Inflammation, glucocorticoids and microvascular disease in the aetiology of cognitive impairment in type 2 diabetes

Lead Research Organisation: University of Edinburgh
Department Name: School of Clinical Sciences

Abstract

People with adult-onset (type 2) diabetes are at increased risk of developing problems with certain functions of the brain, including memory, attentional and problem-solving abilities. These difficulties can significantly impair the ability of a person to carry out routine daily tasks and can have substantial impact on employment and the lives of family and friends. At its severest level, dementia can develop. The prevalence of type 2 diabetes is set to rise dramatically in the years ahead. Therefore, diabetes-related memory impairment could have substantial future social and economic implications.

The cause of these brain function abnormalities is not understood. A range of risk factors, including damage to small blood vessels, inflammation and/or hormonal imbalances can occur in the brains of people with diabetes and it is proposed that this may be a cause of diabetes-related memory impairment.

We plan to test the brain function of 1000 people with type 2 diabetes. At the same time we will take photographs of the back of subjects eyes to determine whether or not there is small vessel disease and measure other potential risk factors for memory impairment in a blood sample. By comparing the brain function of people with and without risk factors, important information about the cause of diabetes-related memory problems will be obtained.

Traditionally, memory problems in elderly people have been regarded as irreversible, but with a better understanding of the causes of brain function abnormalities in type 2 diabetes, it should be possible to start to develop strategies to prevent, reverse or ameliorate the problem.

Technical Summary

People with type 2 diabetes are at increased risk of cognitive impairment and dementia. This is of major concern given the predicted future increase in the prevalence of type 2 diabetes. However, the aetiology of cognitive impairment in people with diabetes is unknown. There are strong theoretical grounds, supported by experimental animal data and observational studies in humans, to suggest that microvascular disease, inflammation and/or dysregulation of the HPA axis are likely to explain a significant proportion of the variation in cognitive function in people with type 2 diabetes and an examination of these potential associations forms the basis of the proposed study. A range of cognitive tests, assessing the major domains of mental function, will be administered to one thousand patients with established type 2 diabetes aged over 60 years, at baseline and again after 4 years. The association between cognitive decline and baseline risk factors will be determined and the independence of any relationship with respect to macrovascular disease (and other risk factors) will be assessed. The cohort will also provide the basis for future cerebral neuroimaging and dynamic HPA axis studies. Traditionally, cognitive decrements in elderly people have been regarded as irreversible, but with a better understanding of the aetiology of cognitive impairment in type 2 diabetes, it should be possible to start to develop preventive and/or therapeutic strategies.

Publications

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Aung PP (2012) Severe hypoglycaemia and late-life cognitive ability in older people with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study. in Diabetic medicine : a journal of the British Diabetic Association

 
Description British Heart Foundation
Amount £90,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2015
 
Description British Heart Foundation
Amount £41,556 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2016
 
Description CSO Programme Support Grant
Amount £23,000 (GBP)
Organisation Chief Scientist Office 
Sector Public
Country United Kingdom
Start 09/2006 
End 08/2007
 
Description Centre Cognitive Aging and Cognitiove Epidemiology, University Edinburgh (PhD Studentship to A. Suliman)
Amount £40,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2015 
End 08/2018
 
Description Diabetes UK
Amount £350,000 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2014
 
Description Diabetes UK (PhD studentship)
Amount £71,656 (GBP)
Funding ID 15/0005353 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Pfizer plc
Amount £347,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 03/2007 
End 02/2011
 
Description PhD Studentship (College of Medicine, University of Edinburgh) - A Price
Amount £40,000 (GBP)
Organisation University of Edinburgh 
Department College of Medicine & Veterinary Medicine
Sector Academic/University
Country United Kingdom
Start 12/2013 
End 11/2016
 
Description PhD Studentship (ESRC allocation to CPHS, University of Edinburgh) - C Robertson
Amount £40,000 (GBP)
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description PhD Studentship (ESRC allocation to CPHS, University of Edinburgh) - I Feinkohl
Amount £40,000 (GBP)
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description PhD Studentship (ESRC allocation to CPHS, University of Edinburgh) - M Keller
Amount £40,000 (GBP)
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description PhD Studentship (MRC allocation to CPHS, University of Edinburgh) - R Marioni
Amount £40,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description PhD Studentship (Mexican Council of Science and Technology (CONACyT) allocation to CPHS, University of Edinburgh) - E Sandoval Garcia
Amount £40,000 (GBP)
Organisation National Council on Science and Technology (CONACYT) 
Sector Public
Country Mexico
Start 04/2014 
End 03/2017
 
Description PhD Studentship, College of Medicine, University of Edinburgh - J Ding
Amount £40,000 (GBP)
Organisation Government of Scotland 
Department Scottish Funding Council
Sector Public
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description Project Grant
Amount £1,000,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2015
 
Title ET2DS database, DNA and plasma banks 
Description Extensive database created for analysis of association between risk factors and complications of type 2 diabetes. High quality DNA, plasma and urine banks created for measurement of additional risk factors. 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact see list of collaborations 
 
Description Apolipoproteins, TFTs and steroid sex hormones as predictors of CVD in type 2 diabetes 
Organisation University of Edinburgh
Department Department of Clinical Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Research led by ET2DS team
Collaborator Contribution Measurement of triglycerides, apolipoproteins, free fatty acids, thyroid function tests and testosterone on ET2DS cohort
Impact Provision of biomarker data on ET2DS cohort over-and-above that funded by original MRC grant. Data analysed as part of successful Masters student project. Data incorporated into publications.
Start Year 2009
 
Description CORNET consortium 
Organisation University of Edinburgh
Department Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of data and materials from ET2DS to this multi-study collaboration on genetic variants influencing plasma cortisol (replication cohort), expertise in interpretation of findings.
Collaborator Contribution Co-ordination of collaboration and data analysis
Impact Formal agreement to act as replication cohort included in successful grant application to CSO. Genotyping undertaken on ET2DS samples. Paper published.
Start Year 2009
 
Description Carotid phenotypes collaboration 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of data and expertise on genetic and non-genetic risk factors potentially affecting carotid intima media thickness and plaque
Collaborator Contribution Co-ordination of multi-centre collaboration and primary data analysis
Impact Establishment of dataset across multiple studies in advance of data analysis. Now incorporated into other collaboration (UCLEB)
Start Year 2011
 
Description Dimethylarginines and CVD 
Organisation University Medical Center Hamburg-Eppendorf
Country Germany 
Sector Hospitals 
PI Contribution Co-lead for collaboration. Provision of samples, data and expertise in interpretation of findings
Collaborator Contribution Measurement of plasma dimethylarginines in ET2DS cohort and expertise in interpretation of findings
Impact Paper published
Start Year 2009
 
Description Fibrinolysis and CVD/Leeds University 
Organisation University of Leeds
Department Leeds Institute of Genetics, Health and Therapeutics (LIGHT)
Country United Kingdom 
Sector Academic/University 
PI Contribution Co-lead for collaboration. Provision of samples, data and epidemiological expertise in analysis and interpretation of findings
Collaborator Contribution Measurements of parameters of clotting and fibrinolysis, data analysis, clinical/biochemical expertise in interpretation of findings
Impact Papers published.
Start Year 2008
 
Description Interleukin 6 receptor as a potential target for CHD prevention: evaluation using Mendelian randomisation 
Organisation London School of Hygiene and Tropical Medicine (LSHTM)
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of DNA samples for genotyping, provision of phenotypic data and expertise in interpretation of findings for this multi-centre study
Collaborator Contribution Key single nucleotide polymorphisms in the IL-6 receptor gene were measured by our collaborators for the purposes of this project. We are now investigating the role of these SNPs in cognitive impairment as part of our own research, without the need for de novo genotyping.
Impact Paper published in Lancet (Lancet 2012;379:1214-24)
Start Year 2010
 
Description Interleukin 6 receptor as a potential target for CHD prevention: evaluation using Mendelian randomisation 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of DNA samples for genotyping, provision of phenotypic data and expertise in interpretation of findings for this multi-centre study
Collaborator Contribution Key single nucleotide polymorphisms in the IL-6 receptor gene were measured by our collaborators for the purposes of this project. We are now investigating the role of these SNPs in cognitive impairment as part of our own research, without the need for de novo genotyping.
Impact Paper published in Lancet (Lancet 2012;379:1214-24)
Start Year 2010
 
Description Leptin, pro-BNP and troponin/Glasgow University 
Organisation University of Glasgow
Department Institute of Cardiovascular and Medical Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Research led jointly with collaborator. Provision of cohort data and samples, expertise in epidemiology, cognition, diabetes and vascular disease
Collaborator Contribution Measurement of plasma leptin, N-terminal pro b-type natriuretic peptide and troponin in ET2DS participants and expertise in interpretation of findings
Impact Paper published (PLOS One 2012;7:e44569). Further paper published 2014. PhD student registered to work on project, results included in successful thesis submission. Further paper published 2017 (Atherosclerosis).
Start Year 2009
 
Description Liver fibrosis/University of Nottingham 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Research led by ET2DS team
Collaborator Contribution Expertise in the measurement of liver fibrosis and development of key research questions addressed in the 4 year follow-up phase of the ET2DS
Impact Successful clinical research fellowship with Diabetes UK (2011 to 2014) - this collaborator was co-supervisor for Research Fellow's PhD. Four papers published.
Start Year 2009
 
Description MRS validation of US for heapatosteatosis 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Study led by ET2DS team
Collaborator Contribution Funding provided to undertake magnetic resonance spectroscopy on a subset of ET2DS cohort and validate findings of US for heapatosteatosis grading
Impact Paper published (Williamson et al . Clinical radiology 2011;66:434-9) Provided validation of research technique used in subsequent analyses.
Start Year 2007
 
Description Metabochip carotid phenotypes multi-centre collaboration 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of data and summary statistics for meta-analysis, epidemiological expertise
Collaborator Contribution Co-ordination of collaboration, expertise in measurement of key phenotype, data meta-analysis
Impact Paper submitted to Nature Genetics, December 2017 - Genome-wide association study of carotid intima-media thickness and plaque identifies novel loci for atherosclerosis and cardiovascular outcomes, and downstream regulatory effects in vascular tissue.
Start Year 2011
 
Description Metabolomics 
Organisation University of Oulu
Department Institute of Clinical Medicine
Country Finland 
Sector Academic/University 
PI Contribution Lead in collaboration, provision of samples from ET2DS for metabolomic analysis, analysis and expertise in interpretation of findings
Collaborator Contribution Expertise in metabolomic measurements and analysis on samples from ET2DS
Impact J Price is co-investigator on BHF grant for further funding for metabolomics work on ET2DS as part of UCLEB consortium. PhD student recently completed work on this project within ET2DS, including results in successful thesis submission.
Start Year 2012
 
Description NAFLD/Pfizer 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution ET2DS study team led this study with financial input from Pfizer.
Collaborator Contribution Financial support for phase two of ET2DS, involving assessment of hepatosteatosis. Support provided by Pfizer for clinical research fellow, ultrasonographer, equipment and consumables.
Impact papers published (including Williamson et al Diabetes care 2011;34:1139-44) (Williamson et al QJM 2012;105:425). Provided baseline data for prospective study on progressive liver disease in people with type 2 diabetes (further funding now obtained from Diabetes UK via clinical research fellowship). Led to further collaborations with academic hepatologists and Echosens.
Start Year 2007
 
Description Peviva collaboration - CK18 as a marker of steatohepatitis 
Organisation Peviva AB
Country Sweden 
Sector Private 
PI Contribution Lead for collaboration. Expertise in epidemiology and use of own dataset/phenotypic data. Provision of samples for biomarker measurement.
Collaborator Contribution Measurement of CK18, a marker of hepatosteatosis, on stored plasma samples from ET2DS
Impact Measurement of CK18 on stored plasma samples. Two papers published.
Start Year 2010
 
Description Pulse wave analysis/velocity 
Organisation University of Edinburgh
Department Centre for Cardiovascular Science
Country United Kingdom 
Sector Academic/University 
PI Contribution Research led by ET2DS team
Collaborator Contribution Expertise and provision of equipment for measurement of pulse wave velocity/analysis in the ET2DS cohort.
Impact Paper published (WL Teoh et al. Metabolic parameters associated with arterial stiffness in older adults with Type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Journal of Hypertension)
Start Year 2007
 
Description Renal disease in ET2DS 
Organisation University of Edinburgh
Department Renal Medicine Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Work led jointly with collaborator
Collaborator Contribution Measurement of urinary biomarkers to be assessed as predictors of diabetic nephropathy and expertise in renal medicine
Impact Measurement of renal tubular biomarkers in stored urine samples from baseline phase of ET2DS. Paper published in Kidney International (2012), further papers published 2014 and 2016, MD student registered to work on project. Further PhD student recruited to work on project (as part of MRC funded UoE Precision Medicine Doctoral training programme), 2019.
Start Year 2011
 
Description Transient elastography for liver fibrosis 
Organisation Echosens
Country France 
Sector Private 
PI Contribution Research led by ET2DS team
Collaborator Contribution Provision of Echosens 'Fibroscan' machine and training for ultrasonographer for 4-year follow-up phase of study to enable measurement of liver fibrosis, at no cost to project
Impact Contribution to successful clinical research fellowship with Diabetes UK. Measurement of liver stiffness in large cohort, making major contribution to liver phenotyping in ET2DS database. Paper published.
Start Year 2009
 
Description UCLEB consortium 
Organisation University College London
Department Institute of Epidemiology and Health Care
Country United Kingdom 
Sector Academic/University 
PI Contribution ET2DS is one of the major cohorts participating in UCLEB (University College London Edinburgh Bristol consortium of major UK prospective population-based studies: applied and translational genomics).
Collaborator Contribution Collaborative analyses of large datasets undertaken as part of consortium of prospective UK-based studies (including ET2DS)
Impact Collaboration has resulted in successful grant applications to BHF (Approx £1M over 5 years from Jan 2011 and approx. £900K over 3 years from Jan 2014) to fund this consortium. Collaboration has resulted in funding for high density genotyping (both 'metabochip' and, in 2016, a high density drug target array) in the ET2DS, as well as metabolomics measurements and data analysis. Genotyping has now been completed and analysis is well underway, with papers published and more being drafted. Further grant renewal application is planned for 2019. Data manager employed in Edinburgh as part of this collaboration is currently submitting intermediate research fellowship application to BHF.
Start Year 2008
 
Description Media release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Media release produced to co-incide with presentation of results (links between retinopathy and cognition) at Diabetes UK annual conference

Dissemination on websites for general public and people with type 2 diabetes
Year(s) Of Engagement Activity 2010
 
Description Media release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Media release via Diabetes UK to co-incide with presentation (links between hypoglycaemia and cognitive impairment) at their Annual Professional Conference.

Publications in media, including BBC news, and interest from members of public in on-going research
Year(s) Of Engagement Activity 2009
 
Description Media release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Media release prepared on research relating to links between stress and memory

Articles published in national press, including national newspaper and BBC news
Year(s) Of Engagement Activity 2010
 
Description Presentation to Diabetes UK Patient Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact This was a presentation on the research being performed in the Edinburgh Type 2 Diabetes Study to the annual meeting of the Edinburgh Branch of Diabetes UK. There were over 50 people with diabetes in the audience; there was considerable interest in the study and numerous questions afterwards.

Increased knowledge of the risks of cognitive impairment and hypoglycaemia in the target patient group.
Year(s) Of Engagement Activity 2009
 
Description Presentation to local members of Diabetes UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact This was a presentation on the research into liver disease being performed in the Edinburgh Type 2 Diabetes Study. There were over 50 people with diabetes in the audience; there was considerable interest in the study and numerous questions afterwards.

Increased awareness of non alcoholic fatty liver disease as a complication of type 2 diabetes
Year(s) Of Engagement Activity 2012