Flavonoids and Their Anti-Diabetic Effects: Cellular Mechanisms and Effects to Improve Blood Sugar Levels

Abstract

Diabetes mellitus (DM) is a prevailing global health metabolic disorder, with an alarming incidence rate and a huge burden on health care providers. DM is characterized by the elevation of blood glucose due either to a defect in insulin synthesis, secretion, binding to receptor, or an increase of insulin resistance. The internal and external factors such as obesity, urbanizations, and genetic mutations could increase the risk of developing DM. Flavonoids are phenolic compounds existing as secondary metabolites in fruits and vegetables as well as fungi. Their structure consists of 15 carbon skeletons and two aromatic rings (A and B) connected by three carbon chains. Flavonoids are furtherly classified into 6 subclasses: flavonols, flavones, flavanones, isoflavones, flavanols, and anthocyanidins. Naturally occurring flavonoids possess anti-diabetic effects. As in vitro and animal model's studies demonstrate, they have the ability to prevent diabetes and its complications. The aim of this review is to summarize the current knowledge addressing the antidiabetic effects of dietary flavonoids and their underlying molecular mechanisms on selected pathways: Glucose transporter, hepatic enzymes, tyrosine kinase inhibitor, AMPK, PPAR, and NF-κB. Flavonoids improve the pathogenesis of diabetes and its complications through the regulation of glucose metabolism, hepatic enzymes activities, and a lipid profile. Most studies illustrate a positive role of specific dietary flavonoids on diabetes, but the mechanisms of action and the side effects need more clarification. Overall, more research is needed to provide a better understanding of the mechanisms of diabetes treatment using flavonoids.

Keywords: anti-diabetic; diabetes mellitus; flavonoids; hyperglycemia; lipogenesis.

Figure 1

Schematic illustration of seven selected pathways modulated by diabetes. The figure is divided into seven columns and three rows. The column headings represent the pathways, while the rows heading represent: target genes/proteins for each pathway (blue), the overview physiological effect of these genes on pathways (Dark yellow), and changes occur on these pathways modulated by diabetes.

Figure 2

Illustration of a flavonoid pathway in the human body. The glycoside of flavonoids enters the body by an oral ingestion. An enzymatic reaction in the stomach (green arrow) breaks down the flavonoids to simpler molecules. In the small intestine, the first conjugation of flavonoids occurs where several reactions take place, such as sulfation and methylation, leading to the formation of o-glucuronides, o-methyl ester, and sulfate ester. The second conjugation of flavonoids take place in the liver to produce sulfates and glucuronides derivatives which could be excreted through bile and urine. Unabsorbed flavonoids enter the colon to be hydrolyzed or fermented into lower molecular compounds which can easily be absorbed.

Figure 3

Flavonoids as anti-diabetic agents: Modes of Action. Aberrant signaling pathways (Glucose transporter, hepatic enzymes, beta cell apoptosis, PPARS, AMPK, Tyrosine kinase inhibitor, and NF-κB) and pathway components targeted by flavonoids (highlighted in green). Flavonoids have a wide range of anti-diabetic actions where one flavonoid could target multiple pathways. These phytochemicals can enhance or suppress (green and red lines respectively) the activity of GLUT 4 translocation, glucose uptake by the tissue, and hepatic enzymes activities; causes a decrease in apoptosis and tyrosine kinase inhibition that improves the pathogenesis of diabetes (see text for detailed modes) of action for flavonoids mentioned). For abbreviation, see abbreviation list.