title: Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-/- and GLUT5-/- mice.
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 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 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 HbA1c levels. These findings explain the hyperfructosemia of human hereditary fructosuria as well as the hyperglycemia of fructose-induced metabolic syndrome.
authors: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey;
authors: Chirag
authors: C
authors: Patel
authors: Research and Development Center, Nagaoka Perfumery Co., Ltd., Ibaraki, Osaka, Japan; Center for Research and Development of Bioresources, Osaka Prefecture University, Sakai, Osaka, Japan;
authors: Keiichiro
authors: K
authors: Sugimoto
authors: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey;
authors: Veronique
authors: V
authors: Douard
authors: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey;
authors: Ami
authors: A
authors: Shah
authors: Center for Research and Development of Bioresources, Osaka Prefecture University, Sakai, Osaka, Japan; Department of Clinical Nutrition, College of Health and Human Sciences, Osaka Prefecture University, Habikino, Osaka, Japan; and.
authors: Hiroshi
authors: H
authors: Inui
authors: Department of Internal Medicine, Teikyo University, Tokyo, Japan.
authors: Toshikazu
authors: T
authors: Yamanouchi
authors: Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, New Jersey; ferraris@njms.rutgers.edu.
authors: Ronaldo P
authors: RP
authors: Ferraris
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000097:blood* / Q000633:toxicity; D005631:Fructokinases / Q000172:deficiency* / Q000235:genetics; D005632:Fructose / Q000008:administration & dosage / Q000097:blood* / Q000633:toxicity; D005838:Genotype; D051246:Glucose Transport Proteins, Facilitative / Q000172:deficiency* / Q000235:genetics; D051296:Glucose Transporter Type 5; D006442:Glycated Hemoglobin / Q000378:metabolism; D006321:Heart; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011169:Portal Vein; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D004040:Dietary Carbohydrates; D005631:Fructokinases; D005632:Fructose; D051246:Glucose Transport Proteins, Facilitative; D051296:Glucose Transporter Type 5; D006442:Glycated Hemoglobin; C465351:Slc2a5 protein, mouse; C021475:ketohexokinase
keywords: diabetes; fructosuria; glucose transporter 5; ketohexokinase; metabolic syndrome