Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 309, Issue 9, Pages G779-G790Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00188.2015
Keywords
diabetes; fructosuria; glucose transporter 5; ketohexokinase; metabolic syndrome
Categories
Funding
- National Science Foundation [IOS-1121049, IOS-1456673]
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-102934]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [1456673] Funding Source: National Science Foundation
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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 hyperfructosemia (> 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 HbA(1c) 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 HbA(1c) levels. These findings explain the hyperfructosemia of human hereditary fructosuria as well as the hyperglycemia of fructose-induced metabolic syndrome.
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