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The role of glucagon and GLP-1 in the regulation of appetite. Katherine Simpson , Jennifer Parker, Niamh Martin, Ben Field, James Minnion , Mohammad Ghatei and Steve Bloom Dept. Investigative Medicine Academic Trainees Annual Event 5 th May 2011. Obesity and type 2 diabetes mellitus. - PowerPoint PPT Presentation
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The role of glucagon and GLP-1 in the regulation of appetite.
Katherine Simpson, Jennifer Parker, Niamh Martin, Ben Field, James Minnion, Mohammad Ghatei and Steve Bloom
Dept. Investigative Medicine
Academic Trainees Annual Event5th May 2011
Obesity and type 2 diabetes mellitus
25% of adults in England are obese (BMI>30 kg/m2)
(Health and Social Care Information Centre, 2010)
Type 2 diabetes
• Insulin resistance and high circulating glucagon• GLP-1 analogues: exenatide, liraglutide
GLP-1 and glucagon co-agonism:reduced body weightimproved glucose profilemarginal reduction in food intakeincreased energy expenditure
(Pocai A et al Oct 2009 and Day JW et al Oct 2009)
Gut-brain axis
GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2 COOHNH
Glucagon GLP-1 IP-2IP-1
major proglucagon fragment
PANCREAS
IP-1 GLP-2GLP-1 IP-2
INTESTINE AND BRAIN
glicentin
oxyntomodulin
Proglucagon
PC2 PC1/3
GLP-2GRPP GlucagonGRPP
Pre-proglucagon processing
GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2 COOHNH
Glucagon GLP-1 IP-2IP-1
major proglucagon fragment
PANCREAS
IP-1 GLP-2GLP-1 IP-2
INTESTINE AND BRAIN
glicentin
oxyntomodulin
Proglucagon
PC2 PC1/3
GLP-2GRPP GlucagonGRPP
Pre-proglucagon processing
GRPP Glucagon IP-1 GLP-1 IP-2 GLP-2 COOHNH
Glucagon GLP-1 IP-2IP-1
major proglucagon fragment
PANCREAS
IP-1 GLP-2GLP-1 IP-2
INTESTINE AND BRAIN
glicentin
oxyntomodulin
Proglucagon
PC2 PC1/3
GLP-2GRPP GlucagonGRPP
Pre-proglucagon processing
• Peripherally administered:decreases food intake in animals
• Peripheral effects prevented by:Vagotomy or lesions in the AP and NTS
• Human studies: Peripheral administration decreases meal size
• c-fos peripheral GLP-1: AP, NTS, amygdalaand PVN
Glucagon and GLP-1
Aims: to answer the following questions
(1) What is the effect of co-administration of glucagon and GLP-1 on food intake?
(2) Which CNS areas are responsible for this effect?
Effects of glucagon on food intake
0-30 mins
Saline 3 10 30 100 300 500 7500.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
**
**
****
A
Fo
od
in
take
(g
)
Glucagon nmol/kg
30-90 mins
Saline 3 10 30 100 300 500 7500.00.10.20.30.40.50.60.70.80.91.0
B
Fo
od
in
take
(g
)
Glucagon nmol/kg
Effects of GLP-1 on food intake
0-30 mins
Saline 3 10 30 50 100 300 6000.0
0.1
0.2
0.3
0.4
0.5
0.6
**
******
GLP-1 nmol/kg
Fo
od
in
take
(g
)
A30-90 mins
Saline 3 10 30 50 100 300 6000.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
**
B
Fo
od
in
take
(g
)GLP-1 nmol/kg
‘Subthreshold doses’ of glucagon and GLP-1
0-30 mins
Saline 3 10 30 100 300 500 7500.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
**
**
****
A
Fo
od
in
take
(g
)
Glucagon nmol/kg
0-30 mins
Saline 3 10 30 50 100 300 6000.0
0.1
0.2
0.3
0.4
0.5
0.6
**
******
GLP-1 nmol/kg
Fo
od
in
take
(g
)
A
Co-administration of glucagon and GLP-1
Question 2:
Which CNS areas are responsible for these effects on food intake?
AP NTSNTS
vagal afferents
Brainstem
Hypothalamus
Glucagon 750 nmol/kg s/c
GLP-1 600 nmol/kg s/c
Saline s/c250 uM
250 uM
250 uM
Dose response c-fos activation in the brainstem following glucagon administration
AP
Saline 30 100 300 500 7500
25
50
75
100
125
150
175
*
Glucagon nmol/kg
c-fli
co
un
ts
NTS
Saline 30 100 300 500 7500
100
200
300
400
*
**
Glucagon nmol/kg
c-fli
co
un
ts
0-30 mins
Saline 3 10 30 100 300 500 7500.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
**
**
****
A
Fo
od
in
take
(g
)
Glucagon nmol/kg
Dose response c-fos activation in the brainstem following GLP-1 administration
AP
Saline 3 30 50 100 6000
50
100
150 ***
GLP-1 nmol/kg
c-fli
co
un
ts
NTS
Saline 3 30 50 100 6000
100
200
300
400*
GLP-1 nmol/kg
c-fli
co
un
ts
0-30 mins
Saline 3 10 30 50 100 300 6000.0
0.1
0.2
0.3
0.4
0.5
0.6
**
******
GLP-1 nmol/kg
Fo
od
in
take
(g
)
A
c-fos activation in the brainstem following co-administration of glucagon and GLP-1
Central nuclei of the amygdala
saline GLP-1 GlucagonGLP-1/Glucagon0
100
200
300
400
500 #
**
c-fo
s im
mun
orea
ctiv
ity
• No significant differences in hypothalamus• Central nucleus of amygdala and reward
Summary
Co-administration of glucagon and GLP-1:
– decreases food intake to a greater degree than either peptide alone
– Increases c-fos expression in similar brainstem areas: AP and NTS
Future work
(1)Food intake and CNS pathways:- which neuronal population
(2)Chronic effects of dual receptor agonism:- chronic feeding studies in rodents
(3) Effects in humans: - glucagon/GLP-1 co-infusion and the effect on food intake
(4) Glucose homeostasis:- glucose tolerance tests(5) Energy expenditure:- calorimetry
- BAT mass and UCP-1 mRNA
AcknowledgementsProfessor Steve BloomDr Niamh Martin
Jenny Parker, Klara Hostomska, Jamie PlumerDr James Minnion, Dr Ben Field and Dr Tricia TanProfessor Mohammad Ghatei
Wellcome Trust