Insulin internalizes GLUT2 in the enterocytes of healthy but not insulin-resistant mice.
OBJECTIVE
A physiological adaptation to a sugar-rich meal is achieved by increased sugar uptake to match dietary load, resulting from a rapid transient translocation of the fructose/glucose GLUT2 transporter to the brush border membrane (BBM) of enterocytes. The aim of this study was to define the contributors and physiological mechanisms controlling intestinal sugar absorption, focusing on the action of insulin and the contribution of GLUT2-mediated transport.


METHODS
The studies were performed in the human enterocytic colon carcinoma TC7 subclone (Caco-2/TC7) cells and in vivo during hyperinsulinemic-euglycemic clamp experiments in conscious mice. Chronic high-fructose or high-fat diets were used to induce glucose intolerance and insulin resistance in mice.


CONCLUSIONS
In Caco-2/TC7 cells, insulin action diminished the transepithelial transfer of sugar and reduced BBM and basolateral membrane (BLM) GLUT2 levels, demonstrating that insulin can target sugar absorption by controlling the membrane localization of GLUT2 in enterocytes. Similarly, in hyperinsulinemic-euglycemic clamp experiments in sensitive mice, insulin abolished GLUT2 (i.e., the cytochalasin B-sensitive component of fructose absorption), decreased BBM GLUT2, and concomitantly increased intracellular GLUT2. Acute insulin treatment before sugar intake prevented the insertion of GLUT2 into the BBM. Insulin resistance in mice provoked a loss of GLUT2 trafficking, and GLUT2 levels remained permanently high in the BBM and low in the BLM. We propose that, in addition to its peripheral effects, insulin inhibits intestinal sugar absorption to prevent excessive blood glucose excursion after a sugar meal. This protective mechanism is lost in the insulin-resistant state induced by high-fat or high-fructose feeding.
Tobin
Vanessa
V
Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S 872, Paris, France.
Le Gall
Maude
M
Fioramonti
Xavier
X
Stolarczyk
Emilie
E
Blazquez
Alba G
AG
Klein
Christophe
C
Prigent
Magali
M
Serradas
Patricia
P
Cuif
Marie-Hélène
MH
Magnan
Christophe
C
Leturque
Armelle
A
Brot-Laroche
Edith
E
D000818:Animals; D018938:Caco-2 Cells; D050260:Carbohydrate Metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D015309:Glucose Clamp Technique; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008871:Microvilli / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology
D051273:Glucose Transporter Type 2; D007328:Insulin; C495682:Slc2a2 protein, mouse