Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies
Abstract
:1. Introduction
2. Main Citrus Flavonoids with Antidiabetic Effects
2.1. 8-Prenylnaringenin
2.2. Cosmosiin
2.3. Diosmin
2.4. Nobiletin
2.5. Rhoifolin
Flavonoids | Class | Concentrations and Duration of the Treatment | In Vitro Models | Effects and Molecular Mechanisms | Ref. |
---|---|---|---|---|---|
Nobiletin | Flavone | 1, 2.5, 5, 10, and 20 µM; 24 h | HepG2 cells (human hepatoma cells) | Nobiletin activated mitogen-activated protein kinase-extracellular signal-related kinase (MAPK/ERK), resulting in the marked inhibition of apolipoprotein B100 secretion. It neither induced the phosphorylation of the insulin receptor (IR) or insulin receptor substrate-1(IRS-1) tyrosine nor triggered lipogenesis associated with insulin resistance. | [41] |
Rhoifolin and cosmosiin from Citrus grandis (L.) Osbeck leaves | Flavone | Rhoifolin: 0.001–5 μM; cosmosiin: 1–20 μM; 24 h | 3T3-L1 adipocyte cells | Rhoifolin and cosmosiin exerted antidiabetic effects by promoting adiponectin secretion, the tyrosine phosphorylation of IR-β, and glucose transporter 4 (GLUT4) translocation. These bioactive molecules may help in insulin resistance-related treatment for diabetic complications. | [30] |
Tangeretin and nobiletin | Flavone | 5–50 mM; 24 h | 3T3-F442A preadipocytes | Tangeretin and nobiletin induced increased glucose uptake in murine adipocytes, suggesting that the action was mediated by phosphatidylinositol 3-kinase (PI3K) as well as protein kinase B (Akt) and protein kinase A (PKA)/cAMP-response element-binding protein (CREB) signaling-dependent pathways. | [42] |
Flavonoids from Citrus aurantium Linn. include naringin, esperidin, poncirin, sosiennsetin, sineesytin, nobiletin, and tangeretin | Flavone and flavanone | 0, 10, and 50 μg/mL; 0–6 days | 3T3-L1 preadipocytes | C. aurantium containing flavonoids decreased the expression of key adipocyte differentiation regulators, including CCAAT-enhancer binding protein family (C/EBPβ and C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ); it reduced adipogenesis and the accumulation of cytoplasmic lipid droplets during differentiation in 3T3-L1 cells. | [53] |
Nobiletin | Flavone | 0, 1, 10, and 100 μM; 7 days | 3T3-L1 preadipocytes | Nobiletin suppressed the differentiation of 3T3-L1 preadipocytes into adipocytes by down-regulating the expression of the gene coding for PPARγ2. In addition, nobiletin reduced the phosphorylation of CREB and strongly improved the phosphorylation of signal transducer and activation of transcription (STAT)5. | [43] |
Sudachitin | Flavone | 30 mmol/L; 48 h | Primary myoblasts | Sudachitin increased mitochondrial biogenesis and improved mitochondrial function, leading to an improvement in lipid and glucose metabolism mediated via the sirtuin (Sirt) 1-AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor gamma coactivator-1- alpha (PGC-1α) pathway. | [54] |
Naringenin | Flavanone | 0, 10, and 50 μM; 3 h | RAW 264 (macrophages) cells and 3T3-L1 adipocytes | Naringenin inhibited the monocyte chemoattractant protein-1 (MCP-1)’s mRNA expression and secretion in the adipocytes in a dose-dependent manner. It also prevented the MCP-1 production stimulated by the interaction between the adipocytes and the infiltrated macrophages. | [55] |
Hesperidin and naringin | Flavanone | 0.25, 0.5, 1, and 2 mg/mL; 1 and 24 h | Pancreatic islets | Hesperidin and naringin increased the production and the release of insulin from the islet cells and decreased the intestinal glucose absorption. | [56] |
Quercetin | Flavanol | 10 and 100 mM; 24 h | L6 myotubes | Quercetin activated the adenosine monophosphate kinase (AMPK)-P38 MAPK pathway and up-regulated glucose transporter type 4 (GLUT4)/AKT mRNA expression to induce glucose uptake in skeletal muscle cell lines. | [57] |
Diosmin | Flavone | 0.01–1 μmol/L; 24 h | Transfected imidazoline receptor (I-R) gene in CHO-K1 cells (Chinese hamster ovary cell) | Diosmin enhanced calcium influx in I-R gene-transfected CHO-K1 cells. Diosmin effectively activated the I-R gene via inducing opioid secretion, showing utility as an antidiabetic drug. | [35] |
Hesperidin | Flavanone | 12.5, 25, and 50 μmol/L; 6 h | RGC-5 cells (retinal ganglial cells) | Hesperidin protected against a high level of glucose-induced cell apoptosis by down-regulating caspase-9, caspase-3, and Bax/Bcl-2. Furthermore, it significantly inhibited the phosphorylation of c-Jun N-terminal kinases (JNK) and activated p38 MAPK in high glucose-fed RGC-5 cells. | [58] |
Hesperidin and hesperetin | Flavanone | 40, 80, 120, 160, and 200 μM; 24 h | Rat liver cells | Flavonoids hesperidin and hesperetin inhibited the activities of two gluconeogenesis enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating their effectiveness in treating AST and ALT-mediated metabolic disorders, including in diabetes mellitus. | [59] |
Tangeretin | Flavone | 0, 2.5, 5, and 10 μM; 24 h | Human glomerular mesangial cells (MCs) | Tangeretin very effectively inhibited high glucose (HG)-induced cell proliferation, oxidative stress, and extracellular matrix (ECM) expression in the human glomerular mesangial cells (MCs) via inactivating the extracellular signal-regulated kinase (ERK) signaling pathway. It also displayed therapeutic potential in the management of diabetic nephropathy. | [60] |
Didymin | Flavanone | 10 and 20 μM; 6 and 24 h | Human umbilical vein endothelial cells (HUVECs) | Didymin protected against high glucose (HG)-induced human umbilical vein endothelial cells by modulating the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion protein (VCAM)-1, and regulating nuclear factor kappa B (NF-κB)-mediated inflammatory cytokines and chemokines. Didymin prevented HG-induced endothelial dysfunction and death via antioxidative and anti-inflammatory activities. | [61] |
Didymin | Flavanone | 10–30 μM; 15 and 30 min, 1 and 24 h, 28 days | HepG2 (human hepatocarcinoma) cell line | Didymin inhibited α-glucosidase, activated the insulin-signaling pathway, and improved insulin sensitivity. It showed potent inhibitory activity against the key enzymes involved in diabetes mellitus, including protein tyrosine phosphatase 1B (PTP1B), α- glucosidase, advanced glycation end products (AGEs), and aldose reductase (AR). | [62] |
Naringenin | Flavanone | 0.01–1 μM; 1 and 24 h | NSC34 (mouse neuroblastoma and embryonic spinal cord motor neurons) cell line | Naringenin suppressed neuronal apoptosis and enhanced antioxidant protective effects in methylglyoxal (MG)-treated NSC34 cells. It prevented MG-induced hyperglycemia-related neurotoxicity via regulating insulin-like growth factor 1 receptor (IGF-1R)-mediated signaling. | [63] |
Naringenin | Flavanone | 0, 1, 10, and 50 μM; 30 min, 3 and 6 h | 3T3-L1 (adipocytes) and RAW264 (macrophages) cells | Naringenin inhibited monocyte chemotactic protein (MCP)-3 expression in 3T3-L1 adipocytes and a coculture of 3T3-L1 adipocytes and RAW264 macrophages. It did not affect the expression of macrophage inflammatory protein-2 (MIP-2), a key chemokine for neutrophil migration and activation, in macrophages or a coculture of adipocytes and macrophages. | [64] |
Nobiletin | Flavone | 10 μM; 1 and 4 h | HepG2 (human hepatocarcinoma) cell line | Nobiletin increased pAMPK in HepG2 incubated with high glucose content, in which the phosphorylation of AMPK was suppressed, which was comparable to the action carried out by the reference standards (resveratrol and metformin). | [46] |
2.6. Sudachitin
2.7. Tangeretin
2.8. Didymin
2.9. Hesperidin
2.10. Hesperetin
Flavonoids | Class | Animal Models | Dose/Route/Duration of the Experiment | Effects and Molecular Mechanisms | Ref. |
---|---|---|---|---|---|
Hesperidin | Flavanone | Wistar Rats | Hesperidin-containing animal diet (10 g/kg diet); 28 days | Hesperidin attenuated hyperglycemia and hyperlipidemia by decreasing blood glucose and normalizing hepatic glucose-regulating enzyme activities but did not affect bone tissue and bone metabolic parameters in streptozotocin (STZ)-injected marginal diabetic weanling rats. | [82] |
Rutin | Flavonol | Wistar Rats | 50 mg/kg (intraperitoneal); 45 days | Rutin significantly reduced the blood glucose level, improved the lipid profiles, and normalized the activities of hepatic enzymes in STZ-induced diabetic rats. It also regulated hyperglycemia and dyslipidemia, and inhibited the progression of liver and heart dysfunction in STZ-induced diabetic rats. | [99] |
Nobiletin | Flavone | C57BL/6 Ldlr-/- Mice | Nobiletin (0.1 or 0.3% mixed in high-fat Western diet); 56 to 182 days | Nobiletin regulated liver biomarkers by increasing hepatic and peripheral insulin sensitivity, improving glucose tolerance, and protecting against the development of atherosclerosis. | [41] |
Naringenin | Flavanone | Wistar Rats | 10 mg/kg (intraperitoneal); 35 days | Naringenin ameliorated aortic reactivity dysfunction in diabetic rats by attenuating lipid peroxidation and oxidative injury via a nitric acid-dependent pathway. | [100] |
Hesperidin and naringin | Flavanone | Wistar Rats | 50 mg/kg (oral administration); 28 and 30 days | Hesperidin and naringin lowered the level of pro-inflammatory cytokine (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6) production and enhanced antioxidant defenses in a type 2 diabetes rat model by normalizing the altered blood glucose and antioxidant parameters in the liver. | [83] |
Diosmin | Flavone | Wistar Rats | 100 mg/kg (intragastric); 45 days | Diosmin attenuated lipid abnormalities in the diabetic rats via reducing the plasma and tissue lipids significantly, along with a profound increase in high-density lipoprotein cholesterol (HDL-C) levels. | [33] |
Hesperidin | Flavanone | Wistar Rats | 25, 50, or 100 mg/kg (oral administration); 21 days | Hesperidin reduced hyperglycaemia, decreased malondialdehyde (MDA) and IL-6 levels, and enhanced the brain-derived neurotrophic factor (BDNF) and monoamines in the brain, thereby enabling it to be effective in treating and managing neurogenesis in diabetic rats. | [84] |
Naringenin | Flavanone | Wistar Rats | 20, 50, and 100 mg/kg (oral administration); 56 days | Naringenin restored hyperglycemia, down-regulated superoxide dismutase activity, and reversed chemical and thermal hyperalgesia in the diabetic rats, showing its preventive and therapeutic effectiveness in diabetic neuropathy treatment. | [101] |
Diosmin | Flavone | Sprague-Dawley Rats | 50 and 100 mg/kg (oral administration); 28 days | Diosmin significantly restored the blood glucose levels, antioxidant parameters, and lipid profiles in the diabetic rats. It also improved their thermal hyperalgesia, cold allodynia, and walking function. | [34] |
Sudachitin | Flavone | C57BL/6 J and db/db Mice | 5 mg/kg (oral administration); 84 days | Sudachitin significantly improved dyslipidemia, reduced triglyceride and free fatty acid contents, enhanced glucose tolerance, and reduced insulin resistance in the diabetic mice. β-oxidation of fatty acids was also markedly enhanced via increased mitochondrial biogenesis. | [54] |
Tangeretin | Flavone | Wistar Rats | 25, 50, and 100 mg/kg (intragastric); 30 days | Tangeretin normalized the levels and activities of plasma glucose, insulin, glycosylated hemoglobin, and key enzymes of carbohydrate metabolism in the livers of diabetic rats. | [71] |
Hesperidin | Flavanone | Sprague-Dawley Rats | 25, 50, and 100 mg/kg (oral administration); 28 days | Hesperidin decreased the levels of STZ-induced hyperglycemia and pro-inflammatory cytokines and increased the nociceptive threshold, motor nerve conduction velocity, sensory nerve conduction velocity, insulin levels, and Na-K-adenosine triphosphate (ATP)ase activity in the diabetic rats. | [85] |
Naringenin | Flavanone | C57BL/6J Mice | 100 mg/kg (oral administration); 14 days | Naringenin suppressed macrophage infiltration into the adipose tissues of the high-fat diet (HFD)-fed obese mice. It also down-regulated monocyte chemoattractant protein-1 (MCP-1) in the adipose tissues via inhibiting the c-Jun NH2-terminal kinase (JNK) pathway. | [55] |
Neohesperidin | Flavanone | KK-Ay and C57BL/6 Mices | 50 mg/kg (oral administration); 42 days | Neohesperidin attenuated fasting blood glucose and insulin resistance. The levels of total cholesterol, triglycerides, and leptins were significantly decreased, while the phosphorylation of AMP-activated protein kinase (AMPK) and its target genes was increased in the drug-treated mice. It also significantly decreased the size of epididymal adipocytes in the diabetic mice. | [102] |
Hesperidin and naringin | Flavanones | Wistar Rats | 50 mg/kg (oral administration); 30 days | Hesperidin and naringin significantly reduced the glucose level, restored the altered parameters of glucose metabolism, and enhanced adipose tissue glucose transporter type 4 (GLUT4) mRNA and protein expression in the diabetic rats. | [56] |
Tangeretin | Flavone | Wistar Rats | 100 mg/kg (intragastric); 30 days | Tangeretin significantly reduced plasma and cardiac lipid profiles by regulating key lipid metabolic enzymes in the livers of diabetic rats. It also markedly restored the GLUT4 expression, antioxidant enzyme activities, and levels of inflammatory cytokines in the heart tissues of the the tangeretin-treated diabetic rats. | [72] |
Nobiletin | Flavone | Wistar rats | 10 and 25 mg/kg (oral administration); 28 days | Nobiletin substantially ameliorated hemodynamic parameters, oxidative stress, collagen levels, matrix metalloproteinase (MMP)-2 levels, and MMP-9 levels in the diabetic rats. It also markedly attenuated deterioration in the morphology of cardiomyocytes. | [44] |
Nobiletin | Flavone | C57BL/6 Mice | 50 mg/kg (oral administration); 77 days | Nobiletin significantly decreased the expression of nicotinamide adenine dinucleotide (NADH) oxidase isoforms p67phox, p22phox, and p91phox, and attenuated oxidative stress in diabetic mice. It also ameliorated the development of cardiac dysfunction and interstitial fibrosis by down-regulating the c-Jun N-terminal kinase (JNK), P38, and nuclear factor kappa B NF-κB signaling pathways. | [45] |
Diosmin | Flavone | Sprague-Dawley Rats | 160 mg/kg (intraperitoneal); 7 days | Diosmin reduced hyperglycemia by enhancing the secretion of β-endorphin from the adrenal glands via imidazoline 1–2 receptor (I-2R) activation, which triggered the opioid receptors to attenuate gluconeogenesis metabolism in the livers of diabetic rats. It decreased the hepatic glycogen content and plasma lipid profiles in STZ-induced diabetic rats. However, it did not adversely affect the body weight, food intake, and plasma insulin level in the diabetic rats. | [35] |
Hesperidin and quercetin | Flavanone and flavone | Wistar Rats | 100 mg/kg (oral administration); 15 days | Hesperidin and quercetin exerted positive effects on insulin metabolism. They lowered the levels of triglycerides, MDA, TNFα, and IL-6, and restored the level of glutathione (GSH) in experimental diabetic rats induced by STZ. | [87] |
Hesperidin | Flavanone | Sprague-Dawley Rats | 25, 50, and 100 mg/kg (oral administration); 21 days | Hesperidin ameliorated the increased levels of blood glucose, serum insulin, food intake, and water intake in STZ- induced diabetes. It also had a protective effect on the wound architecture by accelerating angiogenesis and vasculogenesis via the up-regulation of vascular endothelial growth factor c (VEGF-c), Angiopoietin (Ang)-1/Tie-2, transforming growth factor (TGF-β), and small mothers against decapentaplegic (Smad)-2/3 mRNA expression to enhance wound healing in the chronic diabetic foot ulcer condition in the diabetic rats. | [86] |
Xanthohumol and 8-prenylnaringenin | Prenylflavonoid | C57Bl/6 Mice | 0.1% of flavonoids dissolved in ethanol; 140 days | Xanthohumol and 8-prenylnaringenin have a potent therapeutic effect on diabetic mice, as evidenced by the decreased levels of diabetes-linked biochemical parameters in the liver and kidney. They also decreased the overexpression of galectin-3 (Gal3), which was correlated with oxidative stress in diabetic mice. | [27] |
Naringin | Flavanone | Sprague-Dawley Rats | 100 mg/kg (oral administration); 28 days | Naringin reduced blood glucose, total cholesterol, triglycerides, and low-density lipoproteins in fructose-fed rats. Naringin restored acetylcholine-mediated vasorelaxation, suggesting its potential influence on fructose-induced metabolic alterations and endothelial dysfunction. Naringin improved serum nitrate/nitrite (NOx), endothelial nitric oxide synthase (eNOS), and phosphorylated eNOS (p-eNOS) protein expression, and preserved endothelium-dependent relaxation in the aortae of the fructose-fed rats. | [103] |
Hesperetin | Flavanone | Wistar Rats | 40 mg/kg (intragastric); 45 days | Hesperetin reduced the blood glucose level and enhanced the plasma insulin and the hepatic glycogen levels in the STZ-induced diabetic rats. It also restored the altered hepatic glucose metabolic enzymes, lipid profiles, and serum biomarkers, and protected from STZ-mediated structural alterations and functional changes in the liver, kidneys, and pancreatic β-cells of diabetic animals. | [97] |
Hesperetin | Flavanone | Wistar Rats | 50 mg/kg (oral administration); 46 days | Hesperetin significantly reduced the serum glucose level and improved the serum testosterone level in the STZ-induced diabetic rats. Additionally, it augmented the testicular antioxidant enzymes and attenuated the testicular inflammatory markers, such as TNFα and IL-17, besides preventing the seminiferous tubules’ damage in diabetic rats. | [98] |
Naringenin | Flavanone | C57BL/6J Mice | 100 mg/kg (oral administration); 14 days | Naringenin inhibited neutrophil infiltration into the adipose tissues of the high-fat diet (HFD)-fed mice by reducing the expression of several chemokines, including monocyte chemoattractant protein (MCP)-1 and MCP-3, in the adipose tissues. | [64] |
Nobiletin | Flavone | Ldlr-/- and Ampkβ1-/- mice from a C57BL/6J background | 0.3% of nobiletin mixed in HFD; 84–126 days | Nobiletin attenuated obesity, hepatic steatosis, dyslipidemia, and insulin resistance, and improved energy utilization in HFD-fed mice. It conferred metabolic protection independently of AMPK activation in the liver and adipose tissues. | [46] |
2.11. Naringenin
2.12. Naringin
2.13. Neohesperidin
2.14. Xanthohumol
2.15. Quercetin
2.16. Rutin
3. Composition of Antidiabetic Citrus Flavonoids in Common Citrus Fruit Sources
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Gandhi, G.R.; Vasconcelos, A.B.S.; Wu, D.-T.; Li, H.-B.; Antony, P.J.; Li, H.; Geng, F.; Gurgel, R.Q.; Narain, N.; Gan, R.-Y. Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies. Nutrients 2020, 12, 2907. https://doi.org/10.3390/nu12102907
Gandhi GR, Vasconcelos ABS, Wu D-T, Li H-B, Antony PJ, Li H, Geng F, Gurgel RQ, Narain N, Gan R-Y. Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies. Nutrients. 2020; 12(10):2907. https://doi.org/10.3390/nu12102907
Chicago/Turabian StyleGandhi, Gopalsamy Rajiv, Alan Bruno Silva Vasconcelos, Ding-Tao Wu, Hua-Bin Li, Poovathumkal James Antony, Hang Li, Fang Geng, Ricardo Queiroz Gurgel, Narendra Narain, and Ren-You Gan. 2020. "Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies" Nutrients 12, no. 10: 2907. https://doi.org/10.3390/nu12102907
APA StyleGandhi, G. R., Vasconcelos, A. B. S., Wu, D.-T., Li, H.-B., Antony, P. J., Li, H., Geng, F., Gurgel, R. Q., Narain, N., & Gan, R.-Y. (2020). Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies. Nutrients, 12(10), 2907. https://doi.org/10.3390/nu12102907