DIABETES and ENDOCRINOLOGY

Name and Title of Academic Director

Professor Solomon Tesfaye

Overview of Experimental Medicine Research in Theme

  • Main themes

Diabetes

a)Hypoglycaemia

b)Studies in Type 1 diabetes

c)CNS imaging and diabetes

d)Biomarkers of diabetic autonomic neuropathy

Endocrinology

e)Endocrine hormone replacement.

f) Treatment of hormone excess.

Overview

In hypoglycaemia we are planning to develop our work undertaking mechanistic studies which might explain mortality in both types of diabetes. We have entered into a collaborative research agreement with Eli Lilly, Indianapolis to develop this work in joint studies and are contributing to work with them and the FDA in clarifying the relevance of abnormal cardiac repolarisation in diabetes when developing new medications. We are planning collaborative studies exploring mechanisms of hypoglycaemia unawareness and closed loop treatment in Type 1 diabetes.

In diabetic neuropathy we will be initiating novel studies that will identify objective, perfusion and fMRI correlates of pain in diabetes to develop of new and more effective analgesic compounds in painful diabetic neuropathy. In autonomic neuropathy we will explore the potential of heart rate variability as a predictor of autonomic neuropathy in prospective work and determine whether intensive intervention including new medication can prevent established neuropathy.

In endocrinology our main goal is to translate new endocrine therapies into commercial products by 2017 including, Chronocort treatment of congenital adrenal hyperplasia and adrenal insufficiency, Infacort for the treatment of neonatal and infant congenital adrenal hyperplasia and adrenal insufficiency, High dose vitamin D for the replacement of vitamin D deficiency, glucocorticoid antagonists for the treatment of sub clinical Cushing’s disease and siRNA as therapy for Cushing’s disease.

Achievements

Hypoglycaemia and studies in Type 1 diabetes - We have published data from the ADVANCE database in a paper in the NEJM demonstrating an association between severe hypoglycaemia and subsequent mortality, which together with data from the ACCORD and VADT trials underpins our EM work exploring potential mechanisms in mortality. On the strength of this work and pilot data, our academic clinical fellow has been awarded a 3 year PhD fellowship by the NIHR to complete these studies. We have published over 50 peer review papers over the last 5 years and attracted over £6m in grant funding.

CNS Imaging and Autonomic neuropathy We have demonstrated uniquely, spinal cord atrophy in the neuropathic process and found that this process is early, found even in those with sub clinical (early) neuropathy. We have recently reported the involvement of the brain by demonstrating: a) the presence of thalamic neuronal dysfunction in DPN using MR Spectroscopy, and b) impaired thalamic blood flow in those with painless DPN and increased thalamic vascularity in those with painful DPN by using MR perfusion imaging. Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes and carries up to a five-fold increased risk of mortality. We have developed a simple test 5 min test for subclinical CAN, based on Spectral Analysis of Heart Rate Variability which may allow the identification of high risk subjects. This test also was found to differentiate patients with painful from painless diabetic neuropathy. We have published over 40 peer reviewed papers in the last 5 years and generated >£1m of grant funding.

Endocrine hormone replacement and treatment of hormone excess. We have developed new therapies for adrenal insufficiency including congenital adrenal hyperplasia, developing chronocort a new modified release formulation of hydrocortisone. We have obtained orphan drug designation for chronocort. We have established University of Sheffield spin out company Diurnal Ltd to develop chronocort in collaboration with the University of Sheffield. Obtained 5.6 million euro framework 7 EU grant to develop neonatal infant preparation of hydrocortisone (infacort) as principle investigator and the University of Sheffield as co-ordinator of the study. We have recently initiated a study in testosterone replacement in young male cancer survivors (TRYMS).We have developed a long acting growth hormone agonist and antagonist, currently in preclinical phase with expectation of phase 1 clinical studies in 2013 backed by a University spin out company Asterion Ltd that has over 25 granted patents in this area. We have developed a novel strategy to treat Cushing’s disease using siRNA for which orphan drug designation has been granted from EMA. We are developing a translational research partnership (TRP) with nine other major UK centres. We have published over 40 peer reviewed papers in the last 5 years and attracted >£5million grant funding.

Infrastructure

We are currently supported by two research nurses and two part time administrators. We are currently advertising for a Research Coordinator to support writing of research applications and helping investigators in the Dept to guide projects through the research process and ensure that studies are undertaken to a high quality.

Experimental Medicine Research Strategy in Theme X 2012-2017

Short, medium and long term plans

  • Hypoglycaemia and Type 1 diabetes studies (Prof Simon Heller)
  1. Pathophysiology of insulin induced hypoglycaemia
  2. We have funding in place to study basic potential mechanisms (electrophysiological, inflammatory, rheological) of mortality in individuals with Type 2 diabetes using an experimental human model (hyperinsulinaemic glucose clamp) and ambulatory studies involving continuous glucose monitoring and ambulatory ECGs.
  3. We are also currently undertaking EM studies exploring the contribution of autonomic neuropathy to hypoglycaemia unawareness and the responses of the autonomic nervous system during experimental hypoglycaemia.
  4. We are planning EM studies to supplement an epidemiological survey measuring the pathophysiological responses of first degree relatives of victims of the dead in bed syndrome in those with Type 1 diabetes.
  5. We are currently engaged in a Hypo-Compass trial (multicentre, funded by Diabetes UK) in which patients with hypoglycaemia unawareness are randomised to continuous glucose monitoring, pump therapy or education. In a sub study funded within the grant we are exploring the effect of autonomic neuropathy which requires additional glucose clamping in patients with unawareness, Type 1 diabetic controls and non-diabetic controls.
  6. We are funded by a Diabetes UK grant in a multicentre study to undertake the first ambulatory trial of a closed loop device and insulin pump designed to control blood glucose automatically in adults with Type 1 diabetes (ANGELA 3). This will involve assessment and monitoring (including overnight stays in the CRF) before a period of ambulatory evaluation in patients who take the device home.
  7. Studies in newly diagnosed Type 1 diabetes
  • We are anticipating being the lead UK site (in collaboration with Dr John Snowdon the Dept of Haemato-oncology) of myelosupressive therapy and autologous bone marrow transplantation in an attempt to maintain insulin secretion and insulin independence in newly diagnosed patients with Type 1 diabetes.
  • We are also co-applicants on an application to HTA proposing a trial of a GLP-1 analogue in newly diagnosed individuals with Type 1 diabetes. This tests the hypothesis that such agents will maintain both endogenous insulin and the glucagon response to hypoglycaemia.
  1. CNS Imaging and diabetes (Prof Solomon Tesfaye)

In a 5 year program grant we now want to determine: 1) the microvascular perfusion characteristics of the thalamus and other areas of the pain matrix in type 1 diabetic subjects with painful diabetic neuropathy, both at the resting state and in response to acute pain, and 2) the effect of improvement in the intensity of painful symptoms on microvascular perfusion of the thalamus and other areas of the pain matrix in subjects with painful diabetic neuropathy and 3)the effect of improvement in the intensity of painful symptoms on fMRI correlates of painful diabetic neuropathy. The proposed work will be the first one to initiate entirely novel studies that will identify objective, perfusion and fMRI correlates of pain in diabetes with great potential for the development of new and more effective analgesic compounds that specifically target key pathological correlates of painful diabetic neuropathy. We are taking a lead in this proposal that will also include investigators from the Mayo Clinic (Prof PJ Dyck) and University of Oxford FMRIB (Prof I Tracey).

  1. Biomarkers of diabetic autonomic neuropathy (Prof Solomon Tesfaye)

The main aims of our 5-year, multi-centre, prospective study are to: 1) determine the concurrent validity of SHRV as a sensitive biomarker of early (subclinical) CAN in a cross-sectional study, 2) determine the predictive validity of SHRV as a biomarker of the future development of established CAN in a prospective study and 3) determine if intensive, multi-factorial intervention including the use of a novel statin/ fenofibrate combination prevents the development of established CAN. On the basis of current CAN Gold standards baroreceptor sensitivity test (BRS) and AFTs, age and sex matched type 1 patients will be allocated to groups with: 1) no CAN with normal BRS and AFTs, 2) subclinical CAN with abnormal BRS but normal AFTs and 3) established CAN with abnormal BRS and AFTs. The ability of SHRV to diagnose subclinical CAN will be tested. A group of matched healthy volunteers will also be recruited for comparison. These 4 groups will be followed for 3 years. The ability of SHRV to predict the development of established CAN will be tested in the prospective study. A subsection of subjects with subclinical CAN will undergo intensive multi-factorial treatment for a period of 3 years. Thus the proposal will simultaneously interrogate if a simple test can identify high risk diabetic subjects for CAN and if such patients can benefit from a novel, intensive multi-factorial therapy, and may have a major impact for the screening and management of CAN in diabetic patients.

  • Endocrinology (Prof Richard Ross, Dr John Newell-Price)

The main goal is to translate new endocrine therapies into commercial products by 2017 these include:

  1. Chronocort for the treatment of congenital adrenal hyperplasia and adrenal insufficiency.
  2. Infacort for the treatment of neonatal and infant congenital adrenal hyperplasia and adrenal insufficiency.
  3. High dose vitamin D for the replacement of vitamin D deficiency – Innovation opportunity with D3 Pharma.
  4. Glucocorticoid antagonists for the treatment of sub clinical Cushing’s disease and as a diagnostic test to stratify patients with functioning adrenal incidentalomas.
  5. siRNA as therapy for Cushing’s disease

How will the CRF facilitate this strategy

The CRF will be crucial to conducting the detailed physiological studies described in this document. These include the detailed physiological studies involving glucose clamps and measurements of autonomic function. The imaging studies are generally conducted in the academic dept of radiology which is where the MRI facilities are housed. However, where research nurses are needed to support this work, these can be provided either from the CRF research nurse complement or those research nurses who although based in the Diabetes/Endocrine Dept, work under the auspices of the CRF. The CRF will be crucial to the first in man studies of siRNA therapy. Phase 1, 2 and 3 studies for chronocort, infacort, vitamin D and glucocorticoid antagonists will also be undertaken in the CRF.

Markers of esteem

Simon Heller

Chairman – Clinical Studies Advisory Committee, Diabetes Research Network

Member – Diabetes UK Research Committee

Member of Diabetes UK Scientific and Research Advisory Group

Member of HTA

Member of Juvenile Diabetes Foundation International, UK Advisory Committee

Solomon Tesfaye:

Chairman – Neurodiab (largest global neuropathy study group) 2006- 2009

Chairman - International Expert Group on Diabetic Neuropathy 2009-Vice Chairman - Science and Research Committee of Diabetes UK 2010-

External reviewer of the NICE guidelines for management of diabetic neuropathies (2008)

and committee member for the neuropathic pain panel in 2010

Executive Committee member of the UK Neuropathy Trust2004-

Member of Global Quantitative Sensation Testing Society; Sets Global Standards 2005-To date.

Trustee of International Insulin Foundation (IIF) 2007-To date

Associate Editor of Diabetologia 2001-2003 (Journal of the European Association for the Study of Diabetes).

Associate Editor of J Experimental Research 2009-To date

Associate Editor of Frontiers in Endocrinology2011-

Richard Ross

Chairman of UK Congenital Adrenal Hyperplasia Cohort CaHASE,

Executive Council European Society for Endocrinology

Council Member Growth Hormone Research Society,

Nominations Committee Society for Endocrinology

Faculty Lead for Innovation.

John Newell-Price

Principle Investigator Endocrine Translational Partnership NOCRI

Chair of the Corporate Liaison Board, Society for Endocrinology

Chair Joint Speciality Committee for Endocrinology and Diabetes Royal College of Physicians

Executive Committee of the UK and Ireland Neuroendocrine Tumour Society

Member NIHR CRN (Yorkshire) Metabolic and Endocrine Specialty Group

Associate Editor ‘Clinical Endocrinology’

Editorial Board Journal of Clinical Endocrinology and Metabolism.

Strategic partnerships – including those with industry

Pfizer

Diurnal Ltd and Asterion Ltd

Endocrine Translational Partnership

HRA Pharma

Novartis

JDRF

Diabetes UK

NIH

Pfizer

Eli Lilly and company

NovoNordisk

Track record in and plans for patient and public involvement

Simon Heller has set up a patient user group to support an NIHR programme grant.

Late Effects Group Sheffield (LEGS) – appointed first nurse consultant in late effects and setting national and international standards for late effect.

Trustee of Pituitary Foundation (JNP) (patient support charity) with dissemination of research at their National meeting (Nov 5th 2012)

Solomon Tesfaye is President of the Sheffield Diabetes UK patients’ group and gives regular annual lectures (including one on user involvement in research in 2010). He is also Trustee of the Neuropathy Trust which the largest neuropathy patients association in the UK and Europe.

Current or recent grant funding

Irish Health Board. April 2006-March 2012. Implementing and evaluating a structured education programme and a new model of ongoing care for Type 1 diabetes in Ireland. In collaboration with Dr S Dinneen, Dr H Courtney, Dr D O’Shea, Prof CP Bradley, Dr K Murphy, Prof E O’Shea, Ms D Casey, Dr J Lawton, Ms F Brown, Dr J Newell 1m euros

STH Special Trustees. April 2006-March 2008. Exploring abnormal cardiac repolarization during hypoglycaemia in Type 1 diabetes. Principal Investigator in collaboration with Dr C Newman. £20,000

Diabetes UK. May 2006-April 2009. Does self monitoring of blood glucose as opposed to urinalysis provide additional benefit to newly diagnosed individuals with Type 2 diabetes receiving structured education? Principal Investigator in collaboration with Dr M Carey, Dr M Davies, Prof M Campbell, Dr S Dixon, Dr C Skinner, Dr H Dallasso, Dr E Pitchforth £350,000

Diabetes UK. October 2006-September 2008. Exploring abnormal cardiac repolarization during hypoglycaemia in Type 1 diabetes. Principal Investigator in collaboration with Dr C Newman, Prof Ian Macdonald £124,000

National Institute of Health Research, Programme Grant October 2007-September 2012. Improving management of Type 1 diabetes in the UK: the DAFNE programme as a research test-bed. Principal Investigator in collaboration with Dr J Lawton, Dr M Clarke, Ms G Thompson, Prof S Amiel, Prof M Campbell, Dr P Mansell, Dr I Lawrence, Ms C Taylor, Ms L Oliver (Chief Investigator) £1.8m

Diabetes UK. Jan 2009-July 2013. KICk-OFF: A multi-centre, randomised controlled trial comparing intensive structured education with standard education in 11-16 year olds on intensive insulin therapy. Dr K Price, Prof C Eiser Dr J Wales, Dr J Freeman(co-investigator) £1.35m

Diabetes UK. April 2008-March 2012. Overnight hypoglycaemia prevention in adult subjects with type 1 diabetes: Closing the loop with Dr R Hovorka, Prof S Amiel Dr M Evans, (co-investigator) £750k

Diabetes UK. Sep 2009-March 2012. Prevention of recurrent severe hypoglycaemia: a definitive RCT comparing optimised MDI and CSII with or without adjunctive real-time continuous glucose monitoring. Hypo-COMPASS Dr J Shaw, Prof D Kerr, Dr D Flanagan, Dr M Evans, Dr J Speight (co-investigator) £1.4m

HTA June 2011- May 2016. The REPOSE (Relative Effectiveness of Pumps over MDI and Structured Education) Trial. Principal Investigator in collaboration with Dr Cindy Cooper, Professor Mike Campbell, Prof Simon Dixon, Dr Julia Lawton, Dr Kath Barnard, Dr R Lindsay, Dr P Hammond, Prof S Amiel, Dr M Evans, Dr A Jaap, Dr F Green. £3.7m

Sanders DS (PI)“The influence of gluten exposure in Diabetes Mellutus” Bardhan Research & Education trust of Rotherham 2004) £72, 460 Role: Co-applicant

Tesfaye S (PI). Central Nervous System involvement in Diabetic Neuropathy Diabetes UK Sheffield Group (December 2008) £7500

Tesfaye (PI). Central pain processing in painful diabetic neuropathy. JDRF (2009) $484,665

Tesfaye S (PI) Dynamic pupillometry & spectral analysis of HRV as early biomarkers of autonomic neuropathy. National Institute of Health (US–NIDDK) (2008) $277,000 USD.

Tesfaye S. (PI) Thalamic neuronal dysfunction in diabetic neuropathy: implications for pathogenesis and treatment”. Diabetes UK (November, 2004) £105,454

Tesfaye S (PI) “Spinal cord in Diabetic neuropathy” Diab UK (2001) £134,000

Tesfaye S (PI). “Randomised, controlled trial studying the addition of CBME to

conventional treatment in painful diabetic neuropathy”. Diabetes UK (2003) £93,563

Malik R (PI). “Pathophysiology of painful diabetic neuropathy” Diabetes UK (2003) £80,284. Role: Co-applicant

CRUK £0.5 million TRYMS study

EUFP7 5.6 million euros, Infacort study

Diurnal Ltd £2 million chronocort studies.

Selected publications relevant to our Experimental Medicine Work

Hypoglycaemia and Type 1 diabetes

  1. Hovorka R, Kumareswaran K, Harris J, Allen JM, Elleri D, Xing D, Kollman C, Nodale M, Murphy HR, Dunger DB, Amiel SA, Heller SR, Wilinska ME, Evans ML: Overnight closed loop insulin delivery (artificial pancreas) in adults with type 1 diabetes: crossover randomised controlled studies. BMJ342:d1855, 2011
  2. Kengne AP, Patel A, Marre M, Travert F, Lievre M, Zoungas S, Chalmers J, Colagiuri S, Grobbee DE, Hamet P, Heller S, Neal B, Woodward M: Contemporary model for cardiovascular risk prediction in people with type 2 diabetes. Eur J Cardiovasc Prev Rehabil 2011
  3. Frier BM, Schernthaner G, Heller SR: Hypoglycemia and cardiovascular risks. Diabetes Care 34 Suppl 2:S132-7, 2011
  4. Choudhary P, Lonnen K, Emery CJ, Freeman JV, McLeod KM, Heller SR: Relationship Between Interstitial and Blood Glucose During Hypoglycemia in Subjects with Type 2 Diabetes. Diabetes Technol Ther 2011
  5. Kengne AP, Patel A, Colagiuri S, Heller S, Hamet P, Marre M, Pan CY, Zoungas S, Grobbee DE, Neal B, Chalmers J, Woodward M: The Framingham and UK Prospective Diabetes Study (UKPDS) risk equations do not reliably estimate the probability of cardiovascular events in a large ethnically diverse sample of patients with diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) Study. Diabetologia 53:821-831, 2010
  6. Choudhary P, Geddes J, Freeman JV, Emery CJ, Heller SR, Frier BM: Frequency of biochemical hypoglycaemia in adults with Type 1 diabetes with and without impaired awareness of hypoglycaemia: no identifiable differences using continuous glucose monitoring. Diabet Med 27:666-672, 2010
  7. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, Woodward M, Ninomiya T, Neal B, MacMahon S, Grobbee DE, Kengne AP, Marre M, Heller S: Severe hypoglycemia and risks of vascular events and death. N Engl J Med 363:1410-1418, 2010
  8. Ferrari G, L, Marques J, L B, Gandhi R, A, Heller S, R, Schneider F, K, Tesfaye S, Gamba H, R: Using dynamic pupillometry as a simple screening tool to detect autonomic neuropathy in patients with diabetes: a pilot study. Biomed Eng Online 9:26, 2010
  9. de Galan BE, Zoungas S, Chalmers J, Anderson C, Dufouil C, Pillai A, Cooper M, Grobbee DE, Hackett M, Hamet P, Heller SR, Lisheng L, Macmahon S, Mancia G, Neal B, Pan CY, Patel A, Poulter N, Travert F, Woodward M: Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia 2009
  10. Choudhary P, Lonnen K, Emery CJ, MacDonald IA, MacLeod KM, Amiel SA, Heller SR: Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin- and sulphonylurea-treated Type 2 diabetes. Diabet Med 26:665-672, 2009
  11. Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, MacMahon S, Marre M, Neal B, Patel A, Woodward M, Chalmers J, ADVANCE Collaborative G: Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes New results from the ADVANCE trial. Diabetes Care 32:2068-2074, 2009
  12. Heller SR: A summary of the ADVANCE Trial. Diabetes Care 32 Suppl 2:S357-61, 2009
  13. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ: Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009
  14. Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, Macmahon S, Marre M, Neal B, Patel A, Woodward M, Chalmers J: The combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes; new results from ADVANCE. Diabetes Care 2009
  15. Heller SR: Minimizing hypoglycemia while maintaining glycemic control in diabetes. Diabetes57:3177-3183, 2008
  16. Heller SR: Hypoglycaemia in Type 2 diabetes. Diabetes Res Clin Pract 82 Suppl 2:S108-11, 2008
  17. Munir A, Choudhary P, Harrison B, Heller S, Newell-Price J: Continuous glucose monitoring in patients with insulinoma. Clin Endocrinol (Oxf) 68:912-918, 2008
  18. Ferrari GL, Marques JL, Gandhi RA, Emery CJ, Tesfaye S, Heller SR, Schneider FK, Gamba HR: An approach to the assessment of diabetic neuropathy based on dynamic pupillometry. Conf Proc IEEE Eng Med Biol Soc 2007:557-560, 2007
  19. Heller S, Kozlovski P, Kurtzhals P: Insulin's 85th anniversary--An enduring medical miracle. Diabetes Res Clin Pract 78:149-158, 2007
  20. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B: Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370:829-840, 2007
  21. Heller SR, Nicholson AN: Aircrew and type 1 diabetes mellitus. Aviat Space Environ Med 77:456-458, 2006

CNS imaging and diabetes, Biomarkers of diabetic autonomic neuropathy.