The new discoveries of Basic Researchers:
bile acids, oxygen radicals, intestinal
glucose metabolism reprogramming,
others?
Gilles Mithieux
« Nutrition and Brain » Inserm U855, university
of Lyon, France
CONTROL OF GLYCEMIA
Insulin
Endogenous
Glucose
Production
liver
kidney
Intestine
glucose
Glucose-6 phosphatase : the key enzyme of EGP
EVIDENCE for its EXPRESSION
In the INTESTINAL MUCOSA
Gastroenterology, 1999
PRODUCTION OF GLUCOSE – FASTING
G6PC
PEPCK
5%
15%
20%
45%
 80%
Normal state
35%
Fasting state
Diabetes, 2001
WHAT’S HAPPENING IN THE DIABETIC STATE ?
CONTROL OF GLYCEMIA - DIABETES
Insulin
Endogenous
Glucose
Production
liver
kidney
Intestine
glucose
% basal glucose
1) Insulin resistance takes place
100
§
80
§
§
60
diabetic
normal
40
20
0
0
15
30
45
Time (mn)
Insulin tolerance test
60
% basal glucose
2) This results in glucose intolerance
400
**
300
**
diabetic
200
100
normal
0
0
20
40
Time (mn)
glucose tolerance test
60
A probable sequence of events is:
1) Peripheral glucose utilization is decreased
2) Insulin secretion is increased, partly compensating insulin resistance
3) Endogenous glucose production is increased
4) End-point: fasting plasma glucose is increased, when insulin
secretion becomes insufficient to compensate insulin resistance
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.
What’s happening in obese diabetic mice (HF-HS diet) ?
banding
bypass = EGA
Esophagus
Esophagus
restrictive
procedure
Stomach
Stomach
Duodenum
Proximal
Proximal
Jejunum
Jejunum
Distal
Distal
Jejunum
Jejunum
Ileum
Ileum
malabsorptive
procedure
The differential efficiency of the various gastric
surgeries is an early event
Daily food intake
Body weight on pair-feeding
45
3
Surgery
2
Band
EGA
1
Body weight (g)
Food intake (g/d)
4
0
40
35
Surgery
30
25
20
15
-6
-4
-2
0
2
4
6
8
10
-6
-4
-2
Days
0
2
4
6
Days
Pair-fed sham
Decreased food intake
band
EGA
No malabsorption
8
10
A
glucose
tolerance
% basal glucose
400
300
$
200
$
*
100
*
EGA
0
4
0
20
40
60
Insulin
secretion
Insulinemia (ng/mL)
Time(mn)
3
$
$
2
1
0
0
40
60
Time(mn)
Pair-fed sham
GLB
EGA
EGA
GLP-1 plasma levels during OGTT
GLP-1 (pmol/l)
25
*
T0
T40
20
§
15
#
10
$
5
0
SD
HFD
Pair-fed
sham
GB
EGA
There is also a marked increase in insulin sensitivity after bypass
% basal glucose
ITT
100
§
80
§
§
60
EGA
40
20
0
0
15
30
45
60
Time (mn)
Pair-fed sham
EGA
Which is the function improved in terms of insulin
sensitivity after bypass?
EGP of peripheral glucose utilization?
Euglycemic hyperinsulinemic clamps reveals
improved suppression of EGP by insulin, and no
effect on glucose utilization
60
mg/kg/mn
50
40
*
30
*
$
$
$
20
*
10
§
0
SD
HFD
Pair-fed
sham
GLB
EGA
Glucose infusion rate (GIR)
Endogenous Glucose Production (EGP)
Peripheral glucose utilization (Rd)
CONTROL OF GLYCEMIA - DIABETES
Insulin
Endogenous
Glucose
Production
liver
kidney
Intestine
glucose
10
5
10
Segment n°3
G6Pase activity
(µmol/min/g)
Segment n°1
G6Pase activity
(µmol/min/g)
G6Pase activity
(µmol/min/g)
10
*
5
HFD
Sham
GLB
EGA
*
5
0
0
0
Segment n°4
HFD
Sham
GLB
HFD Sham
EGA
GLB
EGA
Esophagus
Proximal
Jejunum
Distal
Jejunum
Ileum
G6Pase
actin
1.0
Segment n°4
*
0.5
0
HFD Sham
GLB
EGA
G6Pase (arbitrary units)
Duodenum
PEPCK
actin
PEPCK (arbitrary units)
Stomach
1.0
Segment n°4
*
0.5
0
HFD
Sham GLB
EGA
Hepatic G6Pase activity
*
$
Micromole / min/g
25
NS
NS
20
15
10
5
0
HFD
Pair-fed sham
GLB
EGA
PRODUCTION OF GLUCOSE – BYPASS
5%
15-20%
30%
45%
35%
50%
15-20%
80%
Before surgery
After bypass
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
Is Intestinal Gluconeogenesis a Key Factor in the Early Changes in
Glucose homeostasis following Gastric Bypass?
Hayes et al, OBES SURG (2011) 21:759–762