Resistin-like molecule-beta inhibits SGLT-1 activity and enhances GLUT2-dependent jejunal glucose transport.
OBJECTIVE
An increased expression of RELM-beta (resistin-like molecule-beta), a gut-derived hormone, is observed in animal models of insulin resistance/obesity and intestinal inflammation. Intestinal sugar absorption is modulated by dietary environment and hormones/cytokines. The aim of this study was to investigate the effect of RELM-beta on intestinal glucose absorption.


METHODS
Oral glucose tolerance test was performed in mice and rats in the presence and the absence of RELM-beta. The RELM-beta action on glucose transport in rat jejunal sacs, everted rings, and mucosal strips was explored as well as downstream kinases modulating SGLT-1 and GLUT2 glucose transporters.


RESULTS
Oral glucose tolerance test carried out in rodents showed that oral administration of RELM-beta increased glycemia. Studies in rat jejunal tissue indicated that mucosal RELM-beta promoted absorption of glucose from the gut lumen. RELM-beta had no effect on paracellular mannitol transport, suggesting a transporter-mediated transcellular mechanism. In studies with jejunal mucosa mounted in Ussing chamber, luminal RELM-beta inhibited SGLT-1 activity in line with a diminished SGLT-1 abundance in brush border membranes (BBMs). Further, the potentiating effect of RELM-beta on jejunal glucose uptake was associated with an increased abundance of GLUT2 at BBMs. The effects of RELM-beta were associated with an increased amount of protein kinase C betaII in BBMs and an increased phosphorylation of AMP-activated protein kinase (AMPK).


CONCLUSIONS
The regulation of SGLT-1 and GLUT2 by RELM-beta expands the role of gut hormones in short-term AMPK/protein kinase C mediated control of energy balance.
Krimi
Rim Belharbi
RB
INSERM, U773, Centre de Recherche Bichat Beaujon CRB3, and Université Paris 7 Denis Diderot, Paris, France.
Letteron
Philippe
P
Chedid
Pia
P
Nazaret
Corinne
C
Ducroc
Robert
R
Marie
Jean-Claude
JC
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000493:pharmacokinetics*; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2 / Q000378:metabolism*; D006729:Hormones, Ectopic / Q000378:metabolism* / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism*
D051273:Glucose Transporter Type 2; D006729:Hormones, Ectopic; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C486522:Retnlb protein, mouse; C495682:Slc2a2 protein, mouse; C495683:Slc2a2 protein, rat; C495675:Slc5a1 protein, mouse; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D012964:Sodium; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D055372:AMP-Activated Protein Kinases; D005947:Glucose