Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Developmental Biology, glucose sensing, gut, enterocytes, Beta2-adrenergic receptor, glucose transport, SGLT1, beta2-adrenergic receptor antagonists, PROTEIN-COUPLED RECEPTOR, BETA-ADRENERGIC-RECEPTOR, BRUSH-BORDER, BETA(2)-ADRENERGIC RECEPTOR, CRYSTAL-STRUCTURE, SKELETAL-MUSCLE, NA+/GLUCOSE COTRANSPORTER, DEVELOPMENTAL REGULATION, STRUCTURAL INSIGHTS, BROWN ADIPOCYTES, I008520N#55635602, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor (β 2-AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1. Upon heterologous expression in different reporter systems, the β 2-AR responds to multiple sugars in the mM range, consistent with estimated gut sugar levels after a meal. Most adrenergic receptor antagonists inhibit sugar signaling, while some differentially inhibit epinephrine and sugar responses. However, sugars did not inhibit binding of I125-cyanopindolol, a β 2-AR antagonist, to the ligand-binding site in cell-free membrane preparations. This suggests different but interdependent binding sites. Glucose uptake into everted sacs from rat intestine was stimulated by epinephrine and sugars in a β 2-AR-dependent manner. STD-NMR confirmed direct physical binding of glucose to the β 2-AR. Oral administration of glucose with a non-bioavailable β 2-AR antagonist lowered the subsequent increase in blood glucose levels, confirming a role for enterocyte apical β 2-ARs in stimulating gut glucose uptake, and suggesting enterocyte β 2-AR as novel drug target in diabetic and obese patients. Future work will have to reveal how glucose sensing by enterocytes and neuroendocrine cells is connected, and whether β 2-ARs mediate glucose sensing also in other tissues.