Oxford BRC Clinical Research Fellowship (Diabetes Theme)
Project Booklet
Project Title: Novel metabolic predictors of graft survival following whole organ pancreas
transplantation for type 1 diabetes (T1DM) and the impact of pancreas transplantation on long term
diabetes outcomes
Supervisors: Professor Stephen Gough, Professor Peter Friend
Project Outline
Whole organ pancreas transplantation is a viable treatment option for many people with T1DM.
Whilst success rates are high, individual graft function can decline, with only 65% of recipients
remaining insulin independent at 3 years. Predicting loss of graft function ahead of returning to the
administration of exogenous insulin, is currently not possible. Oxford is the major European centre
for pancreas transplantation, performing between 80 and 90 transplants annually. As part of an
ongoing programme looking at both metabolic and genetic predictors of graft survival, the aims of
this fellowship are to determine (i) the predictive value of dynamic tests of insulin and glucagon
secretion performed before and immediately after transplantation as predictors of short and long
term graft survival and (ii) the impact of successful pancreas transplantation on diabetes-related
complications.
Over 450 people with T1DM have undergone pancreas transplantation in Oxford. A detailed data
base of clinical and biochemical information has been collected on all graft recipients including the
collection of prospective data as per a predefined protocol. This includes regular oral glucose
tolerance (OGTT) data at pre-specified time points, for up 8 years on some patients. Frequently
sampled OGTTs are also being performed with proposed plans for more detailed pancreatic function
tests including intravenous glucose tolerance and arginine stimulated insulin secretion studies.
Incretin profiling pre and post-transplantation will also be carried out as part of the programme. The
research fellow will coordinate and help develop the proposed assessment of pancreatic function
and will analyse data in terms of clinical phenotype and long term graft function. Using the
transplant register and related databases including, for example, the retinopathy screening
database, a unique opportunity exists to determine the impact of transplantation on diabetes
complications.
Training opportunities
The clinical fellow will gain experience of, oral and intravenous glucose tolerance testing, glucose
clamp studies, incretin profiling and CGM analysis alongside statistical analysis and mathematical
modelling of dynamic tests of graft function following pancreas transplantation.
Key References
1.
2.
3.
4.
Pavlakis M, et al. Transplantation. 2010; 89 (11): 1347-53
Nauck MA et al. Acta Diabetol. 1993; 30 (1):39-45
Greenbaum CJ et al. Diabetes Care 2008; 31: 1966-71
Baidal DA, et al. Clinical Transplantation 2009; 87: 1-9
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 2 of 8
Project Title:
OPTIMIZATION OF GLYCAEMIC CONTROL DURING AND AFTER PHYSICAL EXERCISE IN PATIENTS
WITH TYPE 1 DIABETES
Supervisors:
Dr Ian W Gallen, High Wycombe Hospital and Prof Fredrik Karpe, OCDEM, Churchill Hospital
Project Outline:
Postprandial elevation of insulin is the trigger for increased glucose uptake in skeletal muscle. This
process is dependent on mobilization of the glucose transporter GLUT4. However, glucose uptake is
also facilitated by an AMPK dependent process activated by physical exercise independent of insulin.
In healthy people balancing glucose concentrations with an intact islet function this is never a
problem, whilst in patients with type 1 diabetes, a bout of exercise may easily lead to hypoglycaemia
(1). The risk of hypoglycaemia during and post-exercise may even deter patients with type 1 diabetes
from implementing much needed ‘healthy living’ advice. We have recently conducted a thorough
study titrating insulin delivery in exercising type 1 diabetic patients to find new algorithms avoiding
hypoglycaemia (2). The present project will build on these studies and exploring interventions to
avoid night time hypoglycaemia seen after exercise in patients with type 1 diabetes.
What remains to be discovered on the use of CSII, CGMS and the “artificial pancreas” in type diabetes
and exercise?
The appropriate dose reduction in nocturnal basal insulin infusion rate following antecedent
endurance or high intensity exercise is not understood.
Whilst our recent study provides robust evidence for timing and level of the reduction in CSII
infusion rate with endurance exercise, there are clear clinical and physiological data to suggest that
these reductions are not appropriate for mixed intensity (team sport) and high intensity physical
activity. The delays in interstitial glucose equilibration measured by CGMS and arterial glucose
values during rapidly changing blood glucose are not quantified. Lastly the performance of any
“artificial pancreas” algorithm during exercise is not clear.
A three year project is described and it is envisaged that a successful applicant will spend one year
generating pilot data for a competitive clinical training fellowship post (DUK, DWRF, MRC etc).
Study 1: The effect of reduction in nocturnal insulin infusion rate following endurance exercise.
Nocturnal interstitial glucose will be measured at usual, and reduced CSII infusion rates (by 20 and
40%) follow prolonged endurance exercise.
Study 2: A study to find most appropriate CSII infusion rate with simulated team sports
Study 3: Using data from above studies, calibration and modelling of CGMS derived intestinal
glucose and arterialized glucose.
Study 4: Use of Artificial pancreas in controlled surroundings to determine performance of algorithm
during rapidly changing arterial glucose during and following exercise.
Training opportunities:


Organisation and running a of small experimental clinical trials
Implementation of novel technologies in metabolic medicine and diabetes care
Laboratory skills in metabolic medicine including biochemical assays and development of
new assays
Key References
1.
2.
Lumb AN, Gallen IW (2009) Diabetes management for intense exercise. Current Opinion in
Endocrinology, Diabetes & Obesity.16(2):150
Lumb AN, Carr J, Peters G, Karpe F, Gallen IW. Active adults with Type 1 diabetes using CSII
should reduce basal insulin infusion by 80% not 50% to avoid hypoglycaemia during aerobic
exercise. Abstract accepted for ADA June 2012.
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 3 of 8
Project Title:
UNDERSTANDING PARADOXICAL INSULIN SENSITIVITY IN OBESE INDIVIDUALS WITH A
MONOGENIC DISORDER OF CONSITUTUVE INSULIN SENTISISATION
Supervisors:
Dr Anna L Gloyn & Professor Fredrik Karpe
Project Outline:
There is overwhelming evidence from epidemiological studies that obese individuals are insulin
resistant. We have recently identified a monogenic form of constitutive insulin sensitisation and
demonstrated that subjects with this condition are paradoxically obese (Pal et al in press). Analysis
of body composition has shown that the increased BMI in these individuals is driven by adiposity and
that regional differences in fat distribution (ie. increased gluteal-femoral fat) cannot explain the
improved metabolic phenotype.
The aim of this project is to explore the mechanisms driving this increase in adiposity and to better
understand the favourable metabolic profile observed in these individuals. This will be achieved
through detailed anthropometric (inc. DXA, MRI) and metabolic phenotyping (inc. OGTT,
hyperinsulinaemic euglycaemic clamp, whole body calorimetry) of individual’s harbouring rare fully
penetrant mutations in this newly described gene and in healthy subjects with rare variants of
unknown pathogenicity identified through targeted re-sequencing of individuals at the extremes for
insulin sensitivity in the Oxford BioBank. The successful candidate will determine insulin sensitivity
in these individuals compared to age, gender and BMI matched controls and study insulin signalling
in muscle and adipose tissue from these individuals. Energy balance will be assessed by whole body
calorimetry whilst the central effects on appetite regulation will be evaluated through collaborations
within the MRC-Centre for Obesity and Related Disorders which both supervisors are members of.
This project capitalises on access to individuals with this newly described syndrome and substantial
expertise in integrative physiology. It holds the promise to identify novel mechanisms for energy
balance and highlight potential pathways for therapeutic intervention.
Training opportunities:Clinical Skills: Detailed physiological studies including OGTT, hyperinsulinaemic euglycaemic clamps,
muscle and adipose tissue biopsies, assessment of body composition (DXA), whole body calorimetry.
Lab based: DNA sequence analysis, in silico prediction of DNA variants, PCR, Sanger Sequencing,
genotyping, western blot analysis, gene expression profiling.
Key References
1. McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM, Ruge T, Gilbert
M, Fielding BA, Frayn KN, Karpe F. Downregulation of adipose tissue fatty acid trafficking in
obesity: a driver for ectopic fat deposition? Diabetes 2011;60:47-55
2. Rees MG, Ng D, Ruppert S, Turner C, Beer NL, Swift AJ, Morken MA, Below JE, Blech I, NISC
Comparative Sequencing Program, Mullikin JC, McCarthy MI, Biesecker LG, Gloyn AL, Collins
FS. Phenotypic, cellular, and kinetic correlation of rare coding variants in the human
glucokinase regulatory protein. The Journal of Clinical Investigation. 2012; 122(1):205-17.
3. Pinnick KE, Neville MJ, Fielding BA, Frayn KN, Karpe F, Hodson L. Gluteofemoral Adipose
Tissue Plays a Major Role in Production of the Lipokine Palmitoleate in Humans. Diabetes.
2012 Apr 9
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 4 of 8
Project Title:
IDENTIFYING THE GENETIC AETIOLOGY IN YOUNG-ONSET DIABETES USING NEXT GENERATION
SEQUENCING TECHNOLOGIES
Supervisors:
Dr Anna L Gloyn & Dr Katharine Owen
Project Outline:Determining the genetic aetiology for patients with young-onset diabetes is important as it informs
on optimal treatment, prognosis and has implications for family members. With the advent of new
sequencing technologies genetic testing for monogenic forms of diabetes is now possible in greater
numbers of individuals due to a dramatic reduction in cost. In addition exome and whole genome
sequencing in large numbers of patients with early onset type 2 diabetes is being performed as part
of several international resequencing projects. One of the current challenges in the field is to
interpret non-synonymous and loss of function variants identified in known monogenic genes for
diabetes, particularly in individuals where the phenotype does not meet the traditional clinical
criteria. Along with traditional criteria (co-segregation in families, in silico evaluation of genetic
variants, absence from normal chromosomes, physiological and functional studies) non-genetic
biomarkers (e.g. hsCRP, C-peptide, glycan profiles) are likely to have a role to play in assigning
pathogenicity to novel variants. This project will investigate the pathogenicity of recently identified
genetic variants in individuals with early onset diabetes generated through both targeted and whole
exome sequencing efforts using an arsenal of approaches. The successful candidate will use state of
the art bioinformatic tools to explore variant pathogenicity in combination with family and
physiological studies to explore the contribution of novel variants to diabetes susceptibility.
Functional studies on specific variants are also possible. The overall aim of this project will be to
contribute to guidelines for the interpretation of genetic variants identified through large scale
sequencing efforts in patients with early onset diabetes. This project offers the opportunity to work
at the cutting edge of translational human genetics and the chance to capitalise on recently
generated large data sets.
Training opportunities:Clinical Skills:-Family recruitment for genetic studies, physiological investigation of effects of variants
on beta-cell function and insulin sensitivity, integration of large datasets, statistical analysis.
Lab based:- DNA sequence analysis, in silico prediction of DNA variants, PCR, Sanger Sequencing,
genotyping, functional characterisation of selected DNA variants in appropriate assays.
Key References
1. Thanabalasingham G, Owen KR (2011) Diagnosis and management of maturity onset
diabetes of the young (MODY). BMJ 343: d6044
2. Owen KR, Thanabalasingham G, James TJ, et al. (2010) Assessment of high-sensitivity Creactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young
due to HNF1A mutations. Diabetes Care 33: 1919-1924
3. Steele AM, Tribble ND, Caswell R, et al. (2011) The previously reported T342P GCK missense
variant is not a pathogenic mutation causing MODY. Diabetologia 54: 2202-2205
4. Beer NL, Osbak K, van de Bunt M, et al. (in press) Insights into the pathogenecity of rare
missense GCK varians from the identification and functional characterisation of compound
heterzygous and double mutations inherited in cis. . Diabetes Care.
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 5 of 8
Project Title:
THE INFLUENCE OF DIETARY SUGARS OF ADIPOSE TISSUE: A POSTPRANDIAL STUDY IN HUMANS
Supervisors:
Dr Leanne Hodson, OCDEM and Prof Fredrik Karpe, OCDEM, Churchill Hospital
Project Outline:
Although there is convincing evidence that diets high in fructose can promote obesity, insulin
resistance and dyslipidaemia in animals, direct experimental evidence that fructose consumption
promotes the development of the metabolic syndrome in humans is much less clear. At the level of
the liver, fructose supplementation in humans promotes the process of de novo lipogenesis, which
results in increased plasma triglyceride concentrations, which is a risk factor for cardiovascular
disease. The process of de novo lipogenesis has not been well studied in human adipose tissue but it
could be speculated that consumption of fructose would up-regulate this process, resulting in
greater deposition of fat within adipose tissue possibly altered metabolic function of the tissue due
to the channelling of nutrients through the pentose phosphate pathway. Indeed, a recent study
noted that fructose, compared to glucose supplementation, resulted in an increase in visceral
adiposity. Therefore the aim of project is to investigate the metabolic effects of fructose compared
to glucose consumption, on subcutaneous abdominal and gluteal adipose tissue function in the
fasting and postprandial states.
Studying adipose tissue metabolism:
Glucose and Fructose with stable isotope tracers will be infused intravenously and/or given orally to
volunteers over the course to assess distribution, transport and metaobolism.
Adipose tissue specific measurements will be gathered by arterio-venous techniques and by
analysing biopsies, from subcutaneous abdominal and gluteal adipose tissue
Mechanistic studies will be conducted as cellular level (adipocytes) in which specific genes can be
targeted for knock-down to assess critical steps using metabolic tracers.
study day, blood and breath samples will be collected regularly.
Training opportunities: Metabolic tracer studies in humans
 Physiological techniques in metabolic medicine
 Laboratory skills in metabolic medicine including biochemical assays and development of
new assays, gas chromatography/mass spectrometry
 Cell culture, gene knockdown techniques
Key References
1. Hodson L, Bickerton AS, McQuaid SE, Roberts R, Karpe F, Frayn KN, Fielding BA. The
contribution of splanchnic fat to VLDL triglyceride is greater in insulin-resistant than insulinsensitive men and women: studies in the postprandial state. Diabetes 2007;56:2433-41
2. McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM, Ruge T, Gilbert
M, Fielding BA, Frayn KN, Karpe F. Downregulation of adipose tissue fatty acid trafficking in
obesity: a driver for ectopic fat deposition? Diabetes 2011;60:47-55
3. Pinnick KE, Neville MJ, Fielding BA, Frayn KN, Karpe F, Hodson L. Gluteofemoral Adipose
Tissue Plays a Major Role in Production of the Lipokine Palmitoleate in Humans. Diabetes.
2012 Apr 9
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 6 of 8
Project Title: Evaluation of Novel Biomarkers for the diagnosis of Maturity-onset diabetes of the
young (MODY)
Supervisors: Dr Katharine Owen Prof Mark McCarthy
Project Outline
Background: Monogenic forms of diabetes are commonly seen in young adults with diabetes, but
are frequently misclassified as T1DM or T2DM diabetes. An accurate diagnosis allows management
changes, including stopping insulin and follow-up of family members. Despite this, uptake of genetic
testing is low and costs preclude all patients from being tested. Finding a simple biochemical marker
for MODY subgroups would have great clinical utility.
A major success of the BRC funded work in the Diabetes theme was the discovery of hsCRP and
plasma glycan profile as highly specific and sensitive markers for HNF1A-MODY. This project
continues that work, to further assess the performance of these biomarkers in unselected and new
datasets and assess their potential for clinical translation. Tasks 1 and 2 comprise the initial projects.
Task 1: Use of hsCRP and glycan profile to screen clinically-labelled young-onset T2DM.
500 previously uninvestigated subjects from primary and secondary care will be screened with both
hsCRP and plasma glycan profile. Those at high risk for HNF1A-MODY will undergo genetic testing.
The relative performance of the biomarkers will be compared.
Task 2: Development of a postal test for measuring plasma glycan profile.
Currently blood taken for plasma glycan profile requires rapid processing after sampling, limiting
everyday use. Pilot data shows that glycan profile can be measured from dried blood spots collected
and stored at room temperature on filter paper. A postal collection pack will be developed and
evaluated for use in Task 3 below.
Task 3: Use of glycan profile to screen recently-diagnosed clinically-labelled T1DM.
It is hard to distinguish MODY from T1DM at diabetes onset, but early diagnosis means insulin can be
stopped as soon as possible. We will measure plasma glycan profile, β-cell antibodies and C-peptide
in 500 subjects with T1DM to identify those at highest risk of HNF1A-MODY for genetic testing.
Task 4: Assessment of Health Economic Impact of making a diagnosis of HNF1A-MODY
Working with senior Health Economist Sarah Wordsworth, we will assess the health economics of
making a diagnosis of monogenic diabetes. Resource-use data will be collected for the diagnostic
tests, clinical assessments and any changes in treatment. The main health economic analysis will
calculate the average cost and outcome on a per patient basis and from this the incremental costeffectiveness ratios for the different diagnostic approaches will be derived.
Training opportunities
Recruitment of patients for genetic studies, follow-up of families with MODY (including genetic
screening and treatment changes), database skills, statistical analysis and working with statistical
software packages, training in health economics methods, writing and presentation skills, working
with a multi-disciplinary team.
Key References
1. Thanabalasingham, G and K.R. Owen, Diagnosis and management of maturity onset diabetes of the young
(MODY). BMJ, 2011. 343: p. d6044.
2. Shields BM et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing?
Diabetologia 2010 53(12):2504-8.
3. Thanabalasingham, G et al. A large multi-centre European study validates high-sensitivity C-reactive protein
(hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia, 2011. 54(11): p. 280110.
4. Thanabalasingham G et al. Systematic assessment of etiology in adults with a clinical diagnosis of youngonset type 2 diabetes is a successful strategy for identifying Maturity-onset diabetes of the young. Diabetes
Care 2012 Epub
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 7 of 8
Project Title:
EVALUATION OF THE UTILITY OF A POINT OF CARE INSULIN ASSAY FOR DIABETES MANAGEMENT
Supervisors:
Professor Rury Holman (OCDEM), Dr Jason Davis (Department of Chemistry)
Project Outline:
T2DM is a heterogeneous disease, driven mainly by two core defects, the loss of insulin sensitivity
and beta cell function.1 Patients with T2DM may have very similar plasma glucose levels but these
can be as a result of widely varying degrees of beta cell function and insulin sensitivity. These two
important physiological parameters can be estimated quite simply using the Homeostasis Model
Assessment (HOMA) calculator,2 but cannot be assessed readily In routine clinical practice, as insulin
measurements require time consuming and expensive laboratory assay.
The aim of this project is to explore the utility of using electrochemical impedance spectroscopy3 to
implement a novel insulin biosensor that can provide finger prick insulin measurements, in tandem
with glucose measurements. Currently there are 8 classes of antidiabetic drugs licensed with several
more on the horizon. International and national guidelines highlight the need for T2DM patients to
receive personalised diabetes treatment, but little is known of how this should be done. The
successful candidate will first confirm the in vivo accuracy and reliability of the new insulin biosensor
and then proceed to evaluate the utility of clinic-based HOMA %B and HOMA %S estimates to help
select and adjust a range of glucose-lowering therapies.
This project capitalises on access to novel technology and the BRC supported DTU Translational
Trials Group. It holds the promise to usher in a new era of evidence-based personalised treatment
selection and adjustment for people with T2DM.
Training opportunities:Clinical Skills: Design and implementation of translational clinical studies, including physiological
studies such as continuous glucose monitoring, and oral glucose, lipid and meal tolerance tests.
Statistical Skills: Trial design, sample estimation and analyses
Lab based: Insulin assay optimisation and calibration
Key References
1. Beta cell deficiency in maturity onset of diabetes.
Turner RC, Holman RR. Diabetologia 1976;12:398-399
2. http://www.dtu.ox.ac.uk/homacalculator/index.php
3. Daniels JS, Pourmand N. Electroanal 2007;19:1239-1257
Oxford NIHR Clinical Training Fellow (Diabetes Theme)
Project Booklet
May 2012
Page 8 of 8