the preservation of dietary flavonoid quercetin on pancreatic β-cell mass and function in fructose-treated rats and INS-1 β-cells. Quercetin was confirmed to reduce serum insulin and leptin levels and blockade islet hyperplasia in fructose-fed rats. It also prevented fructose-induced β-cell proliferation and insulin hypersecretion in INS-1 β-cells. High fructose increased forkhead box protein O1 (FoxO1) expressions in vivo and in vitro, which were reversed by quercetin. Quercetin downregulated Akt and FoxO1 phosphorylation in fructose-fed rat islets and increased the nuclear FoxO1 levels in fructose-treated INS-1 β-cells. The elevated Akt phosphorylation in fructose-treated INS-1 β-cells was also restored by quercetin. Additionally, quercetin suppressed the expression of pancreatic and duodenal homeobox 1 (Pdx1) and insulin gene (Ins1 and Ins2) in vivo and in vitro. In fructose-treated INS-1 β-cells, quercetin elevated the reduced janus kinase 2/signal transducers and activators of transcription 3 (Jak2/Stat3) phosphorylation and suppressed the increased suppressor of cytokine signaling 3 (Socs3) expression. These results demonstrate that quercetin protects β-cell mass and function under high-fructose induction through improving leptin signaling and preserving pancreatic Akt/FoxO1 activation.

Leptin Inhibits Preproinsulin mRNA Expression Induced by Suppression of Cytokine Signalling 3 in Beta-Cells

“…Furthermore, fructose increased SOCS3 expression, decreased STAT3 phosphorylation, increased Pdx1 and insulin gene expression, and induced hyperinsulinemia both in rats and in INS-1 cells [19]. Quercetin treatment suppressed the increased SOCS3 level, elevated the reduced STAT3 level, and improved leptin signalling, thereby protecting beta-cell function under high-fructose conditions [19]. In accordance with the previous studies, in our study, over expression of SOCS3 inhibited STAT3 phosphorylation and then increased preproinsulin mRNA expression.…”

“…However, Seufert et al found that leptin increases the binding of STAT5b to the upstream sequences of the rat preproinsulin 1 promoter and inhibits insulin biosynthesis via transcriptional repression [18]. Furthermore, fructose increased SOCS3 expression, decreased STAT3 phosphorylation, increased Pdx1 and insulin gene expression, and induced hyperinsulinemia both in rats and in INS-1 cells [19]. Quercetin treatment suppressed the increased SOCS3 level, elevated the reduced STAT3 level, and improved leptin signalling, thereby protecting beta-cell function under high-fructose conditions [19].…”

Quercetin liposomes ameliorate streptozotocin-induced diabetic nephropathy in diabetic rats

“…STZ is a natural compound that can induce DN through selectively destroying islet β cells of animals, because DN is usually associated with reduced viability and dysfunction of pancreatic β cells 23 . The rat DN model induced by STZ increased FBG and proteinuria in our study.…”

Innate Immune Programing by Endotoxin and Its Pathological Consequences

“…Activation of Akt through the mTOR–PI3K pathway both counteracts MAPK signaling and activates CREB ( 59 ), at the same time directly inactivating FoxO1 ( 55 ). Quercetin treatment activates Akt in multiple cell types, leading to decreased activity of FoxO1 in pancreatic islets ( 60 ), and ameliorating the inflammatory response of adipocytes to TNFα ( 61 ). Akt activation has also been shown to correlate with suppression of FoxO1 in HEK293 cells ( 62 ).…”