Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies

Abstract

The consumption of plant-based food is important for health promotion, especially concerning the prevention and management of chronic diseases. Flavonoids are the main bioactive compounds in citrus fruits, with multiple beneficial effects, especially antidiabetic effects. We systematically review the potential antidiabetic action and molecular mechanisms of citrus flavonoids based on in vitro and in vivo studies. A search of the PubMed, EMBASE, Scopus, and Web of Science Core Collection databases for articles published since 2010 was carried out using the keywords citrus, flavonoid, and diabetes. All articles identified were analyzed, and data were extracted using a standardized form. The search identified 38 articles, which reported that 19 citrus flavonoids, including 8-prenylnaringenin, cosmosiin, didymin, diosmin, hesperetin, hesperidin, isosiennsetin, naringenin, naringin, neohesperidin, nobiletin, poncirin, quercetin, rhoifolin, rutin, sineesytin, sudachitin, tangeretin, and xanthohumol, have antidiabetic potential. These flavonoids regulated biomarkers of glycemic control, lipid profiles, renal function, hepatic enzymes, and antioxidant enzymes, and modulated signaling pathways related to glucose uptake and insulin sensitivity that are involved in the pathogenesis of diabetes and its related complications. Citrus flavonoids, therefore, are promising antidiabetic candidates, while their antidiabetic effects remain to be verified in forthcoming human studies.

Keywords: citrus; diabetes; flavonoids; inflammation; polyphenols.

Figure 1

The flowchart of study selection for this systematic review.

Figure 2

The 19 main citrus flavonoids with antidiabetic effects summarized from 38 articles.

Figure 3

Proposed antidiabetic mechanisms of action of citrus flavonoids. The pictorial representation summarizes the current knowledge that citrus flavonoids could improve the pathogenesis of diabetes and its complications via attenuating cellular oxidative stress, inflammatory markers (interleukin (IL) -1beta, IL-6, tumor necrosis factor (TNF)-alpha), and insulin resistance.

Figure 4

Citrus flavonoids target several molecular markers that are involved in the regulation of blood glucose levels. Citrus flavonoids can increase adipose tissue glucose transporter 4 (GLUT4), insulin receptors (IR), protein kinase B (PKB) or Akt, and protein kinase A (PKA); decrease skeletal muscle protein tyrosine phosphatase 1B (PTP1B); and up-regulate GLUT4, phosphoinositide 3-kinases (PI3K), insulin receptor substrate (IRS)-1, Akt, PKA, and glycogen synthase kinase 3β (GSK3β) expression in the skeletal muscle tissue. They also improve β-cell function. On the other hand, citrus flavonoid molecules can decrease c-Jun N-terminal kinase (JNK) and monocyte chemoattractant protein (MCP)-1 in the adipose tissue, and down-regulate nuclear factor kappa B (NF-κB), nitrate/nitrite (NOx), endothelial nitric oxide synthase (eNOS), matrix metalloproteinases (MMPs), and inflammatory mediators in the heart tissue. They also reduce the glycation end products (AGEs), Galectin-3 (Gal3), and caspase 3 expression in the kidney and decrease the uncoupling protein (UCP), proliferator-activated receptor (PPAR), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels in the liver tissue.