The β2-adrenergic receptor in the apical membrane of intestinal enterocytes senses sugars to stimulate glucose uptake from the gut

Front Cell Dev Biol. 2023 Jan 9:10:1041930. doi: 10.3389/fcell.2022.1041930. eCollection 2022.

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.

Keywords: Beta2-adrenergic receptor; SGLT1; beta2-adrenergic receptor antagonists; enterocytes; glucose sensing; glucose transport; gut.

Grants and funding

This work was supported by a predoctoral fellowship to FP from the Agency for Innovation by Science and Technology (IWT-Flanders), by mainly personal self-financing to WL and by grants from the COSAT program (Johnson and Johnson–VIB), the Fund for Scientific Research—Flanders, Interuniversity Attraction Poles Network P5/30 and P6/14, the Research Fund of the KU Leuven (Concerted Research Actions) and the Hercules Foundation (Flanders). The NMR study made use of the BioMacs facility at KU Leuven. Equipment in the facility was purchased with funds from the Flemish government (“impuls project”) and FWO-Flanders.