Adopt - A - Project updates
- 25 January 2017
- Diabetes News
The following updates are on research projects which the group has been able to support through the generosity of its helpers and supporters.
Banking on retinopathy research
Dr Marcus Fruttiger of University College London
Project grant: Advanced histopathology for diabetic retinopathy
Funding needed: £171,732
January 2014 – January 2019
In brief: Dr Marcus Fruttiger and his team will collect and study eyes donated by people with diabetic retinopathy after their death. This will help to improve our understanding of what leads to retinopathy and lay the foundation for a retinopathy tissue bank that will, in the long run, become a valuable resource for research in this area.
Background to research: Diabetes-related retinopathy is a complication of long-term diabetes and the leading cause of blindness amongst people of working age. The treatment options for retinopathy are limited because we don’t fully understand how the condition develops. It’s assumed that, over time, high blood glucose levels damage the blood vessels in the retina (the light-sensitive area at the back of the eye). However, we need further research to help us understand the effects of diabetes on other parts of the retina.
Studies in animals (like mice) help us to understand the biology of retinopathy quickly and easily, but they don’t give the complete picture of how this condition develops in humans. Dr Fruttiger and his colleagues have recently developed ways to study retinopathy in eyes donated by people with retinopathy after their death. This approach could really help to bridge the gaps in our knowledge, but will require a large collection.
Research aims: Dr Fruttiger and his team will develop and begin to study a ‘tissue bank’ of eyes donated by people with diabetes-related retinopathy after their death.
They will take high-resolution images of cells taken from the donated retinas with medical information collected before the donors had passed away. This way, the team can study the impact of retinopathy on a range of different types of cell and learn more about the development of this condition.
Potential benefit for people with diabetes: This project will help to improve our understanding of how diabetes-related retinopathy develops, which is essential for the production of future retinopathy treatments for people with diabetes. It will also lay the foundation for a retinopathy tissue bank that will, in the long run, become a valuable resource for research in this area.
Summary of progress: In the first year of their study, Dr Fruttiger and his team have made good progress in setting up the project. The team have started to build up the tissue collection of eyes from donors who had diabetes-related retinopathy. So far they have collected tissue from 25 donors and this number will increase over the coming year.
Analysis of some of this tissue has already provided some interesting insights. Specifically, the researchers have found that the blood vessels die in areas of the eye where blood stops flowing to parts of the retina; but the outside sleeve of the blood vessel remains intact. The researchers are currently preparing an article for publication in academic journal to highlight their findings and will also present their findings at a major eye research conference later this year.
The team have now collected eyes from 30 people with diabetes and 10 people without diabetes, and they’re in the process of analysing and comparing the tissue. They believe that this will take just under one year to complete and they will then write up their findings for a scientific paper.
They have also analysed eye tissue from a donor with diabetes-related macula oedema (where blood vessels leak fluid into the eye and vision becomes blurry). They have made some interesting observations in terms of the molecules that are involved in making blood vessels ‘leaky’ and controlling fluid levels. They’re currently writing up these findings and will present them at the European Association for the Study of Diabetes Complications meeting in June 2016.
Unfortunately, the researcher employed to carry out this work has resigned due to a promising career opportunity. Dr Fruttiger is therefore currently interviewing new candidates for the role.
Plans for the next 12 months: Dr Fruttiger and his team plan to write two scientific papers: one detailing their findings around macular oedema and one for retinopathy. They will also continue to build up their collection of eye samples for the tissue bank, and will complete their ethics applications so that they can begin to collect medical information from the original donors.
Publications and outputs:
Abstract to be presented at The Association for Research in Vision and Ophthalmology Conference in 2015.
Fate of non-perfused vessels in ischemic retina. 2014. M. Fruttiger., M. Powner., R. Jones., W. Tan., M. Zhu., A. Chang., D.Sim., P. Keane., A. Tufail and C. Egan.
Mrs Jean Postlewaithe
Chichester Voluntary Group
North Norfolk Voluntary Group
An artificial pancreas for Type 2 inpatients
Dr Roman Hovorka, University of Cambridge
Project grant: Improving glucose control in non-critically ill inpatients with Type 2 diabetes
Funding needed: £240,106
Jan 2015 – Jan 2017
In brief: Dr Roman Hovorka will build on his successful research into an artificial pancreas for people with Type 1 diabetes to study its safety and effectiveness for the treatment of hospital inpatients with Type 2 diabetes. His work could lead to shorter hospital stays and fewer health problems for people with Type 2.
Background to research: The National Diabetes Inpatient Audit has highlighted the shortcomings of diabetes care among hospital inpatients, with many not achieving blood glucose targets. Problems with diabetes management can prolong hospital stays unnecessarily and lead to hypos in people treated with insulin if the incorrect dose is prescribed or if meals are missed. A range of different issues need to be addressed in order to resolve this problem, but one useful approach might be to give people with insulin-treated Type 2 diabetes access to an artificial pancreas that could manage their blood glucose automatically during hospital stays. Trials supported by Diabetes UK in 2011 revealed that a prototype artificial pancreas could be used safely and effectively to improve the management of Type 1 diabetes in a hospital setting.
Research aims: Dr Roman Hovorka and his team will build on their successful studies of a prototype artificial pancreas for people with Type 1 diabetes to investigate its use for the management of Type 2 diabetes in hospital inpatients. The researchers will study the safety and effectiveness of the system in 20 inpatients with insulin-treated Type 2 diabetes over a 72-hour period. They will compare the results obtained to those achieved by 20 inpatients using conventional insulin injection therapy. As in previous trials, the artificial pancreas system will involve using a portable computer to link a continuous glucose sensor with an insulin pump – enabling them to talk intelligently to each other. The system will continuously measure glucose levels in the body and rapidly adjust the insulin dose provided to maintain these levels within a target range.
Potential benefit for people with diabetes: Research published in 2014 has shown that the majority of people using insulin in the UK have Type 2 diabetes. Dr Hovorka hopes to see the artificial pancreas being used in clinical practice in around 10 years and expects it to be safer and more effective than conventional insulin therapy. Results from this study could improve care for Type 2 diabetes inpatients by helping to eliminate medication errors, reduce hypos and improve overall glucose control. Ultimately, this could lead to shorter stays in hospital and fewer associated health problems (such as infections and kidney failure) for people with Type 2 diabetes.
Summary of progress: So far, the team have recruited 24 people with Type 2 diabetes who are already taking insulin therapy and were admitted to the general ward for health problems, such as feet ulcers. The participants have been randomly assigned to be treated with usual therapy or the artificial pancreas system.
They followed the group over a 72-hour period in hospital, measuring glucose levels using two methods to ensure safety. The proportion of time spent within the target range of glucose levels was significantly higher for people using the artificial pancreas system. These early results suggest that the artificial pancreas is beneficial for people with Type 2 diabetes in a hospital setting.
Plans for the next 12 months: The team will complete their analysis of the first study, and will apply for approval to start the second study from the Ethics Committee and Medical and Healthcare products Regulatory Agency. This second study aims to investigate whether the artificial pancreas system can be used to reduce the risk of hypoglycaemia in older patients with Type 2 diabetes.
Publications and outputs:
The team hope to present the results of the first study at the American Diabetes Association conference in June 2016.
Investigating new beta cell proteins
Dr Stefan Amisten of the Imperial College London
RD Lawrence Fellowship: Functional characterisation of novel islet G-protein coupled receptors as drug targets for the treatment of diabetes
Funding needed: £493,522
May 2012 – March 2017
In brief: Dr Stefan Amisten will investigate how three specific proteins regulate insulin secretion, beta cell growth and beta cell survival. He aims to determine whether they could be used as targets for new diabetes treatments.
Background to research: The pancreas contains insulin-producing beta cells, which are affected in different ways in both Type 1 and Type 2 diabetes. Researchers are focusing on the biology of these cells, to try to understand what goes wrong and how it could be prevented.
Dr Stefan Amisten has recently found two new proteins in human beta cells, called GPRC5B and GPRC5C. His early research suggests that GPRC5B stimulates beta cells to produce insulin, and GPRC5C helps beta cell to grow and stay alive. Another similar protein, called GPR75, can protect nerve cells from dying, but nothing is known about how it works in islets.
Research aims: During his RD Lawrence Fellowship, Dr Amisten will investigate how these three proteins regulate insulin secretion, beta cell growth and survival. He will use new CRISPR technology to make cells that have deactivated versions of these proteins, so that he can study the impact this has on cell function and find ways to rescue them. He hopes that this research will decide whether new drugs could target the proteins in the future. This could lead to new treatments that can help beta cells function properly.
Potential benefit for people with diabetes: Understanding how beta cells work, and how we could keep them alive and functioning for longer, is important for people with both Type 1 and Type 2 diabetes. This project could help researchers to find the key molecules involved in keeping beta cells well, so that drugs that can target and activate these molecules can be developments into new diabetes treatments.
Summary of progress: Dr Amisten and his research team have so far created several different types of cell that come from humans, mice and rats. The cells are special, in that the two proteins, GPRC5B and GPRC5C, have been deactivated using a new gene editing technology called CRISPR.
The researchers hope that by deactivating these proteins, they will be able to see how the behaviour of the cells changes. The team will then have a better idea of how important GPRC5B and GPRC5C are when it comes to keeping cells alive and encouraging them to grow.
The team are using the special cells to look for new drugs that are able to activate the two proteins and correct the behaviour of the cells. Any drugs that they find could be developed into new diabetes treatments that help beta cells to function in the future.
Plans for the next 12 months: The researchers plan to complete the development of the specialised cells that they’re using, where GPRC5C and GPRC5B have been deactivated by the new CRISPR technology. They will also complete the development of the cells used to test new drugs that might be able to activate the two proteins.
If the cells work as they predict, the researchers will then begin to search for new drugs that can activate GPRC5B and GPRC5C.
Publications and outputs:
Quantification of the mRNA expression of G protein-coupled receptors in human adipose tissue. Amisten S. Methods Cell Biol. 2016;132:73-105
Annexin A1 Is a Key Modulator of Mesenchymal Stromal Cell-Mediated Improvements in Islet Function. Rackham CL, Vargas AE, Hawkes RG, Amisten S, Persaud SJ, Austin AL, King AJ, Jones PM. Diabetes. 2016 Jan;65(1):129-39.
Oral and poster presentations
Oral presentation at the 2015 EASD meeting in Stockholm, Sweden - “Defining the islet ‘GPCR peptidome’: quantification and functional modelling of all GPCR peptide ligand signalling pathways in human and mouse islets"
Poster presentation at the Diabetes UK Professional Conference 2016 in Glasgow - "Identification and quantification of species differences in human and mouse islet G-protein coupled receptor – peptide ligand signalling pathways and their relevance for translation of mouse data to the human context"
Diabetes UK Groups
Statins and ACE inhibitors for teens with Type 1
Professor David Dunger of the University of Cambridge
Care and Treatment grant: The adolescent Type 1 diabetes cardio-renal intervention trial (AdDIT)
Funding needed: £1,260,133;
September 2007 – September 2016
Reference number: 12/0004468 and 06/0003341
In brief: ACE inhibitors and statins are used to lower blood pressure and lipid levels in adults, but have not been evaluated for adolescents. In this international study, 11–15-year-olds from the UK, Australia and Canada will trial these medications. Results could impact future recommendations for the management of Type 1 diabetes during adolescence.
Background to research: Many adolescents with Type 1 diabetes find it difficult to maintain good control of their blood glucose. This can lead to early evidence of diabetes-related complications such as increased protein in the urine, which suggests that damage is being done to the kidneys. ACE inhibitors and statins are drugs used in adults to help protect the heart and kidneys by lowering blood pressure and lipid levels. However, they have not yet been evaluated for use in adolescents.
Research aims: This study, which is being co-funded by Diabetes UK, JDRF and the British Heart Foundation, will use a randomised controlled trial to determine whether ACE inhibitors and statins are safe, effective and well tolerated in adolescents with Type 1 diabetes. The study will involve screening 4,500 adolescents aged 11-15 in the UK, Australia and Canada in order to recruit 500 participants at ‘high risk’ of complications and 400 in the study of low-risk young people. Participants will then be randomised to receive either an ACE inhibitor, a statin, a combination of both or a placebo (dummy medication with no active ingredient) and their progress studied over a three to four year follow-up period.
Potential benefit for people with diabetes: The AdDIT study will provide important data on the potential protective effects of ACE inhibitors and/or statins in high-risk adolescents with Type 1 diabetes. Ultimately this will have an important impact on future recommendations relating to the management of Type 1 diabetes during adolescence and the effect of early treatment at this stage. Specifically the study will determine whether these types of drugs should be implemented in addition to encouraging young people to achieve good glucose control.
Summary of progress:
Progress in 2014
The progress of the study was initially limited by delays related to regulatory and ethical approvals and supply of the study drugs. The first participant was recruited to AdDIT in Perth, Australia in April 2009.
Recruitment of almost 4,500 teenagers across Australia, Canada and the UK proved much more complex and took longer than originally anticipated, but the researchers have now recruited enough young people to ensure the future of the study.
To date, 3,392 young people have been screened across 31 study sites in the three countries. Of these, 401 people are taking part in the observational study and 442 have been randomly assigned to receive either an ACE inhibitor, a statin, a combination of both or a placebo. 117 participants have now reached the end of the intervention phase of the study, while 34 have completed the observational study. All of the participants have now completed at least one year of follow up monitoring and more than a quarter have now completed three years of follow up.
As expected, initial data suggests that all of those selected to take part are potentially at higher risk of cardiovascular or kidney problems.
Progress in 2015
2015 was a good year for AdDIT: the treatment group finished the trial, and the observational group are in their last year.
Equal to last year, 3392 young people have been screened from 31 study sites. Of these, 443 have been randomly assigned to reive either a treatment option (listed above) and 401 are taking part in the observational study. This means the team reached 95 percent of their original target.
378 participants who were given a treatment option have now reached the end of the trial, including 170 who were followed for the maximum period of 4 years. Only 9 percent of the participants decided to withdraw from the study after signing up, which is actually very low.
116 participants have who were assigned to the observational study have now finished.
Plans for the next 12 months: The team plan to complete the observational study by September 2016, and will be spending 2016 analysing all of the data from the completed treatment group. The team hope to announce the results of the trial in late 2016.
The team have also secured further funding from Diabetes UK, JDRF and BHF to follow up all of the participants long-term. This will help to confirm the effects of the drugs and will also provide insight into whether there are any indicators of cardiovascular or kidney problems that they can use to identify young people that are most at risk of developing these complications.
Publications and outputs:
Cho YH, Craig ME, Davis EA, Cotterill AM, Couper JJ, Cameron FJ, Benitez-Aguirre PZ, Dalton RN, Dunger DB, Jones TW, Donaghue KC; on behalf of Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). Cardiac Autonomic Dysfunction Is Associated With High-Risk Albumin-to-Creatinine Ratio in Young Adolescents With Type 1 Diabetes in AdDIT (Adolescent Type 1 Diabetes Cardio-Renal Interventional Trial). Diabetes Care. 2015 Jan 8.
RLH Har, HN Reich, JW Scholey, D Daneman et al. The Urinary Cytokine/Chemokine Signature of Renal Hyperfiltration in Adolescents with Type 1 Diabetes. PloS one, November 13, 2014.
Cherney, D. Z. I., Scholey, J. W., Daneman, D., Dunger, D. B., Dalton, R. N., Moineddin, R., Mahmud, F. H., Dekker, R., Elia, Y., Sochett, E. and Reich, H. N. (2012) Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria. Diabetic Medicine, 29: 1297-1302.
Marcovecchio ML, Dalton RN, Turner C, Prevost AT, Widmer B, Amin R, Dunger DB. Plasma symmetric dimethylarginine, an endogenous biomarker of glomerular filtration rate, and the risk for the development of microalbuminuria in young people with Type 1 diabetes. Arch Dis Child. 2010; 95(2):119-24
Marcovecchio ML, Widmer B,Turner C, Dunger DB, Dalton RN. Asymmetric dimethylarginine in young people with Type 1 diabetes: a paradoxical association with HbA (1c). Diabet Med. 2011;28(6):685-91.
Marcovecchio ML, Dalton RN, Chiarelli F, Dunger DB. A1C Variability as an Independent Risk Factor for Microalbuminuria in Young People with Type 1 Diabetes. Diabetes Care. 2011; 34(4):1011-3