title: GLUT2 accumulation in enterocyte apical and intracellular membranes: a study in morbidly obese human subjects and ob/ob and high fat-fed mice.
abstract: OBJECTIVE
  In healthy rodents, intestinal sugar absorption in response to sugar-rich meals and insulin is regulated by GLUT2 in enterocyte plasma membranes. Loss of insulin action maintains apical GLUT2 location. In human enterocytes, apical GLUT2 location has not been reported but may be revealed under conditions of insulin resistance.
  
  
  METHODS
  Subcellular location of GLUT2 in jejunal enterocytes was analyzed by confocal and electron microscopy imaging and Western blot in 62 well-phenotyped morbidly obese subjects and 7 lean human subjects. GLUT2 locations were assayed in ob/ob and ob/+ mice receiving oral metformin or in high-fat low-carbohydrate diet-fed C57Bl/6 mice. Glucose absorption and secretion were respectively estimated by oral glucose tolerance test and secretion of [U-(14)C]-3-O-methyl glucose into lumen.
  
  
  RESULTS
  In human enterocytes, GLUT2 was consistently located in basolateral membranes. Apical GLUT2 location was absent in lean subjects but was observed in 76% of obese subjects and correlated with insulin resistance and glycemia. In addition, intracellular accumulation of GLUT2 with early endosome antigen 1 (EEA1) was associated with reduced MGAT4a activity (glycosylation) in 39% of obese subjects on a low-carbohydrate/high-fat diet. Mice on a low-carbohydrate/high-fat diet for 12 months also exhibited endosomal GLUT2 accumulation and reduced glucose absorption. In ob/ob mice, metformin promoted apical GLUT2 and improved glucose homeostasis. Apical GLUT2 in fasting hyperglycemic ob/ob mice tripled glucose release into intestinal lumen.
  
  
  CONCLUSIONS
  In morbidly obese insulin-resistant subjects, GLUT2 was accumulated in apical and/or endosomal membranes of enterocytes. Functionally, apical GLUT2 favored and endosomal GLUT2 reduced glucose transepithelial exchanges. Thus, altered GLUT2 locations in enterocytes are a sign of intestinal adaptations to human metabolic pathology.
authors.affiliation: INSERM, U872, Team 9, Paris, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Ait-Omar
authors.forename: Milena
authors.initials: M
authors.lastname: Monteiro-Sepulveda
authors.forename: Christine
authors.initials: C
authors.lastname: Poitou
authors.forename: Maude
authors.initials: M
authors.lastname: Le Gall
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cotillard
authors.forename: Jules
authors.initials: J
authors.lastname: Gilet
authors.forename: Kevin
authors.initials: K
authors.lastname: Garbin
authors.forename: Anne
authors.initials: A
authors.lastname: Houllier
authors.forename: Danièle
authors.initials: D
authors.lastname: Château
authors.forename: Amélie
authors.initials: A
authors.lastname: Lacombe
authors.forename: Nicolas
authors.initials: N
authors.lastname: Veyrie
authors.forename: Danielle
authors.initials: D
authors.lastname: Hugol
authors.forename: Joan
authors.initials: J
authors.lastname: Tordjman
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.forename: Patricia
authors.initials: P
authors.lastname: Serradas
authors.forename: Karine
authors.initials: K
authors.lastname: Clément
authors.forename: Armelle
authors.initials: A
authors.lastname: Leturque
authors.forename: Edith
authors.initials: E
authors.lastname: Brot-Laroche
mesh_terms: D000328:Adult; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage*; D020895:Enterocytes / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008875:Middle Aged; D009767:Obesity, Morbid / Q000378:metabolism*; D055815:Young Adult
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D051273:Glucose Transporter Type 2; D007004:Hypoglycemic Agents; C495680:SLC2A2 protein, human; C495682:Slc2a2 protein, mouse; D008687:Metformin