The new discoveries of Basic Researchers: bile acids,

oxygen radicals, intestinal glucose metabolism

reprogramming, others?Gilles Mithieux

« Nutrition and Brain » Inserm U855, universityof Lyon, France

CONTROL OF GLYCEMIA

Insulin

glucose

Endogenous Glucose

Production liver Intestinekidney

Glucose-6 phosphatase : the key enzyme of EGP

EVIDENCE for its EXPRESSIONIn the INTESTINAL MUCOSA

Gastroenterology, 1999

PRODUCTION OF GLUCOSE – FASTING

Normal state

15%

80%

5%

Fasting state

20%45%

35%

G6PC

PEPCK

Diabetes, 2001

WHAT’S HAPPENING IN THE DIABETIC STATE ?

CONTROL OF GLYCEMIA - DIABETES

Insulin

glucose

Endogenous Glucose

Production liver Intestinekidney

1) Insulin resistance takes place

0

20

40

60

80

100

0 15 30 45 60

Time (mn)

% b

asal

glu

cose

§ §§

normal

diabetic

Insulin tolerance test

2) This results in glucose intolerance

0

100

200

300

400

0 20 40 60

Time (mn)

% b

asal

glu

cose

** **

normal

diabetic

glucose tolerance test

3) Endogenous glucose production is increased

1) Peripheral glucose utilization is decreased

4) End-point: fasting plasma glucose is increased, when insulin

secretion becomes insufficient to compensate insulin resistance

2) Insulin secretion is increased, partly compensating insulin resistance

A probable sequence of events is:

WHAT ARE THE MODIFICATIONS OBSERVED AFTER OBESITY SURGERY?

especially after bypass procedures…

In morbid obese:

- marked decrease in appetite (hunger sensations)

- modifications of liking for some foods

In diabetic obese:

- dramatic and rapid amelioration of diabetes

The rationale the most often put forward to account for

this amelioration is based on the restoration of postprandial

secretion of incretin hormones (e.g.GLP-1), promoting

a restored secretion of insulin.

Ileum

Duodenum

Esophagus

ProximalJejunum

Stomach

DistalJejunum

Ileum

Esophagus

ProximalJejunum

Stomach

DistalJejunum

banding bypass = EGA

What’s happening in obese diabetic mice (HF-HS diet) ?

restrictive

procedure

malabsorptive

procedure

The differential efficiency of the various gastric

surgeries is an early event

Pair-fed sham band EGA

0

1

2

3

4

-6 -4 -2 0 2 4 6 8 10

Days

Fo

od

in

take

(g

/d)

Surgery

Daily food intake

15

20

25

30

35

40

45

-6 -4 -2 0 2 4 6 8 10

Days

Bo

dy

wei

gh

t (g

)

Surgery

Body weight on pair-feeding

Decreased food intake No malabsorption

EGABand

Time (mn)

Pair-fed sham GLB EGA

0

1

2

3

4

0 40 60

Insu

lin

emia

(n

g/m

L)

$$

A

0

100

200

300

400

0 20 40 60

Time (m n)

% b

asal

glu

cose

*

*

$

$

glucose

tolerance

Insulin

secretion

EGA

EGA

0

5

10

15

20

25

SD HFD Pair-fedsham

GB EGA

GL

P-1

(p

mo

l/l)

T0T40

$#

§

*

GLP-1 plasma levels during OGTT

0

20

40

60

80

100

0 15 30 45 60

Time (mn)

% b

asal

glu

cose § §

§

ITT

Pair-fed sham EGA

There is also a marked increase in insulin sensitivity after bypass

EGA

Which is the function improved in terms of insulin

sensitivity after bypass?

EGP of peripheral glucose utilization?

sham

mg

/kg

/mn

Glucose infusion rate (GIR)Endogenous Glucose Production (EGP)Peripheral glucose utilization (Rd)

0

10

20

30

40

50

60

SD HFD Pair-fed GLB EGA

*

*

*

§

$ $

$

Euglycemic hyperinsulinemic clamps reveals improved suppression of EGP

by insulin, and no effect on glucose utilization

CONTROL OF GLYCEMIA - DIABETES

Insulin

glucose

Endogenous Glucose

Production liver Intestinekidney

0

0.5

1.0

HFD Sham GLB EGA

Segment n°4

G6P

ase

(arb

itra

ry u

nit

s)

*

G6Pase

actin

0

0.5

1.0

HFD Sham GLB EGA

Segment n°4*

actin

PEPCK

PE

PC

K (

arb

itra

ry u

nit

s)

Segment n°1

0

5

10

HFD Sham GLB EGA

G6P

ase

acti

vity

(µ

mo

l/m

in/g

) *

0

5

10

HFD Sham GLB EGA

Segment n°3

G6P

ase

acti

vity

(µ

mo

l/m

in/g

)

*

0

5

10

HFD Sham GLB EGA

Segment n°4

G6P

ase

acti

vity

(µ

mo

l/m

in/g

)

Ileum

Duodenum

Esophagus

Proximal

Jejunum

Stomach

Distal

Jejunum

0

5

10

15

20

25

HFD Pair-fed sham GLB EGA

Mic

rom

ole

/

min

/g

NS

$

NS

*

Hepatic G6Pase activity

PRODUCTION OF GLUCOSE – BYPASS

Before surgery

5%

After bypass

15-20%

45%

35%

15-20%

80%

50%

30%

Early after bypass in mice: there is a dramatic change in

whole body glucose metabolism

- recovery of insulin sensitivity (of EGP)

- recovery of pancreatic function (GLP-1and insulin secretions)

- amelioration of glucose tolerance

- no change in basal EGP, but a new repartition among the 3

gluconeogenic organs, with an increased participation of the gut

Hayes et al, OBES SURG (2011) 21:759–762

Is Intestinal Gluconeogenesis a Key Factor in the Early Changes in Glucose homeostasis following

Gastric Bypass?