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231 and augmented by the CasR agonist, NPS-R568. GLUT2 and CasR regulate K- and L-cell activity in response to nutrient and non-nutrient stimuli.

5 Abbreviations SGLT1, sodium-dependent glucose cotransporter 1;

GLUT2, facilitative glucose transporter 2;

glycylsar, glycylsarcosine;

OEA, oleoylethanolamide;

GIP, gluco-insulinotropic peptide;

GLP-1, glucagon-like peptide- 1;

PYY, peptide tyrosine tyrosine;

IEC, intestinal enteroendocrine cell;

GPCR, G protein coupled receptor;

Gln, glutamine;

Phe, phenylalanine;

Trp, tryptophan;

Asn, Asparagine;

Arg, Arginine;

Tas1R1+Tas1R3, amino acid taste receptor;

Tas1R2+Tas1R3, sweet taste receptor, CCK, cholecystokinin;

CasR, calcium- sensing receptor;

6 Introduction The gut releases hormones to initiate activities throughout the body that control gut motility, nutrient absorption &

disposal and satiety in response to the arrival of food. The gut hormone, gluco-insulinotropic peptide (GIP) is secreted from intestinal enteroendocrine (IEC) K-cells and the gut hormones glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) are secreted from IEC L-cells. Both IECs are distributed throughout the gastrointestinal tract and are targets for anti-diabetic therapies since GIP and GLP-1 directly stimulate insulin secretion. The secretion of these peptides has been extensively investigated and the current model of IEC sensing involves both raised intracellular Ca2+ and cAMP (Reimann et al., 2008;

Tolhurst et al., 2009;

Parker et al., 2010);

the former through either electrogenic transport to directly depolarise the membrane and open voltage-gated Ca2+ channels or activation of Gq protein coupled receptors, and the latter through Gs protein coupled receptors. Luminal nutrients including glucose and L-amino acids trigger GIP, GLP-1 and PYY secretion. It is well established that glucose can regulate GLP-1 secretion through electrogenic Na+ -coupled uptake via SGLT1. Sweet taste receptors, Tas1R2+Tas1R3, have also been demonstrated to regulate GLP-1 secretion which was impaired in mice lacking the coupling G protein, Gαgustducin (Margolskee et al., 2007). Another glucose transporter, GLUT2, which has a well established glucose- sensing role mediating insulin secretion from the pancreatic β-cell, also resides in the apical membrane of intestine. When rat small intestine is exposed with increasing glucose concentrations, the density and intrinsic activity of GLUT2 residing at the apical membrane transiently increases (Kellett &

Helliwell, 2000) to accommodate the increased absorptive capacity required to meet increased glucose concentration. This experimental observation has been confirmed by independent laboratories in both mice (Tobin et al., 2008;

Gorboulev et al., 2012), rat (Au et al., 2002;

Wei N et al., 2011), in intestinal cell lines (Zheng et al., 2012) and clinically in morbidly obese patients (Ati-Omar et al., 2011). GLUT2 is permanently expressed in the apical membrane of the intestine during diabetes (Gouyon et al., 2008;

Tobin et al., 200........