Role of cilia in developing hyperinsulinaemia and insulin resistance

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

Patients with type 2 diabetes and obesity have a higher insulin content in the blood than people without those conditions. It is still not clear whether high insulin content is a cause or a result of these diseases. Currently it is known that there are two key elements driving insulin levels up and thus it is important for us to understand; 1. why pancreatic cells are producing/secreting more insulin and what factors control it? and 2. why do muscle and fat cells (the target cells for insulin) not respond to normal levels of insulin? Recent evidence suggests that defects in cilia, a hair like structure protruding from most cells, might be involved in the development of obesity. Our study is designed to understand whether there may be too many insulin producing cells (in the pancreas), or too little response from muscle and fat cells. Once that is known we will then determine the novel molecular and cellular mechanisms of cilia involvement in hyperinsulinaemia (increased level of insulin). Only through understanding the mechanisms of disease and the factors controlling it, can we begin to design therapy or management regimens to combat these increasingly common diseases.

Technical Summary

Obesity and diabetes mellitus are the most common chronic metabolic disorders in the world. In spite of their complex aetiology, hyperinsulinaemia and insulin resistance are key factors in causation of these disorders. Investigation of the molecular and cellular mechanisms of hyperinsulinaemia and insulin resistance are, therefore, crucial for understanding the pathogenesis of obesity and diabetes mellitus. Primary cilia are microtubule-based, hair like organelles protruding from the apical cell membrane and contain a high concentration of receptors and other signalling molecules. New evidence suggest that it might act as a signalling organelle. Our data, as well as the research of others suggest that cilia/basal body/IFT proteins are involved in developing obesity, hyperinsulinaemia, insulin and leptin resistance. Our main objective will be to investigate the mechanism of hyperinsulinaemia in knockout mice with cilia defects (Bbs/IFT80/polaris). We will focus on potential underlying defects in insulin secretion and target cellular responses. We propose several ciliary mechanisms, which might be involved in impaired insulin secretion including Wnt and somatostatin signalling - these will also be investigated. Our final goal will be to identify differentially expressed/localised proteins in deciliated MIN6B1 cells using a proteomic approach.

Publications

10 25 50
 
Title Development of reagents and resources for studying Bardet-Biedl syndrome 
Description We have generated gene modified cells, GPCR libraries, MRI assays, physical exercise protocols, applied RNASeq techniques and Proteomics to the study of Bardet-Biedl syndrome. We have implemented CRISPR gene editing in cells to model disease, established ELISA assays, new Immmunohistochemistry tools, developed FACS sorting methods for studying ciliopathies and new cloning strategies. 
Type Of Material Technology assay or reagent 
Year Produced 2015 
Provided To Others? Yes  
Impact Part of this resource was published in JOVE. 
 
Title Primary cell lines 
Description Primary islet cells from Bbs4 and Bbs6 mice have been created and used in current research. 
Type Of Material Cell line 
Year Produced 2011 
Provided To Others? Yes  
Impact Paper in preparation 
 
Description Adrenal gland analysis in Bbs mice 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We provided mice to Peter King for adrenal analysis
Impact Abnormal zonulation
Start Year 2009
 
Description Analysis of MIN6 cells 
Organisation Global Medical Excellence Cluster (GMEC)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We provided knockdown cells (BBS) to better understadn the role of these proteins in pancreatic function
Impact Research results have not yet been publsihed as they were equivocal.
Start Year 2009
 
Description FTO is required for ciliogenesis 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We have discovered the effects of loss of FTOgene function on development in zerbafish and demonstrated its role in ciliogenesis.
Collaborator Contribution Sharing of reagents and IP
Impact Paper in preparation Multidicsiplinary - including endocrine, developmental biology, genetics
Start Year 2009
 
Description Functional characterisation of FTO 
Organisation University of Cambridge
Department Institute of Metabolic Science (IMS)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have led on a novel understanding of the cellular function of FTO, the gene associated with obesity.
Collaborator Contribution Sharing of reagents
Impact Paper in preparation
Start Year 2010
 
Description Islet cell cilia and secretion 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution We have provided murine pancreata for dynamic studies of insulin secretion and hosted a researcher from the Karolinska Institute
Impact Manuscript in revision
Start Year 2011
 
Description Bardet-Biedl Syndrome UK Annual Family Conference 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Over 200 delegates made up of Bardet-Biedl syndrome patients, their relatives and friends as well as healthcare professionals and scientists, attended the residential weekend. Beales chairs and presents a round of the latest medical and scientific advance relating to Bardet-Biedl syndrome patients. There is always a patient perspective and involved public debate. New and old patients alike value this occasion for its information content and social engagement.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
URL http://www.lmbbs.org
 
Description CILIA2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Discussions and further actions

Patients have organised further meetings in next 2 years
Year(s) Of Engagement Activity 2014
 
Description CILIA2016 Amsterdam 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Organisation and support for the premier international conference of Cilia and disease held biennially. Beales chaired opening scientific session and assisted in patient facing activity and panel debate.
Year(s) Of Engagement Activity 2016
URL http://events.embo.org/16-cilia/
 
Description Patient Support Group Patient Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact 120 families attended the annual support group weekend conference of BBSUK in Northampton where they listened to a programme of talks on patient care and research. Later they participated in workshops providing further interaction with researchers and medical workers.

Patients have been willing to take part in further studies and surveys.
The support scoiety has also received further financial support from bodies such as the lottery to support these PPEs.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
URL http://www.lmbbs.org.uk