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

3

Nutrient sensing Receptor-mediated signaling Uptake and Metabolism

Sweet Taste Receptor sensing: Same machinery, different context

4

mouth cavity intestinal lumen blood

Curr Opin Clin Nutr Metab Care. 2014 Jul;17(4):379-85.

intra-gastric glucose tolerance test (IG.GTT)

STRs regulate plasma glucose homeostasis in response to “oral” glucose delivery

Plasma Glucose Glucose (1.0g/kg)

5

0 3 6 9 1 21 5 3 0

1 0 0 2 0 0 3 0 0 T 1 R 2 W T m in u te s

G lu c o s e (m g /d L )

p = 0 .0 4 2 A U C (0 -1 5 m in )

W T T 1 R 2 5 0 0 1 0 0 0 1 5 0 0

** Smith et al, Mol Metab. 2018

5 1 5 3 0 1 2 3 4 m in u te s [U-

1 3C 6 ]-g lu c o s e (m M )

W T T 1 R 2

p = 0 .0 1 6 2 0 4 0 6 0

A U C (0 -15 m in )

W T T 1 R 2

*

W T T 1 R 2

0 .0 0 .2 0 .4 0 .6 0 .8 F e c al G lu c o se (µg /m g )

Glucose malabsorption

W T T 1 R 2

2 0 4 0 6 0 8 0 1 0 0 Lu m in al g lu co se tran sit (% o f total in testin e)

Glucose transit

Kyriazis GA et al. Endocrinology 2014

T im e (m in ) P la s m a G lu c o s e (m g /d L )

0 1 5 3 0 6 0 9 0 1 2 0 1 5 0 1 0 0 2 0 0 3 0 0

W T T 1 R 2

Peripheral glucose disposal

ip.GTT

Gut microbiota Gut metabolites

• 10

10

• 10
• 5

5 10

pre mouse

WT T1R2

unpublished

7

3 0 6 0 9 0 1 2 0 1 0 2 0 3 0 4 0 5 0 6 0 tim e (m in )

F lux (nm o l.cm

• 2.m in
• 1)

T 1 R 2 W T

3 -O M G (3 0 m M )

T1R2 intestines have reduced rate of 3-OMG flux

2 0 4 0 6 0 3 -O M G F lu x (n m o l/m in /c m

2 )

W T T 1 R 2 1 0 3 0 3 -O M G (m M )

*** **

5 1 0 1 5 3 -O M G F lu x (n m o l/m in /c m

2 )

V e h L a c

p =

3 -O M G (3 0 m M )

0 .0 0 2

human intestinal explants

14C 3-O-methylglucose

lactisole

Smith et al, Mol Metab. 2018

3-OMG (10 or 30mM)

mucosa  serosa

• 1 5-1 0 0

3 0 4 5 6 0 9 0 1 2 0 1 5 0 1 8 0

5 0 7 5 1 0 0 1 2 5 1 5 0 T im e (m in ) G lu c o s e (m g /d l)

w a te r g lu c o s e

• 1

• )

• l

• l

• s

• 1 5-1 0 0

3 0 4 5 6 0 9 0 1 2 0 1 5 0 1 8 0

2 0 4 0 6 0 8 0 T im e (m in ) G L P 1 (p m o l/L )

w a te r g lu c o s e

Intragastric infusion Oral bolus

9

Low glucose High glucose Glucose transport in the small intestine

(G. Kellett, E. Brot-Laroche, Diabetes, 2005)

10-20mM

lumen

T1R2 mice have reduced rate of GLUT2 translocation in response to an ig glucose load

10

0 .0 0 .2 0 .4 0 .6 P ea rs o n 's C o rre la tio n C o efficie nt W T T 1 R 2

V e h ic le G lu c o s e

*** ***

0 .0 0 .4 0 .8 1 .2 1 .6 2 .0 G L U T 2 (A U ) W T T 1 R 2

** **

L o w (G 5 ) H ig h (G 5 0 )

Smith et al, Mol Metab. 2018

J Physiol 582.1 (2007) pp 379–392

Intestinal perfusion with sucralose potentiates GLUT2 translocation in rats

GLP2 GLP1

SGLT1 Glucose GLUT2

Enterocyte

Na+

Blood vessels Lumen

GLUT2

Enteroendocrine

T1R2 T1R3 NCAS Glucose

12

Potential mechanisms for the reduced rate of GLUT2 translocation in T1R2 intestines

?

GLP-1 GLP-2 insulin glucocorticoids glucocorticoids insulin

Mechanism for the reduced rate of GLUT2 translocation in T1R2 intestine

1 0

0 .0 0 0 .2 5 0 .5 0 0 .7 5 1 .0 0 1 .2 5

m in u te s In s u lin ( µ g /L )

W T T 1 R 2

GLP2 GLP1 glucocorticoids insulin

5 0 1 0 0 1 5 0 2 0 0 2 5 0 C o rtic o s tro n e (n g /m l)

W T T 1 R 2

5 1 6 fa s tin g (h o u rs )

W T T 1 R 2

1 2 3 A c eta m in o p h en (µg /m L /m in)

p = 0 .1 4

gastric emptying

13

5 1 5 3 0

1 0 2 0 3 0 T im e (m in ) P la s m a G L P -1 (p M ) W T T 1 R 2

p = 0 .0 1 1 1 5 0 2 2 5 3 0 0 H P V p la s m a G L P -2 (p g /m L ) V e h ic le G lu c o s e W T T 1 R 2

**

W T G L P 2 R

1 0 2 0 3 0 4 0 5 0 F lu x (n m o l.c m

• 2.m in
• 1)

***

Ex vivo Glucose flux

Smith et al, Mol Metab. 2018 unpublished

The GLP2 analogue, teduglutide, restores plasma glucose response during an igGTT in T1R2 mice

1 5 3 0 4 5 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 T im e (m in ) G lu c o s e (m g /d l) W T -V e h W T -T e d T 1 R 2 -V e h T 1 R 2 -T e d 5 1 0 1 5 2 0 2 5 G lu c o s e R a te (m g /d l/m in )

*

W T T 1 R 2 V e h ic le T e d u g lu tid e

glucose

(1g/kg)

Veh or Ted

(0.9µg/g)

IG.GTT

14 Smith et al, Mol Metab. 2018

2 0 4 0 6 0 8 0

1 4C -3 O M G F lu x

(n m o l.c m

• 2.m in
• 1)

*

V e h T e d W T T 1 R 2

3-OMG (+/- Ted)

Current working model

15 Smith et al, Mol Metab. 2018

16

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

pancreas intestine

glucose

insulin

glucose fructose

?

Functional adaptations of intestinal STRs in response to dietary sugars GLP1/2 glucose absorption

? ?

mRNA mRNA

17 Kyriazis GA et al, Endocrinology 2014

Overnight high sucrose diet (HSD) downregulates intestinal STR expression

18

T 1 r2 0 .0 0 .5 1 .0 1 .5 F o ld C h a n g e

D J I

* *

0 .07

T 1 r3

D J I

**** **

*

C O N H S D

W T T 1 r3

*** *** ****

D J I

T 1 R 2 2 0 4 0 6 0 8 0 [U -1 3 C 6 ]-g lu c o s e A U C (0 -3 0 m in ) W T T 1 R 2

* *

C O N H S D

ig.GTT (13C glucose)

2 0 4 0 6 0 8 0 1 0 0 P la sm a G L P -1 A U C (0 -3 0) W T T 1 R 2 C O N H S D

*

GLP-1

100 200 300 400 Ad lib glucose (mg/dL) WT T1R2

** **

CON HSD

Ad lib glucose (7d HSD)

19

Ob/+ Ob/Ob T1R2-Ob/Ob Ob/Ob T1R2-KO X

unpublished

20

5 1 5 3 0 6 0 9 0 1 2 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 T im e (m in ) G lu c o s e (m g /d l)

O b /O b T 1 R 2 -O b /O b

0.0320

p =

*

O b /O b T 1 R 2 -O b /O b 1 0 2 0 3 0 4 0 5 0 G lu c o s e R a te (m g /d L /m in )

**

Deletion of T1R2 decreases glucose excursions during an IG.GTT in Ob/Ob mice

unpublished

3 0 6 0 9 0 1 2 0

2 0 4 0 6 0 8 0

tim e (m in )

F lux (nm o l.cm

• 2.m in
• 1)

T 1 R 2 -O b /O b O b /O b

3 O M G (3 0 m M ) W T T 1 R 2

O b / O b T 1 R 2

• O

b / O b 2 0 4 0 6 0 8 0 1 0 0 F lu x (n m o l.c m

• 2.m in
• 1)

****

Inge Depoortere Gut 2014;63:179-190

Unanswered questions

21

Which type of cell(s) express STR? Where are they located? What are their characteristics? How they regulate gut biology?

22 Funding R21DK110489 R01DK112747 (NIFA-2018-67001-28246) Kyriazis Lab (OSU) Ann Serna, MS Joan Serrano, PhD Amit Rai, PhD (Mehta Lab) Janet Minton, MS Ashley Francois, BS Lydia Dupont Andrea Scofield

Researchers Postdoctoral Associates Graduate Students Undergraduate Volunteers

Kyriazis Lab (SBP) Kathy Smith (Pfizer) Elnaz Karimian Azari (Metagenics) Traci LaMoia (Yale U) Katalin Karolyi (U Penn) Veronika Vargova (Florida Hospital)