NIHR Experimental Medicine Proposal – Theme Diabetic ...



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

a. 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.

b. 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.

2. 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.

3. 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.

4. 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.

5. 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).

2. 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 Trust 2004-

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

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 Endocrinology 2011-

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. BMJ 342: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. Diabetes 57:3177-3183, 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.

1. Selvarajah D, Wilkinson ID, Gandhi R, Griffiths PD, Tesfaye S. Microvascular perfusion abnormalities of the Thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes. Diabetes Care 2011 Mar;34(3):718-20. [Epub ahead of print]

2. Kempler P, Amarenco G, Freeman R, Frontoni S, Horowitz M, Stevens M, Low P, Pop-Busui R, Tahrani A, Tesfaye S, Várkonyi T, Ziegler D, Valensi P; on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Gastrointestinal autonomic neuropathy, erectile-, bladder- and sudomotor dysfunction in patients with diabetes mellitus: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011 [Epub ahead of print].

3. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P; on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011 [Epub ahead of print].

4. Tesfaye S, Vileikyte L, Rayman G, Sindrup S, Perkins B, Baconja M, Vinik A Boulton A; on behalf of the Toronto Expert Panel on Diabetic Neuropathy Painful Diabetic Peripheral Neuropathy: Consensus Recommendations on Diagnosis, Assessment and Management. Diabetes Metab Res Rev 2011 [Epub ahead of print].

5. Bernardi L, Spallone V, Stevens M, Hilsted J, Frontoni S, Pop-Busui R, Ziegler D, Kempler P, Freeman R, Low P, Tesfaye S, Valensi P; on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Investigation methods for cardiac autonomic function in human research studies. Diabetes Metab Res Rev 2011 [Epub ahead of print].

6. Malik R, Veves A, Tesfaye S, Smith G, Cameron N, Zochodne D, Lauria G; on behalf of the Toronto Consensus Panel on Diabetic Neuropathy. Small Fiber Neuropathy: Role in the diagnosis of Diabetic Sensorimotor Polyneuropathy. Diabetes Metab Res Rev 2011 [Epub ahead of print].

7. Selvarajah D, Wilkinson ID, Davies J, Gandhi R, Tesfaye S. Central nervous system involvement in diabetic neuropathy. Curr Diab Rep. 2011;11(4):310-22.

8. Gill GV, Tekle A, Reja A, Wile D, English PJ, Diver M, Williams AJ, Tesfaye S. Immunological and C-peptide studies of patients with diabetes in northern Ethiopia: existence of an unusual subgroup possibly related to malnutrition. Diabetologia. 2011; 54(1):51-7.

9. Tesfaye S, Boulton AJM, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P on behalf of The Toronto Diabetic Neuropathy Expert Group. Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity and Treatments. Diabetes Care 2010;33(10):2285-93.

10. Charles M, Soedamah-Muthu SS, Tesfaye S, Fuller JH, Arezzo JC, Chaturvedi N, Witte DR; EURODIAB Prospective Complications Study Investigators. Low peripheral nerve conduction velocities and amplitudes are strongly related to diabetic microvascular complications in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetes Care 2010; 33(12):2648-53.

11. Dyck PJ, Overland CJ, Low PA, Litchy WJ, Davies JL, Dyck PJ, O'Brien PC; Cl vs. NPhys Trial Investigators, Albers JW, Andersen H, Bolton CF, England JD, Klein CJ, Llewelyn JG, Mauermann ML, Russell JW, Singer W, Smith AG, Tesfaye S, Vella A. Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial. Muscle Nerve 2010;42(2):157-64.

12. Gandhi RA, Marques JL, Selvarajah D, Emery CJ, Tesfaye S. Painful diabetic neuropathy is associated with greater autonomic dysfunction than painless diabetic neuropathy. Diabetes Care. 2010 Jul;33(7):1585-90

13. Ferrari GL, Marques JL, Gandhi RA, Heller SR, Schneider FK, Tesfaye S, Gamba HR. Using dynamic pupillometry as a simple screening tool to detect autonomic neuropathy in patients with diabetes: a pilot study. Biomed Eng Online. 2010; 17: 9-26.

14. Selvarajah D, Gandhi R, Emery CJ, Tesfaye S. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care. 2010; 33(1):128-30.

15. Tesfaye S, Selvarajah D. The Eurodiab study: what has this taught us about diabetic peripheral neuropathy? Curr Diab Rep. 2009 Dec;9(6):432-4.

16. Tesfaye S. Advances in the management of painful diabetic neuropathy. Curr Opin Support Palliat Care. 2009;3(2):136-43

17. Elliott J, Tesfaye S, Chaturvedi N, Gandhi RA, Stevens LK, Emery C, Fuller JH; the EURODIAB Prospective Complications Study Group. Large fibre dysfunction in diabetic peripheral neuropathy is predicted by cardiovascular risk factors. Diabetes Care. 2009;32(10):1896-900

18. Istenes I, Keresztes K, Hermányi Z, Putz Z, Vargha P, Gandhi R, Tesfaye S, Kempler P. Non-invasive evaluation of neural impairment in subjects with impaired glucose tolerance. Diabetes Care 2009;32(1):181-3.

19. Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, Griffiths PD, Tesfaye S. Thalamic Neuronal Dysfunction in Type 1 Patients with Diabetic Peripheral Neuropathy. Diabetologia 2008; 51(11):2088-92.

20. Istenes I, Keresztes K, Hermányi Z, Putz Z, Vargha P, Gandhi R, Tesfaye S, Kempler P. Relationship between autonomic neuropathy and hypertension--are we underestimating the problem? Diabet Med 2008;25(7):863-66.

21. Soedamah-Muthu SS, Chaturvedi N, Witte DR, Stevens LK, Porta M, Fuller JH; EURODIAB Prospective Complications Study Group. Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS). Diabetes Care. 2008;31(7): 360-6.

22. Rubino A, Rousculp MD, Davis K, Wang J, Bastyr EJ, Tesfaye S. Diagnosis of diabetic peripheral neuropathy among patients with type 1 and type 2 diabetes in France, Italy, Spain, and the United Kingdom. Prim Care Diabetes 2007 Sep;1(3):129-34.

23. Moustafa M, Bullock AJ, Creagh FM, Heller S, Jeffcoate W, Game F, Amery C, Tesfaye S, Ince Z, Haddow DB, MacNeil S. Randomized, controlled, single-blind study on use of autologous keratinocytes on a transfer dressing to treat non-healing diabetic ulcers. Regen Med. 2007 Nov;2(6):887-902.

24. 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;1:557-60.

25. Tesfaye S, Tandan R, Bastyr EJ, Kles KA, Skljarevski V, Price KA. Factors that impact on symptomatic diabetic peripheral neuropathy in placebo-treated patients from a two 1-year clinical trials. Diabetes Care 2007;30(10):2626-32.

26. Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care 2007;30:655-9

27. Quattrini C, Tavakoli M, Jeziorska M, Kallinikos P, Tesfaye S, Finnigan J, Marshall A, Boulton AJ, Efron N, Malik RA. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56(8):2148-54. .

28. Tesfaye S. Advances in the management of painful diabetic neuropathy. Clinical Medicine 2007; 7: 4-5

29. Selvarajah D, Tesfaye S. Central nervous system involvement in diabetes mellitus. Curr Diab Rep. 2006;6(6):431-8.

30. Jensen TS, Backonja MM, Hernandez Jimenez S, Tesfaye S, Valensi P, Ziegler D. New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res. 2006 ; 3: 108-119.

31. Tesfaye S. Neuropathy in Diabetes. Medicine 2006; 34:3: 91-94

32. Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, Griffiths PD, Tesfaye S. Early involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care 2006 ;29(12):2664-9.

33. Malik R, Veves A, Tesfaye S. Ameliorating human diabetic neuropathy: lessons from hematopoietic mononuclear cells. Exp Neurol 2006: Jun 27

34. Vinik AI, Bril V, Kempler P, Litchy WJ, Tesfaye S et al. Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial. Clin Therapeutics 2005 Aug;27(8):1164-80.

35. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte D, Fuller JH. Vascular risk factors and diabetic neuropathy. New Engl J Med 2005; 352(4): 341-350

36. Malik RA, Tesfaye S, Newrick PG et al. Sural nerve pathology in diabetic patients with minimal but progressive neuropathy. Diabetologia 2005; 48: 578-585.

37. Witte DR, Tesfaye S, Chaturvedi N at al. the EURODIAB Prospective Complications Study Group. Risk factors for cardiac autonomic neuropathy in Type 1 diabetes mellitus. Diabetologia 2005; 48: 164-171.

Endocrinology

1. P G Murray, A Read, I Banerjee, A J Whatmore, L E Pritchard, R A Davies, J Brennand, AWhite, R J Ross and P E Clayton. Reduced appetite and body mass index with delayed puberty in a mother and son: association with a rare novel sequence variant in the leptin gene. European Journal of Endocrinology (2011) 164 521–527

2. I.K. Tailor; M. Akil; I. Rennie; R.J. Ross; J.A. Snowden Reconstitution Graves' disease following autologous haematopoietic stem cell transplantation for severe diffuse systemic sclerosis. QJM 2011; doi: 10.1093/qjmed/hcr050

3. Debono M, Sheppard L, Irving S, Jackson P, Butterworth J, Brookes ZL, Newell-Price J, Ross JJ, Ross RJ. Assessing adrenal status in patients before and immediately after coronary artery bypass graft surgery. Eur J Endocrinol. 2011 Mar;164(3):413-9. Epub 2010 Dec 23

4. Perogamvros I, Owen LJ, Newell-Price J, Ray DW, Trainer PJ, Keevil BG. Simultaneous measurement of cortisol and cortisone in human saliva using liquid chromatography-tandem mass spectrometry: application in basal and stimulated conditions.

5. Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Snowden JA, Shalet SM, DeRogatis LR, Ross RJ Quality of life, self-esteem, fatigue, and sexual function in young men after cancer: a controlled cross-sectional study. Cancer 2010:116:1592-1601

6. Wass J, Toogood A, Brabant G, Ball S, Ross R Survivors of childhood cancer. Integrated follow-up is needed. BMJ 2010:340:c588

7. Verma S, Vanryzin C, Sinaii N, Kim MS, Nieman LK, Ravindran S, Calis KA, Arlt W, Ross RJ, Merke DP A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2010: 72:441-447

8. E. Ferrandis, S. L. Pradhananga, C. Touvay, C. Kinoshita, I. R. Wilkinson, K. Stafford, Z. Wu, C. J. Strasburger, J. R. Sayers, P. J. Artymiuk and R. J. Ross. Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand-receptor fusions. Clin Sci (Lond) 2010:119:483-491

9. Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ. 2010. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab 95:5110-5121.

10. Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J, Darzy K, Merke DP, Arlt W, Ross RJ. Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 2009 May;94(5):1548-54. Epub 2009 Feb 17.

11. Debono M, Ross R, Newell-Price J 2009 Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy. Eur J Endocrinol 2009; 160,719-29.

12. Miguel Debono, Cyrus Ghobadi, Amin Rostami-Hodjegan, Hiep Huatan, Michael J Campbell, John Newell-Price, Ken Darzy, Deborah P Merke, Wiebke Arlt, and Richard J Ross. Modified-release hydrocortisone to provide circadian cortisol profiles. J Clin Endocrinol Metab 2009,94,1548-54.

13. Michel G, Greenfield DM, Absolom K, Ross RJ, Davies H, Eiser C 2009 Follow-up care after childhood cancer: survivors' expectations and preferences for care. Eur J Cancer 45:1616-1623

14. Debono M, Price JN, Ross RJ 2009 Novel strategies for hydrocortisone replacement. Best Pract Res Clin Endocrinol Metab 23:221-232

15. Munir A, Choudhary P, Harrison B, Heller S, Newell-Price J. Continuous glucose monitoring in patients with insulinoma. Clin Endocrinol (Oxf). 2008 Jun;68(6):912-8. Epub 2007 Dec 17.Newell-Price J, Whiteman M, Rostami-Hodjegan A, Darzy K, Shalet S, Tucker GT, Ross RJ. Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.

16. M Whiteman, A. Rostami-Hodjegan, K. Darzy, S. Shalet, G.T. Tucker and R.J.M. Ross. Modified-release hydrocortisone for circadian therapy: A proof of principle study in dexamethasone-suppressed normal volunteers. Clinical Endocrinology 2008 Jan;68(1):130-5.

17. Absolom K, Eiser C, Turner L, Ledger W, Ross R, Davies H, Coleman R, Hancock B, Snowden J, Greenfield D 2008 Ovarian failure following cancer treatment: current management and quality of life. Hum Reprod 23:2506-2512

18. Siyambalapitiya S, Jonsson P, Koltowska-Haggstrom M, Gaillard R, Ho K, Ross RJ. 2008 A cross-sectional analysis of testosterone therapies in hypopituitary men on stable pituitary hormone replacement. Clin Endocrinol (Oxf) 2008,70,907-13.

19. Rinomhota AS, Bulugahapitiya DU, French SJ, Caddy CM, Griffiths RW, Ross RJ 2008 Women gain weight and fat mass despite lipectomy at abdominoplasty and breast reduction. Eur J Endocrinol 158:349-352

20. Munir A, Song F, Ince P, Walters SJ, Ross R, Newell-Price J. Ineffectiveness of rosiglitazone therapy in Nelson's syndrome. J Clin Endocrinol Metab. 2007 May;92(5):1758-63. Epub 2007 Feb 20.

21. Greenfield DM, Walters SJ, Coleman RE, Hancock BW, Eastell R, Davies HA, Snowden JA, Derogatis L, Shalet SM, Ross RJ. Prevalence and Consequences of Androgen Deficiency in Young Male Cancer Survivors in a Controlled Cross-Sectional Study. J Clin Endocrinol Metab. 2007 Sep;92(9):3476-82.

22. Debono M, Ross RJ. Doses and steroids to be used in primary and central hypoadrenalism. Ann Endocrinol (Paris). 2007 Sep;68(4):265-7.

23. Absolom K, Greenfield D, Ross R, Davies H, Hancock B, Eiser C 2007 Reassurance following breast screening recall for female survivors of Hodgkin's lymphoma. Breast (Edinburgh, Scotland) 16:590-596

24. Ian R.Wilkinson, Eric Ferrandis, Peter J. Artymiuk, Marc Teillot, Chantal Soulard, Caroline Touvay, Sarbendra L. Pradhananga, Sue Justice, Zida Wu, Kin C. Leung, Christian J. Strasburger, Jon R. Sayers, and Richard J. Ross. .A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist. Nature Medicine 2007, 9, 1108-1113.

25. Merza Z, Rostami-Hodjegan A, Memmott A, Doane A, Ibbotson V, Newell-Price J, Tucker GT, Ross RJ. Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2006 Jul;65(1):45-50.

26. Maamra M, Milward A, Esfahani HZ, Abbott LP, Metherell LA, Savage MO, Clark AJ, Ross RJ. A 36 residues insertion in the dimerization domain of the growth hormone receptor results in defective trafficking rather than impaired signaling. J Endocrinol. 2006 Feb;188(2):251-61.

27. Kelberman D, Rizzoti K, Avilion A, Bitner-Glindzicz M, Cianfarani S, Collins J, Chong WK, Kirk JM, Achermann JC, Ross R, Carmignac D, Lovell-Badge R, Robinson IC, Dattani MT. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest. 2006 Sep;116(9):2442-55.

28. Fang P, Kofoed EM, Little BM, Wang X, Ross RJ, Frank SJ, Hwa V, Rosenfeld RG. A mutant signal transducer and activator of transcription 5b, associated with growth hormone insensitivity and insulin-like growth factor-I deficiency, cannot function as a signal transducer or transcription factor. J Clin Endocrinol Metab. 2006 Apr;91(4):1526-34. Epub 2006 Feb 7.

29. Merza Z, Blumsohn A, Mah PM, Meads DM, McKenna SP, Wylie K, Eastell R, Wu F, Ross RJ 2006 Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism. Int J Androl 29:381-391

30. Absolom K, Greenfield D, Ross R, Horne B, Davies H, Glaser A, Simpson A, Waite H, Eiser C 2006 Predictors of clinic satisfaction among adult survivors of childhood cancer. Eur J Cancer 42:1421-1427

31. Eiser C, Absolom K, Greenfield D, Glaser A, Horne B, Waite H, Urquhart T, Wallace WH, Ross R, Davies H 2006 Follow-up after childhood cancer: Evaluation of a three-level model. Eur J Cancer

32. Greenfield DM, Wright J, Brown JE, Hancock BW, Davies HA, O'Toole L, Eiser C, Coleman RE, Ross RJ. 2006 High incidence of late effects found in Hodgkin's lymphoma survivors, following recall for breast cancer screening. Br J Cancer 94:469-472

33. Merza Z, Rostami-Hodjegan A, Memmott A, Doane A, Ibbotson V, Newell-Price J, Tucker GT, Ross RJ. Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia. Clin Endocrinol 2006, 65:45-50

34. Fazeli M, Zarkesh-Esfahani H, Wu Z, Maamra M, Bidlingmaier M, Pockley AG, Watson P, Matarese G, Strasburger CJ, Ross RJ. 2006 Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation. J Immunol Methods 312:190-200

35. Bowles CE, Wilkinson I, Smith RA, Moir AJ, Montgomery H, Ross RJ. R 2007 Membrane reinsertion of a myristoyl-peptidyl anchored extracellular domain growth hormone receptor. Endocrinology 148:824-830

36. Siyambalapitiya S, Ibbotson V, Doane A, Ghigo E, Campbell MJ, Ross RJ. Combining growth hormone releasing hormone-arginine and synacthen testing diminishes the cortisol response. J Clin Endocrinol Metab. 2007 Mar;92(3):853-6. Epub 2006 Dec 27.

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