Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-/- and GLUT5-/- mice

Chirag Patel, Keiichiro Sugimoto, Veronique Douard, Ami Shah, Hiroshi Inui, Toshikazu Yamanouchi, Ronaldo Ferraris

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Elevated blood fructose concentrations constitute the basis for organ dysfunction in fructose-induced metabolic syndrome. We hypothesized that diet-induced changes in blood fructose concentrations are regulated by ketohexokinase (KHK) and the fructose transporter GLUT5. Portal and systemic fructose concentrations determined by HPLC in wild-type mice fed for 7 days 0% free fructose were <0.07 mM, were independent of time after feeding, were similar to those of GLUT5-/-, and did not lead to hyperglycemia. Postprandial fructose levels, however, increased markedly in those fed isocaloric 20% fructose, causing significant hyperglycemia. Deletion of KHK prevented fructose-induced hyperglycemia, but caused dramatic hyper-fructosemia (>1 mM) with reversed portal to systemic gradients. Systemic fructose in wild-type and KHK-/-mice changed by 0.34 and 1.8 mM, respectively, for every millimolar increase in portal fructose concentration. Systemic glucose varied strongly with systemic, but not portal, fructose levels in wild-type, and was independent of systemic and portal fructose in KHK-/-, mice. With ad libitum feeding for 12 wk, fructose-induced hyperglycemia in wild-type, but not hyperfructosemia in KHK-/- mice, increased HbA1c concentrations. Increasing dietary fructose to 40% intensified the hyperfructosemia of KHK-/- and the fructose-induced hyperglycemia of wild-type mice. Fructose perfusion or feeding in rats also caused duration- and dose-dependent hyperfructosemia and hyperglycemia. Significant levels of blood fructose are maintained independent of dietary fructose, KHK, and GLUT5, probably by endogenous synthesis of fructose. KHK prevents hyperfructosemia and fructose-induced hyperglycemia that would markedly increase HbAic levels. These findings explain the hyperfructosemia of human hereditary fructosuria as well as the hyperglycemia of fructose-induced metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)G779-G790
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number9
DOIs
StatePublished - Nov 1 2015

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ketohexokinase
Fructose
Serum
Hyperglycemia

All Science Journal Classification (ASJC) codes

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Patel, Chirag ; Sugimoto, Keiichiro ; Douard, Veronique ; Shah, Ami ; Inui, Hiroshi ; Yamanouchi, Toshikazu ; Ferraris, Ronaldo. / Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-/- and GLUT5-/- mice. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2015 ; Vol. 309, No. 9. pp. G779-G790.
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abstract = "Elevated blood fructose concentrations constitute the basis for organ dysfunction in fructose-induced metabolic syndrome. We hypothesized that diet-induced changes in blood fructose concentrations are regulated by ketohexokinase (KHK) and the fructose transporter GLUT5. Portal and systemic fructose concentrations determined by HPLC in wild-type mice fed for 7 days 0{\%} free fructose were <0.07 mM, were independent of time after feeding, were similar to those of GLUT5-/-, and did not lead to hyperglycemia. Postprandial fructose levels, however, increased markedly in those fed isocaloric 20{\%} fructose, causing significant hyperglycemia. Deletion of KHK prevented fructose-induced hyperglycemia, but caused dramatic hyper-fructosemia (>1 mM) with reversed portal to systemic gradients. Systemic fructose in wild-type and KHK-/-mice changed by 0.34 and 1.8 mM, respectively, for every millimolar increase in portal fructose concentration. Systemic glucose varied strongly with systemic, but not portal, fructose levels in wild-type, and was independent of systemic and portal fructose in KHK-/-, mice. With ad libitum feeding for 12 wk, fructose-induced hyperglycemia in wild-type, but not hyperfructosemia in KHK-/- mice, increased HbA1c concentrations. Increasing dietary fructose to 40{\%} intensified the hyperfructosemia of KHK-/- and the fructose-induced hyperglycemia of wild-type mice. Fructose perfusion or feeding in rats also caused duration- and dose-dependent hyperfructosemia and hyperglycemia. Significant levels of blood fructose are maintained independent of dietary fructose, KHK, and GLUT5, probably by endogenous synthesis of fructose. KHK prevents hyperfructosemia and fructose-induced hyperglycemia that would markedly increase HbAic levels. These findings explain the hyperfructosemia of human hereditary fructosuria as well as the hyperglycemia of fructose-induced metabolic syndrome.",
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Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-/- and GLUT5-/- mice. / Patel, Chirag; Sugimoto, Keiichiro; Douard, Veronique; Shah, Ami; Inui, Hiroshi; Yamanouchi, Toshikazu; Ferraris, Ronaldo.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 309, No. 9, 01.11.2015, p. G779-G790.

Research output: Contribution to journalArticle

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