Resistin-Like Molecule-β Inhibits SGLT-1 Activity and Enhances GLUT2-Dependent Jejunal Glucose Transport

OBJECTIVE: An increased expression of RELM-β (resistin-like molecule-β), 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-β on intestinal glucose absorption. RESEARCH DESIGN AND METHODS: Oral glucose tolerance test was performed in mice and rats in the presence and the absence of RELM-β. The RELM-β 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-β increased glycemia. Studies in rat jejunal tissue indicated that mucosal RELM-β promoted absorption of glucose from the gut lumen. RELM-β had no effect on paracellular mannitol transport, suggesting a transporter-mediated transcellular mechanism. In studies with jejunal mucosa mounted in Ussing chamber, luminal RELM-β inhibited SGLT-1 activity in line with a diminished SGLT-1 abundance in brush border membranes (BBMs). Further, the potentiating effect of RELM-β on jejunal glucose uptake was associated with an increased abundance of GLUT2 at BBMs. The effects of RELM-β were associated with an increased amount of protein kinase C βII in BBMs and an increased phosphorylation of AMP-activated protein kinase (AMPK). CONCLUSIONS: The regulation of SGLT-1 and GLUT2 by RELM-β expands the role of gut hormones in short-term AMPK/protein kinase C mediated control of energy balance.