The mechanisms of beta cell regeneration

Lead Research Organisation: University College London
Department Name: Medicine

Abstract

Type 2 diabetes is caused by insulin resistance and failure of the pancreatic beta cells to produce enough insulin. Recent evidence from studies in humans with type 2 diabetes suggests that one of the problems in beta cells is a reduced ability to increase in number and survive. We have recently shown that loss of the gene for insulin receptor substrate 2 in beta cells reduces their number. However, if beta cells escape this process they are able to repopulate the islet and overcome diabetes. I will characterize these cells that repopulate the islet and also the growth factor pathways that are involved in this process. These studies will help to identify ways of treating beta cell failure including producing enough beta cells for transplant treatments.

Technical Summary

Type 2 diabetes is the commonest endocrine disease world-wide. In humans and rodents it is usually characterised by failure of the pancreatic beta cell response to insulin resistance. A critical role for the signalling molecule insulin receptor substrate (Irs) 2 in beta cell compensation has been demonstrated using RIPCreIrs2KO mice with beta cell-specific deletion of this molecule. These studies show that beta cell repopulation of the islet in situations of beta cell failure is dependent on Irs2 and have potentially identified cells that repopulate the islet. Humans with type 2 diabetes have reduced Irs2 expression in their islets suggesting that similar processes may underlie beta cell failure in both mice and humans.
The overall aim of this project, using a combination of mouse genetics, morphological and cell purification techniques, will be to characterise the mechanisms by which Irs2 mediates beta cell compensation by identifying and characterising the precise pancreatic cell types in which Irs2 is required for beta cell regeneration. This will be achieved via the following objectives:
1. Generation and characterisation mice lacking Irs2 in cells expressing PDX or NGN3 beta cell precursor transcription factors.
2. Characterisation in pancreatic sections the cells that escape deletion in the islets of RIPCreIrs2KO mice.
3. Purification, culture and characterisation of cells escaping recombination and regenerating the islets in RIPCreIrs2KO mice.
Objective 1 will use existing genetically modified mouse models to delete Irs2 in PDX and NGN3 expressing cells. Glucose homeostasis and islet function will be studied. Objective 2 will study RIPCreIrs2KO mice in which beta cell mass is lost, but as cells which escape Irs2 deletion repopulate the islets, beta cell mass and normal glucose homeostasis are restored. I will further define this population by employing immunocytochemistry and in situ hybridisation to look for progenitor and endocrine markers. For Objective 3, I will use cell purification and culture techniques to attempt to isolate the cells repopulating the islets. Objectives 2 and 3 will be facilitated by the use of a mouse that permits graded inducible beta cell loss a manoeuvre that potentiates islet repopulation.
Understanding the cell types and signalling pathways that are required for the maintenance of beta cell mass will give insights into the pathogenesis of type 2 diabetes. Furthermore the findings will suggest potential therapeutic strategies not only for the treatment of this condition but also for the ex vivo expansion of beta cells for use in transplant therapy.
 
Description Metabolic hormones in Bariatric surgery 
Organisation University College London
Department Institute of Epidemiology and Health Care
Country United Kingdom 
Sector Academic/University 
PI Contribution I conducted a study to assess endocrine profiles before and after bariatric surgery
Collaborator Contribution I was able to complete this study and a publication of this study is imminent. This study also contributed to my thesisThis enabled me to study patients undergoing bariatric surgery. This study will also contribute to my thesis.
Impact International congress of obesity, Stockholm, July 2010 Appetite suppression, weight loss and PYY profiles are comparable following laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass. Julian Emmanuel, Megan E Drew, Efthimia Karra, Ahmed Yousseif, Alice Gazet, Nicola Cooper, Mohamed Elkallay, Majid Hashemi, Marco Adamo, Alberic Fiennes, Nicholas Finer, Dominic Withers and Rachel L Batterham, University College London, University College London Hospital Poster and presentation: University College London, University College London Hospital Symposium on Cardiovascular and Metabolic Sciences: Processes, disease prevention and therapeutic strategies' Appetite suppression, weight loss and PYY profiles are comparable following laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass. Julian Emmanuel, Megan E Drew, Efthimia Karra, Ahmed Yousseif, Alice Gazet, Nicola Cooper, Mohamed Elkallay, Majid Hashemi, Marco Adamo, Alberic Fiennes, Nicholas Finer, Dominic Withers and Rachel L Batterham
Start Year 2008
 
Description Metabolic hormones in Bariatric surgery 
Organisation University College London Hospital
Country United Kingdom 
Sector Public 
PI Contribution I conducted a study to assess endocrine profiles before and after bariatric surgery
Collaborator Contribution I was able to complete this study and a publication of this study is imminent. This study also contributed to my thesisThis enabled me to study patients undergoing bariatric surgery. This study will also contribute to my thesis.
Impact International congress of obesity, Stockholm, July 2010 Appetite suppression, weight loss and PYY profiles are comparable following laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass. Julian Emmanuel, Megan E Drew, Efthimia Karra, Ahmed Yousseif, Alice Gazet, Nicola Cooper, Mohamed Elkallay, Majid Hashemi, Marco Adamo, Alberic Fiennes, Nicholas Finer, Dominic Withers and Rachel L Batterham, University College London, University College London Hospital Poster and presentation: University College London, University College London Hospital Symposium on Cardiovascular and Metabolic Sciences: Processes, disease prevention and therapeutic strategies' Appetite suppression, weight loss and PYY profiles are comparable following laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass. Julian Emmanuel, Megan E Drew, Efthimia Karra, Ahmed Yousseif, Alice Gazet, Nicola Cooper, Mohamed Elkallay, Majid Hashemi, Marco Adamo, Alberic Fiennes, Nicholas Finer, Dominic Withers and Rachel L Batterham
Start Year 2008
 
Description Metabolic state does influence human decision making 
Organisation University College London
Department Division of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I conducted the metabolic aspects of both studies.
Collaborator Contribution A collaborative study into metabolic influences on human decision making.Study into the role of gut hormones in bariatric surgery.
Impact 19233179 Abstracts and Posters: Weight control: the right prescription Marianne T. Neary, Efthimia Karra, Megan E. Drew, Ahmed Yousseif, Julian Emmanuel and Rachel L. Batterham "The days of molecular medicine, human genetics, stem cells and physiology: The future of individualised medicine". Harvard medical school, Boston, USA, May 2009. Metabolic state influences risk preference in economic decisions M Symmonds1, JJ Emmanuel2, ME Drew2, RL Batterham2, RJ Dolan1 1. Institute of Neurology, University College London 2. Department of Metabolism, University College London. Satellite symposium of the society for neuroscience annual meeting 2009. FTO variant rs9936609 is associated with heightened reward sensitivity and restrained eating behaviour. Marianne T. Neary, Efthimia Karra, Megan E. Drew, Julian Emmanuel, Ahmed Yousseif and Rachel L. Batterham. Keystone Symposia; *Neuronal Control of Appetite.* 24-29 January 2010, Colorado, U.S.A. Annual American endocrine society meeting, Sandiego, June 2010 Gamble on a full stomach: monetary risk-taking is altered by metabolic state in normal-weight human male subjects. Julian Emmanuel1, Mkael Symmonds2, Megan E Drew1, Efthimia Karra1, RJ Dolan2, Dominic J Withers1 and Rachel L Batterham1. 1-Centre for Obesity Research, Department of Medicine, University College London, London, WC1E 6JJ, 2- Wellcome Trust Centre for Neuroimaging, University College London, London, WC1N 3BG
Start Year 2007
 
Description Metabolic state does influence human decision making 
Organisation Wellcome Trust
Department Wellcome Trust Cente for Neuroimaging
Country United Kingdom 
Sector Academic/University 
PI Contribution I conducted the metabolic aspects of both studies.
Collaborator Contribution A collaborative study into metabolic influences on human decision making.Study into the role of gut hormones in bariatric surgery.
Impact 19233179 Abstracts and Posters: Weight control: the right prescription Marianne T. Neary, Efthimia Karra, Megan E. Drew, Ahmed Yousseif, Julian Emmanuel and Rachel L. Batterham "The days of molecular medicine, human genetics, stem cells and physiology: The future of individualised medicine". Harvard medical school, Boston, USA, May 2009. Metabolic state influences risk preference in economic decisions M Symmonds1, JJ Emmanuel2, ME Drew2, RL Batterham2, RJ Dolan1 1. Institute of Neurology, University College London 2. Department of Metabolism, University College London. Satellite symposium of the society for neuroscience annual meeting 2009. FTO variant rs9936609 is associated with heightened reward sensitivity and restrained eating behaviour. Marianne T. Neary, Efthimia Karra, Megan E. Drew, Julian Emmanuel, Ahmed Yousseif and Rachel L. Batterham. Keystone Symposia; *Neuronal Control of Appetite.* 24-29 January 2010, Colorado, U.S.A. Annual American endocrine society meeting, Sandiego, June 2010 Gamble on a full stomach: monetary risk-taking is altered by metabolic state in normal-weight human male subjects. Julian Emmanuel1, Mkael Symmonds2, Megan E Drew1, Efthimia Karra1, RJ Dolan2, Dominic J Withers1 and Rachel L Batterham1. 1-Centre for Obesity Research, Department of Medicine, University College London, London, WC1E 6JJ, 2- Wellcome Trust Centre for Neuroimaging, University College London, London, WC1N 3BG
Start Year 2007
 
Description American Endocrine Society conference-abstract: Metabolic State Alters Economic Decision Making under Risk in Humans. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact My abstract and poster at this conference led to stimulating discussions with several healthcare professionals.

A reporter from the Chronicle of Higher Education came across the abstract: " Metabolic State Alters Economic Decision Making under Risk in Humans." and wanted to write a comment about my abstract.
Year(s) Of Engagement Activity 2010
 
Description European congress of obesity- abstract and poster 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Several delegates attended the poster presentation

A collaboration with psychologist
Year(s) Of Engagement Activity 2013
 
Description International congress on Obesity- abstract: 'Laparoscopic sleeve gastrectomy causes equivalent appetite suppression, weight-loss and PYY profiles to Roux-en-Y gastric bypass 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact My abstract and poster led to several discussions with other healthcare professionals and other researchers in my field.

I was able to inform other healthcare professionals about the positive changes in endocrine profiles after bariatric surgery.
Year(s) Of Engagement Activity 2010