Modulation of glucose transporter protein by dietary flavonoids in type 2 diabetes mellitus

Abstract

Diabetes mellitus (DM) is a metabolic diseases characterized by hyperglycemia due to insufficient or inefficient insulin secretory response. This chronic disease is a global problem and there is a need for greater emphasis on therapeutic strategies in the health system. Phytochemicals such as flavonoids have recently attracted attention as source materials for the development of new antidiabetic drugs or alternative therapy for the management of diabetes and its related complications. The antidiabetic potential of flavonoids are mainly through their modulatory effects on glucose transporter by enhancing GLUT-2 expression in pancreatic β cells and increasing expression and promoting translocation of GLUT-4 via PI3K/AKT, CAP/Cb1/TC10 and AMPK pathways. This review highlights the recent findings on beneficial effects of flavonoids in the management of diabetes with particular emphasis on the investigations that explore the role of these compounds in modulating glucose transporter proteins at cellular and molecular level.

Keywords: Glucose transporter protein; flavonoids; glucose uptake.; insulin; type 2 diabetes mellitus.

Figure 1

The insulin action can be inhibited by inflammatory signaling pathways. Inflammation and stressful stimuli activates c-jun amino terminal kinase (JNK), IκB kinase (IKK), and protein kinase Cθ (PKC-θ) which result in inhibition of insulin signaling. The activation of sterol regulatory element binding protein-1c (SREBP-1C), upstream stimulatory factor 1 (USF1), and liver X receptor (LXR)induces fatty acid synthesis.

Figure 2

Basic structure of flavonoid.

Figure 3

Insulin binding causes activation of the insulin receptor (IR), which phosphorylates different substrate adaptors such as the insulin receptor substrate (IRS). Upon tyrosine phosphorylation, IRS displays binding sites for many signaling partners. Among this signaling pathways PI3K has the main role in insulin function, through the activation of the Akt/PKB and the PKCζ cascades. Activated Akt leads to induction of glycogen synthesis via inhibition of glycogen synthase kinase (GSK-3); protein synthesis through mammalian target of rapamycin (mTOR) and downstream molecules; and regulation of cell proliferation via inhibition of pro-apoptotic agents such as forkhead family transcription factors, bcl-2-associated death promoter (Bad) and GSK-3. The activated Akt eventually leads to translocation GLUT4 to plasma membrane and glucose uptake. In addition to PI3K/Akt pathway.

Figure 4

GLUT-4 translocation takes place by IR-mediated phosphorylation of CAP, and formation of the CAP:Cbl:CrkII complex.

Figure 5

AMP-activated protein kinase (AMPK) which is the central energy leads to decreases hepatic glucose production via inhibiting the activation of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase); induction of glucose uptake through inducing GLUT-4 and GLUT-1 and stimulation of lipid metabolism via declining malonyl CoA levels by inhibiting acetyl CoA carboxylate (ACC) and activation of malonyl CoA decarboxylase.