British Journal of Nutrition

Full Papers

Nutritional Endocrinology

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

Christiane E. Kocha1, Goutham K. Ganjama1, Juliane Stegera1, Karen Leglera1, Sigrid Stöhra1, Daniela Schumachera1, Nigel Hoggarda2, Gerhard Heldmaiera1 and Alexander Tupsa1 c1

a1 Department of Animal Physiology, Faculty of Biology, Philipps University Marburg, Karl-von-Frisch-Straße 8, 35043 Marburg, Germany

a2 Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, UK

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.

(Received February 22 2011)

(Revised June 01 2012)

(Accepted June 04 2012)

(Online publication August 01 2012)

Key Words:

  • Phosphoinositide-3-kinase/insulin receptor substrate signalling;
  • Arcuate nucleus;
  • Glucose homoeostasis

Correspondence

c1 Corresponding author: A. Tups, fax +49 6421 28 28937, email alexander.tups@staff.uni-marburg.de

Footnotes

  Abbreviations: ARC, arcuate nucleus; AUC, area under the curve; ICV, intracerebroventricular; IGFBP2, insulin-like growth factor-binding protein 2; ip, intra-peritoneal; LD, long day; pAkt, phospho-Akt; PI3K, phosphoinositide-3-kinase; RQ, respiratory quotient; SD, short day