Targeting therapy to molecular mechanism of disease in obesity and related metabolic disorders

Lead Research Organisation: University of Cambridge
Department Name: Biochemistry

Abstract

Obesity and its complications such as diabetes are major and growing public health problems. We have been investigating genetic factors involved in human obesity and a condition called insulin resistance which leads to diabetes, by focusing on patients with severe forms of these diseases from an early age. We have found defects in several genes that cause these diseases. In one disease, called congenital leptin deficiency, we have been able to show the dramatically beneficial effects of leptin therapy. We now want to study the effects of different diets and drug treatments including leptin in additional patient groups. Defining treatment responses in patients with a known genetic condition that effects a key system in the body will help us to understand and treat these patients but also guide our approach to the more common forms of these important diseases.

Technical Summary

Despite the fact that obesity and type 2 diabetes are among the most common chronic diseases, the range of therapeutic options available for the treatment of these disorders is very limited and the therapeutic responses to such interventions are highly variable. This is likely to reflect, at least in part, the underlying heterogeneity of these disorders with multiple pathophysiological routes leading to the end points of increased adipose mass or hyperglycaemia respectively. Over the past decade or more we have been attempting to unravel the aetiological complexity of these disorders. By focusing on subjects with extreme phenotypes of obesity or insulin resistance we have discovered several previously unknown monogenic/digenic disorders leading to these conditions. These include disorders of the leptin-melanocortin signalling pathways leading to obesity and defects in insulin signalling molecules and PPARgamma leading to extreme insulin resistance.

We now propose to undertake interventional studies in patients with genetically defined syndromes of severe obesity and insulin resistance. These will allow the efficacy of commonly used interventions to be tested in patients with a specific defect in a particular physiological pathway. We will perform a range of detailed metabolic measurements in well-defined subgroups of patients and controls before and in response to dietary and pharmacological manipulations. These mechanistic studies in humans will provide novel information about the requirement for the intactness of specific pathways in the mediation of a therapeutic effect. These interventions will provide novel information about the mechanism of drug action in humans and may pave the way for better targeting of therapy in commoner forms of diabetes and obesity.

Publications

10 25 50
 
Description Biomedical Research Centre
Amount £6,493,079 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description Wellcome Investigator Award
Amount £1,601,565 (GBP)
Funding ID 210755/Z/18/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2018 
End 07/2023
 
Description amylin corp 
Organisation Amylin Pharmaceuticals
Country United States 
Sector Private 
PI Contribution identification of suitable patients
Collaborator Contribution provision of recombinant leptin for human use
Impact clinical benefits for patients. to be reported
 
Description Genetic causes of obesity 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact Berzelius symposium, Umea

improved knowledge of health professionals regarding advances in obesity
Year(s) Of Engagement Activity 2008
 
Description Human obesity & insulin resistance: lessons from the extremes 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact presentation as the Wilkins Visiting Professor for Evan Days

improved knowledge of health professionals regarding advances in obesity
Year(s) Of Engagement Activity 2008
 
Description SOR Academy of Medical Sciences 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
 
Description SOR BBC TV and Radio Interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Raise awareness of research and IMS to the public

None
Year(s) Of Engagement Activity 2013
 
Description SOR CSaP 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Member of Centre for Science & Policy Executive Committee, University of Cambridge

None
Year(s) Of Engagement Activity 2013,2014
 
Description SOR Irish Medical News feature 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
URL http://www.imn.ie/index.php?option=com_content&view=article&id=5418:arise-sir-orahilly&catid=57:clin...
 
Description SOR JCI Interview-Conversations with Giants in Medicine 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
URL http://www.jci.org/videos/cgms
 
Description SOR Lancet article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS

None
Year(s) Of Engagement Activity 2013
URL http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673613616220.pdf
 
Description SOR MRC Centenary Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Raised awareness of research and IMS among public

None
Year(s) Of Engagement Activity 2013
 
Description SOR Naked Scientist Question of the Week 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS to public

None
Year(s) Of Engagement Activity 2013
URL http://www.thenakedscientists.com/HTML/podcasts/qotw/show/20130307/
 
Description SOR RTE interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Raised awareness of research and IMS to the public

None
Year(s) Of Engagement Activity 2013
 
Description SOR Research Lecture Karolinska Institute, Stockholm 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Raised awareness of research and IMS among peers

None
Year(s) Of Engagement Activity 2013
 
Description SOR SAC Conway 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Scientific Advisory Board

None
Year(s) Of Engagement Activity 2013
 
Description SOR SAC Crick Institute 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Scientific Advisory Board

None
Year(s) Of Engagement Activity 2013
 
Description SOR SAC Fondation Leducq 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Scientific Advisory Committee

None
Year(s) Of Engagement Activity 2013,2014
 
Description SOR, Galway Diabetes Research Centre 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact http://www.conference.ie/Conferences/menu.asp?menu=1088&Conference=190

raised awareness of research are and IMS among peers
Year(s) Of Engagement Activity 2012