Skip to main content Accessibility help
×
Home

The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling

  • Christiane E. Koch (a1), Goutham K. Ganjam (a1), Juliane Steger (a1), Karen Legler (a1), Sigrid Stöhr (a1), Daniela Schumacher (a1), Nigel Hoggard (a2), Gerhard Heldmaier (a1) and Alexander Tups (a1)...

Abstract

Secondary metabolites of herbs and spices are widely used as an alternative strategy in the therapy of various diseases. The polyphenols naringenin, quercetin and curcumin have been characterised as anti-diabetic agents. Conversely, in vitro, naringenin and quercetin are described to inhibit phosphoinositide-3-kinase (PI3K), an enzyme that is essential for the neuronal control of whole body glucose homoeostasis. Using both in vitro and in vivo experiments, we tested whether the inhibitory effect on PI3K occurs in neurons and if it might affect whole body glucose homoeostasis. Quercetin was found to inhibit basal and insulin-induced phosphorylation of Akt (Ser473), a downstream target of PI3K, in HT-22 cells, whereas naringenin and curcumin had no effect. In Djungarian hamsters (Phodopus sungorus) naringenin and quercetin (10 mg/kg administered orally) diminished insulin-induced phosphorylation of Akt (Ser473) in the arcuate nucleus, indicating a reduction in hypothalamic PI3K activity. In agreement with this finding, glucose tolerance in naringenin-treated hamsters (oral) and mice (oral and intracerebroventricular) was reduced compared with controls. Dietary quercetin also impaired glucose tolerance, whereas curcumin was ineffective. Circulating levels of insulin and insulin-like growth factor-binding protein were not affected by the polyphenols. Oral quercetin reduced the respiratory quotient, suggesting that glucose utilisation was impaired after treatment. These data demonstrate that low doses of naringenin and quercetin acutely and potently impair glucose homoeostasis. This effect may be mediated by inhibition of hypothalamic PI3K signalling. Whether chronic impairments in glucose homoeostasis occur after long-term application remains to be identified.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      The dietary flavonoids naringenin and quercetin acutely impair glucose metabolism in rodents possibly via inhibition of hypothalamic insulin signalling
      Available formats
      ×

Copyright

Corresponding author

*Corresponding author: A. Tups, fax +49 6421 28 28937, email alexander.tups@staff.uni-marburg.de

References

Hide All
1Ross, JA & Kasum, CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 22, 1934.
2Nijveldt, RJ, van, NE, van Hoorn, DE, et al. (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 74, 418425.
3Aggarwal, BB, Sundaram, C, Malani, N, et al. (2007) Curcumin: the Indian solid gold. Adv Exp Med Biol 595, 175.
4Jagetia, GC & Aggarwal, BB (2007) ‘Spicing up’ of the immune system by curcumin. J Clin Immunol 27, 1935.
5Justesen, U, Knuthsen, P & Leth, T (1998) Quantitative analysis of flavonols, flavones, and flavanones in fruits, vegetables and beverages by high-performance liquid chromatography with photo-diode array and mass spectrometric detection. J Chromatogr A 799, 101110.
6Del, RD, Stewart, AJ, Mullen, W, et al. (2004) HPLC–MSn analysis of phenolic compounds and purine alkaloids in green and black tea. J Agric Food Chem 52, 28072815.
7Wang, HF & Helliwell, K (2001) Determination of flavonols in green and black tea leaves and green tea infusions by high-performance liquid chromatography. Food Res Int 34, 223227.
8Kannappan, S & Anuradha, CV (2010) Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. Eur J Nutr 49, 101109.
9Kobori, M, Masumoto, S, Akimoto, Y, et al. (2009) Dietary quercetin alleviates diabetic symptoms and reduces streptozotocin-induced disturbance of hepatic gene expression in mice. Mol Nutr Food Res 53, 859868.
10Na, LX, Zhang, YL, Li, Y, et al. (2011) Curcumin improves insulin resistance in skeletal muscle of rats. Nutr Metab Cardiovasc Dis 21, 526533.
11Ortiz-Andrade, RR, Sanchez-Salgado, JC, Navarrete-Vazquez, G, et al. (2008) Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation. Diabetes Obes Metab 10, 10971104.
12Bruning, JC, Gautam, D, Burks, DJ, et al. (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289, 21222125.
13Koch, L, Wunderlich, FT, Seibler, J, et al. (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest 118, 21322147.
14Walker, EH, Pacold, ME, Perisic, O, et al. (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6, 909919.
15Harmon, AW & Patel, YM (2003) Naringenin inhibits phosphoinositide 3-kinase activity and glucose uptake in 3T3-L1 adipocytes. Biochem Biophys Res Commun 305, 229234.
16Kizhakkayil, J, Thayyullathil, F, Chathoth, S, et al. (2010) Modulation of curcumin-induced Akt phosphorylation and apoptosis by PI3K inhibitor in MCF-7 cells. Biochem Biophys Res Commun 394, 476481.
17Okamoto, H, Nakae, J, Kitamura, T, et al. (2004) Transgenic rescue of insulin receptor-deficient mice. J Clin Invest 114, 214223.
18Okamoto, H, Obici, S, Accili, D, et al. (2005) Restoration of liver insulin signaling in Insr knockout mice fails to normalize hepatic insulin action. J Clin Invest 115, 13141322.
19Mercer, JG & Tups, A (2003) Neuropeptides and anticipatory changes in behaviour and physiology: seasonal body weight regulation in the Siberian hamster. Eur J Pharmacol 480, 4350.
20Saha, JK, Xia, J, Grondin, JM, et al. (2005) Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models. Exp Biol Med (Maywood) 230, 777784.
21Koch, C, Augustine, RA, Steger, J, et al. (2010) Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 30, 1618016187.
22Tups, A, Anderson, GM, Rizwan, M, et al. (2010) Both p110alpha and p110beta isoforms of phosphatidylinositol 3-OH-kinase are required for insulin signalling in the hypothalamus. J Neuroendocrinol 22, 534542.
23Heldmaier, G & Ruf, T (1992) Body temperature and metabolic rate during natural hypothermia in endotherms. J Comp Physiol B 162, 696706.
24Hedbacker, K, Birsoy, K, Wysocki, RW, et al. (2010) Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metab 11, 1122.
25Heldmaier, G, Klingenspor, M, Werneyer, M, et al. (1999) Metabolic adjustments during daily torpor in the Djungarian hamster. Am J Physiol 276, E896E906.
26Harmon, AW & Patel, YM (2004) Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation. Breast Cancer Res Treat 85, 103110.
27Nomura, M, Takahashi, T, Nagata, N, et al. (2008) Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3T3-G2/PA6 adipose cells. Biol Pharm Bull 31, 14031409.
28Strobel, P, Allard, C, Perez-Acle, T, et al. (2005) Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. Biochem J 386, 471478.
29Cheatham, B, Vlahos, CJ, Cheatham, L, et al. (1994) Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14, 49024911.
30Clarke, JF, Young, PW, Yonezawa, K, et al. (1994) Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem J 300, 631635.
31Okada, T, Kawano, Y, Sakakibara, T, et al. (1994) Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem 269, 35683573.
32Kannappan, S & Anuradha, CV (2009) Insulin sensitizing actions of fenugreek seed polyphenols, quercetin & metformin in a rat model. Indian J Med Res 129, 401408.
33Mulvihill, EE, Allister, EM, Sutherland, BG, et al. (2009) Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes 58, 21982210.
34Woo, JH, Kim, YH, Choi, YJ, et al. (2003) Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis 24, 11991208.
35Yu, S, Shen, G, Khor, TO, et al. (2008) Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Mol Cancer Ther 7, 26092620.
36Siwak, DR, Shishodia, S, Aggarwal, BB, et al. (2005) Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer 104, 879890.
37Nishiyama, T, Mae, T, Kishida, H, et al. (2005) Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice. J Agric Food Chem 53, 959963.
38Mercer, JG, Hoggard, N, Williams, LM, et al. (1996) Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett 387, 113116.
39Niswender, KD, Morrison, CD, Clegg, DJ, et al. (2003) Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227231.
40Sanderson, TH, Kumar, R, Murariu-Dobrin, AC, et al. (2009) Insulin activates the PI3K-Akt survival pathway in vulnerable neurons following global brain ischemia. Neurol Res 31, 947958.
41Unger, JW, Livingston, JN & Moss, AM (1991) Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 36, 343362.
42Werther, GA, Hogg, A, Oldfield, BJ, et al. (1987) Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121, 15621570.
43Kanoski, SE, Hayes, MR, Greenwald, HS, et al. (2011) Hippocampal leptin signaling reduces food intake and modulates food-related memory processing. Neuropsychopharmacology 36, 18591870.
44Satoh, N, Ogawa, Y, Katsuura, G, et al. (1997) The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neurosci Lett 224, 149152.
45Perkins, S, Verschoyle, RD, Hill, K, et al. (2002) Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev 11, 535540.
46Sharma, RA, Ireson, CR, Verschoyle, RD, et al. (2001) Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin Cancer Res 7, 14521458.
47Felgines, C, Texier, O, Morand, C, et al. (2000) Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol 279, G1148G1154.
48Youdim, KA, Dobbie, MS, Kuhnle, G, et al. (2003) Interaction between flavonoids and the blood–brain barrier: in vitro studies. J Neurochem 85, 180192.
49Youdim, KA, Qaiser, MZ, Begley, DJ, et al. (2004) Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic Biol Med 36, 592604.
50Youdim, KA, Shukitt-Hale, B & Joseph, JA (2004) Flavonoids and the brain: interactions at the blood–brain barrier and their physiological effects on the central nervous system. Free Radic Biol Med 37, 16831693.
51El Mohsen, MA, Marks, J, Kuhnle, G, et al. (2004) The differential tissue distribution of the citrus flavanone naringenin following gastric instillation. Free Radic Res 38, 13291340.
52Sabarinathan, D & Vanisree, AJ (2010) Naringenin, a flavanone alters the tumorigenic features of C6 glioma cells. Biomed Pharmacother (Epublication ahead of print version 20 December 2010).
53Chen, Y, Xiao, P, Ou-Yang, DS, et al. (2009) Simultaneous action of the flavonoid quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase and xanthine oxidase activity in healthy volunteers. Clin Exp Pharmacol Physiol 36, 828833.
54Manzano, S & Williamson, G (2010) Polyphenols and phenolic acids from strawberry and apple decrease glucose uptake and transport by human intestinal Caco-2 cells. Mol Nutr Food Res 54, 17731780.
55Zygmunt, K, Faubert, B, MacNeil, J, et al. (2010) Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun 398, 178183.
56Plum, L, Rother, E, Munzberg, H, et al. (2007) Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation. Cell Metab 6, 431445.
57Al-Qassab, H, Smith, MA, Irvine, EE, et al. (2009) Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab 10, 343354.
58Hill, JW, Elias, CF, Fukuda, M, et al. (2010) Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11, 286297.
59Wymann, MP & Pirola, L (1998) Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta 1436, 127150.
60Erlund, I, Meririnne, E, Alfthan, G, et al. (2001) Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J Nutr 131, 235241.
61Ho, PC, Saville, DJ, Coville, PF, et al. (2000) Content of CYP3A4 inhibitors, naringin, naringenin and bergapten in grapefruit and grapefruit juice products. Pharm Acta Helv 74, 379385.
62Kuhnau, J (1976) The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 24, 117191.

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed