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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.

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the role of glucagon and glp 1 in the regulation of appetite

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

5th May 2011

obesity and type 2 diabetes mellitus
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
Type 2 diabetes
  • Insulin resistance and high circulating glucagon
  • GLP-1 analogues: exenatide, liraglutide

GLP-1 and glucagon co-agonism:

reduced body weight

improved glucose profile

marginal reduction in food intake

increased energy expenditure

(Pocai A et al Oct 2009 and Day JW et al Oct 2009)

glucagon and glp 1
Glucagon and GLP-1
  • 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
aims to answer the following questions
Aims: to answer the following questions
  • What is the effect of co-administration of glucagon and GLP-1 on food intake?

(2) Which CNS areas are responsible for this effect?

co administration of glucagon and glp 1
Co-administration of glucagon and GLP-1

Saline

GLP-1

Glucagon

combined

slide14

Question 2:

Which CNS areas are responsible for these effects on food intake?

slide15

Hypothalamus

Brainstem

AP

NTS

NTS

vagal afferents

slide16

250 uM

Saline s/c

Glucagon 750 nmol/kg s/c

250 uM

GLP-1 600 nmol/kg s/c

250 uM

c fos activation in the brainstem following co administration of glucagon and glp 1
c-fos activation in the brainstem following co-administration of glucagon and GLP-1
slide20

No significant differences in hypothalamus

  • Central nucleus of amygdala and reward
summary
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
Future work
  • 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

slide23

(4) Glucose homeostasis:

- glucose tolerance tests

(5) Energy expenditure:

- calorimetry

- BAT mass and UCP-1 mRNA

acknowledgements
Acknowledgements

Professor Steve Bloom

Dr Niamh Martin

Jenny Parker, Klara Hostomska, Jamie Plumer

Dr James Minnion, Dr Ben Field and Dr Tricia Tan

Professor Mohammad Ghatei

Wellcome Trust