Sweet Taste Receptors Modulate Glucose Absorption George A Kyriazis - PowerPoint PPT Presentation

“Sweet Taste Receptors Modulate Glucose Absorption” George A Kyriazis Assistant Professor Biological Chemistry & Pharmacology College of Medicine 1

Taste Receptors are nutrient chemosensors beyond the tongue

Nutrient sensing Uptake and Metabolism Receptor-mediated signaling 3

Sweet Taste Receptor sensing: Same machinery, different context mouth cavity intestinal lumen blood Curr Opin Clin Nutr Metab Care. 2014 Jul;17(4):379-85. 4

STRs regulate plasma glucose homeostasis in response to “oral” glucose delivery W T (0 -1 5 m in ) ** 1 5 0 0 T 1 R 2 A U C 1 0 0 0 3 0 0 5 0 0 G lu c o s e (m g /d L ) intra-gastric glucose 0 W T T 1 R 2 tolerance test 2 0 0 (IG.GTT) 1 0 0 Glucose (1.0g/kg) p = 0 .0 4 2 0 3 6 9 1 21 5 3 0 m in u te s * 6 0 (0 -15 m in ) W T A U C 4 0 T 1 R 2 4 2 0 1 3 C 6 ]-g lu c o s e (m M ) 0 W T T 1 R 2 3 2 1 [U- p = 0 .0 1 6 Plasma Glucose 0 0 5 1 5 3 0 5 Smith et al, Mol Metab. 2018 m in u te s

Gut microbiota Peripheral glucose disposal 3 0 0 P la s m a G lu c o s e (m g /d L ) 2 0 0 ip.GTT 1 0 0 W T T 1 R 2 0 0 1 5 3 0 6 0 9 0 1 2 0 1 5 0 T im e (m in ) Kyriazis GA et al. Endocrinology 2014 Gut metabolites Glucose transit Glucose malabsorption 1 0 0 pre mouse 0 .8 Lu m in al g lu co se tran sit WT F e c al G lu c o se ( µ g /m g ) 10 (% o f total in testin e) T1R2 8 0 0 .6 5 6 0 0 .4 4 0 -10 10 -5 0 .2 2 0 -10 unpublished 0 0 .0 W T T 1 R 2 W T T 1 R 2

T1R2 intestines have reduced rate of 3-OMG flux 3-OMG (10 or 30mM) 14 C 3-O-methylglucose lactisole mucosa  serosa human intestinal explants W T T 1 R 2 2 ) 3 -O M G (3 0 m M ) -1 ) 0 .0 0 2 p = 6 0 3 -O M G F lu x (n m o l/m in /c m ** 1 5 2 ) -2 .m in 3 -O M G F lu x (n m o l/m in /c m 6 0 *** 5 0 4 0 1 0 F lux (nm o l.cm 4 0 3 0 2 0 5 2 0 1 0 W T T 1 R 2 0 0 0 0 3 0 6 0 9 0 1 2 0 1 0 3 0 V e h L a c tim e (m in ) 3 -O M G (m M ) 3 -O M G (3 0 m M ) 7 Smith et al, Mol Metab. 2018

Intragastric infusion Oral bolus 1 5 0 G lu c o s e (m g /d l) 1 2 5 g lu c o s e 1 0 0 7 5 5 0 -1 5-1 0 0 3 0 4 5 6 0 9 0 1 2 0 1 5 0 1 8 0 w a te r T im e (m in ) ( - ) L a c t i s o l e ( + ) L a c t i s o l e 1 5 0 ) L / p = 0 . 0 1 2 U 1 0 0 m ( n g l u c o s e i l u 5 0 s n I 0 - 1 5 - 1 0 0 3 0 4 5 6 0 9 0 1 2 0 1 5 0 1 8 0 w a t e r T i m e ( m i n ) 8 0 G L P 1 (p m o l/L ) 6 0 g lu c o s e 4 0 2 0 0 -1 5-1 0 0 3 0 4 5 6 0 9 0 1 2 0 1 5 0 1 8 0 w a te r T im e (m in )

Glucose transport in the small intestine lumen 10-20mM High glucose Low glucose (G. Kellett, E. Brot-Laroche, Diabetes, 2005) 9

T1R2 mice have reduced rate of GLUT2 translocation in response to an ig glucose load V e h ic le G lu c o s e *** *** P ea rs o n 's C o rre la tio n 0 .6 C o efficie nt 0 .4 0 .2 0 .0 W T T 1 R 2 ** ** L o w (G 5 ) 2 .0 H ig h (G 5 0 ) G L U T 2 (A U ) 1 .6 1 .2 0 .8 0 .4 0 .0 T 1 R 2 W T 10 Smith et al, Mol Metab. 2018

Intestinal perfusion with sucralose potentiates GLUT2 translocation in rats J Physiol 582.1 (2007) pp 379–392

Potential mechanisms for the reduced rate of GLUT2 translocation in T1R2 intestines GLP1 NCAS Lumen Glucose T1R3 Glucose T1R2 Na + SGLT1 GLP2 GLUT2 GLP-1 GLP-2 GLUT2 insulin Enterocyte Enteroendocrine insulin ? glucocorticoids glucocorticoids Blood vessels 12

Mechanism for the reduced rate of GLUT2 translocation in T1R2 intestine GLP1 GLP2 insulin 1 .2 5 3 0 p = 0 .0 1 1 P la s m a G L P -1 (p M ) H P V p la s m a G L P -2 (p g /m L ) 3 0 0 V e h ic le In s u lin ( µ g /L ) 1 .0 0 ** G lu c o s e 0 .7 5 2 0 2 2 5 0 .5 0 W T 0 .2 5 W T 1 0 T 1 R 2 T 1 R 2 1 5 0 0 .0 0 0 1 0 0 5 1 5 3 0 m in u te s T im e (m in ) W T T 1 R 2 glucocorticoids Ex vivo Glucose flux gastric emptying 2 5 0 W T C o rtic o s tro n e (n g /m l) 5 0 *** - 1 ) T 1 R 2 2 0 0 - 2 .m in p = 0 .1 4 4 0 3 1 5 0 A c eta m in o p h en F lu x (n m o l.c m ( µ g /m L /m in) 3 0 1 0 0 2 2 0 5 0 1 1 0 0 fa s tin g 0 5 1 6 0 (h o u rs ) 0 W T G L P 2 R W T T 1 R 2 13 unpublished Smith et al, Mol Metab. 2018

The GLP2 analogue, teduglutide, restores plasma glucose response during an igGTT in T1R2 mice IG.GTT 3-OMG (+/- Ted) W T -V e h T 1 R 2 -V e h V e h ic le W T -T e d T 1 R 2 -T e d T e d u g lu tid e G lu c o s e R a te (m g /d l/m in ) 5 0 0 2 5 * G lu c o s e (m g /d l) 4 0 0 2 0 3 0 0 1 5 2 0 0 1 0 1 0 0 5 0 0 V e h W T T 1 R 2 0 1 5 3 0 4 5 T e d T im e (m in ) * 8 0 glucose - 1 ) 1 4 C -3 O M G F lu x (1g/kg) - 2 .m in 6 0 4 0 (n m o l.c m 2 0 Veh or Ted (0.9 µ g/g) 0 T 1 R 2 W T 14 Smith et al, Mol Metab. 2018

Current working model 15 Smith et al, Mol Metab. 2018

Is T1R2-mediated nutrient chemosensing relevant to the development of metabolic disease? 16

Functional adaptations of intestinal STRs in response to dietary sugars glucose ? glucose absorption ? GLP1/2 mRNA ? intestine pancreas mRNA insulin glucose fructose Kyriazis GA et al, Endocrinology 2014 17

Overnight high sucrose diet (HSD) downregulates intestinal STR expression H S D C O N ig.GTT ( 13 C glucose) GLP-1 T 1 r3 T 1 r2 T 1 r3 1 .5 * *** *** **** 0 .07 ** * **** * C O N F o ld C h a n g e H S D 1 .0 [U -1 3 C 6 ]-g lu c o s e A U C (0 -3 0 m in ) * 1 0 0 C O N * * 8 0 P la sm a G L P -1 A U C (0 -3 0) H S D 0 .5 8 0 6 0 6 0 0 .0 I D J I I D J D J 4 0 4 0 T 1 R 2 W T 2 0 2 0 0 0 W T T 1 R 2 W T T 1 R 2 CON HSD 400 Ad lib glucose (mg/dL) ** ** 300 Ad lib glucose (7d HSD) 200 100 0 18 WT T1R2

Ob/Ob X T1R2-KO Ob/+ Ob/Ob T1R2-Ob/Ob unpublished 19

Deletion of T1R2 decreases glucose excursions during an IG.GTT in Ob/Ob mice ** G lu c o s e R a te (m g /d L /m in ) 5 0 O b /O b 6 0 0 G lu c o s e (m g /d l) T 1 R 2 -O b /O b 4 0 5 0 0 * 4 0 0 3 0 3 0 0 2 0 2 0 0 1 0 0.0320 p = 1 0 0 0 0 5 1 5 3 0 6 0 9 0 1 2 0 O b /O b T 1 R 2 -O b /O b T im e (m in ) O b /O b **** T 1 R 2 -O b /O b -1 ) 1 0 0 8 0 - 1 ) -2 .m in - 2 .m in 8 0 6 0 F lu x (n m o l.c m 6 0 W T F lux (nm o l.cm 4 0 4 0 T 1 R 2 2 0 2 0 0 3 O M G (3 0 m M ) unpublished 0 b b O O 0 3 0 6 0 9 0 1 2 0 / / b b O O tim e (m in ) 20 - 2 R 1 T

Unanswered questions Which type of cell(s) express STR? Where are they located? What are their characteristics? How they regulate gut biology? Inge Depoortere Gut 2014;63:179-190 21

Kyriazis Lab (OSU) Ann Serna, MS Joan Serrano, PhD Amit Rai, PhD (Mehta Lab) Janet Minton, MS Kyriazis Lab (SBP) Ashley Francois, BS Kathy Smith (Pfizer) Lydia Dupont Elnaz Karimian Azari (Metagenics) Andrea Scofield Traci LaMoia (Yale U) Katalin Karolyi (U Penn) Veronika Vargova (Florida Hospital) Researchers Postdoctoral Associates Graduate Students Funding Undergraduate R21DK110489 Volunteers R01DK112747 (NIFA-2018-67001-28246) 22