Intestinal glucose and peptide transporters: their role in sensing and hormone secretion and their adaptation in obesity and diabetic states
Nuclear Medicine, Radiotherapy, Radiobiology
Final Report Abstract
According to physiology text books the sodium-dependent glucose transporter SGLT1 and the fructose transporter GLUT5 are responsible for the uptake of glucose and fructose from the intestine into the intestinal cell whereas the glucose transporter GLUT2 mediates the release of both sugars into circulation. Some years ago, it was proposed that GLUT2 is recruited into the apical membrane at high luminal glucose concentrations to mediate bulk absorption of glucose in addition to SGLT1. This recruitment would also allow increased fructose influx and this could explain a phenomenon known from humans suffering from fructose malabsorption in which glucose provided with fructose can completely prevent fructose malabsorption. In this respect, the concept of a GLUT2 trafficking into the apical membrane was appealing but also caused huge controversies in the science community on whether it was valid per se or of any relevance. Recent findings have demonstrated that nutrient transporters such as SGLT act as “transceptors” allowing luminal nutrients to be sensed for increasing gastrointestinal hormone secretion from endocrine cells. This is particularly relevant for the incretins by their action on insulin release and for maintaining β-cell mass. Such a function was proven for SGLT1 and GLUT2 is also suggested to play a role as a glucose sensor. Similarly, GLUT5 could serve as a fructose sensor triggering GLP-1 secretion as shown to occur after fructose intake. Since peptone/peptides are as well known to induce incretin secretion we got interested to study whether PEPT1 also acts as a transceptor. Moreover, it is known that in the obese state incretin output is impaired and we thus asked whether the transceptor function of the corresponding protein is altered. In the project described here for the first time radiolabeled glucose or fructose was orally administered to investigate in vivo intestinal glucose or fructose uptake by SGLT1, GLUT2 and GLUT5 with the use of the corresponding mouse models lacking each of the transporters. We would like to stress that animals were fed under standardized conditions with the need of using particular diets as the transporter-deficiency requires either diets low in carbohydrates (SGLT1) or fructose (GLUT5). Based on the work described here and in the adjacent publications we would like to summarize: SGLT1 is responsible for glucose uptake even at high luminal glucose concentrations whereas GLUT2 mediates the release into the blood. SGLT1 but not GLUT2 is essential for glucose-induced release of GIP and GLP-1. We did not find evidence for a GLUT2 trafficking into apical membranes or a role in apical fructose transport. GLUT5 is the prime fructose transporter that seems to be involved in fructose-induced GLP-1 secretion. Our in vivo and in vitro studies suggest an interplay of SGLT1 and GLUT5 in the glucose-stimulated increase in fructose absorption as well as in the glucose- or fructose-induced release of GLP-1. PEPT1 similar to SGLT1 seems to act as a transceptor in endoenterocrine cells translating the presence of luminal peptides into an incretin secretion based on its electrogenic nature. In obese mice and animals treated with STZ to cause type 1 diabetes, evidence was found that the intestinal transporters undergo changes in expression, transport and sensory function that may contribute to the metabolic impairments known to be associated with the obese state.
Publications
- Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor (2013); Diabetologia, 56:2688-2696
Diakogiannaki, E, Pais, R, Tolhurst, G, Parker, HE, Horscroft, J, Rauscher, B, Zietek, T, Daniel, H, Gribble, FM, Reimann, F
(See online at https://doi.org/10.1007/s00125-013-3037-3) - The role of SGLT1 and GLUT2 in intestinal glucose transport and sensing. PLoS ONE 9(2): e89977, 2014
Röder, PV, Geillinger, KE, Zietek, TS, Thorens, B, Koepsell, H, Daniel, H
(See online at https://doi.org/10.1371/journal.pone.0089977)
