1. Richard Smith Consultant Nephrologist Ipswich Hospital Beta cell replacement: Islet and whole pancreas transplantation

2. Whole pancreas usually transplanted as simultaneous kidney pancreas transplant Should be considered for all patients with type 1 diabetes listed for kidney transplantation Solitary pancreas transplantation also performed May be pancreas transplantation alone (PTA) or pancreas after kidney transplant (PAK) Indication is usually severe hypoglycaemia

3. Whole pancreas usually transplanted as simultaneous kidney pancreas transplant Should be considered for all patients with type 1 diabetes listed for kidney transplantation Solitary pancreas transplantation also performed May be pancreas transplantation alone (PTA) or pancreas after kidney transplant (PAK) Indication is usually severe hypoglycaemia Islet transplantation is usually performed as islet transplant alone (ITA). May also be performed as islet after kidney transplant Indication is severe hypoglycaemia

4. Figure 4a: Islet registrations by patient residence Figure 4b: Isolated pancreas registrations by patient residence Registrations by Strategic Health Authority – Maps, 1 February to 31 July 2011 * Three additional patients had overseas postcodes (including one from the Republic of Ireland)

6. Bristol Manchester Newcastle Royal Free Kings Oxford Edinburgh Single allocation scheme for whole pancreas and islet transplantation

7. 3 Indications for pancreas transplant alone 3.1 Criteria Presence of insulin dependent type 1 diabetes mellitus Significant diabetic complications Life threatening complications ie frequent and severe episodes of hypoglycaemia Hypoglycaemia unawareness Impairment of quality of life Other metabolic or behavioural problems causing referral by a diabetologist Indications: PTA

8. 3 Indications for pancreas transplant alone 3.1 Criteria Presence of insulin dependent type 1 diabetes mellitus Significant diabetic complications Life threatening complications ie frequent and severe episodes of hypoglycaemia Hypoglycaemia unawareness Impairment of quality of life Other metabolic or behavioural problems causing referral by a diabetologist. Indications: PTA

9. Indications: ITA Severe hypoglycaemia Two or more episodes of hypoglycaemia requiring outside help in the previous 6 months Hypoglycaemia unawareness

10. Outcomes: UK SPK 1 April 2003 to 31 March 2009 Pancreas graft survivalPatient survival

11. Outcomes: UK PTA/PAK 1 April 2003 to 31 March 2009 Pancreas graft survivalPatient survival

12. Islet transplantation: Bristol 3 Patients 1 achieved insulin independence with first transplant Acute graft failure 3 months post transplant 1 achieved complete resolution of hypoglycaemic for 1 year Reduction in insulin dose Has now received pancreas transplant 1 achieved resolution of hypoglycaemia with one transplant Second transplant 14.2.10 achieved insulin independence Remains insulin independent

13. UK Outcomes 54 islet infusions in 34 recipients 27 ITA 6 IAK 1 SIK 1 infusion n=16 2 infusions n=16 3 infusions n=2 96% graft function at one month Severe hypoglycaemia reduced by >95% HbA 1c reduced (8.4% vs 7.0%) International Outcomes (www.citregistry.org) 1072 infusions in 571 recipients 1 infusion 31% 2 infusions 47% 3 infusions 20% >3 2% Graft survival 40-80% five years 70% patients free of severe hypoglycaemia at 1 year 18 deaths over mean of 6 years follow up

14. Hypoglycaemia

15. In ‘typical’ month 1 patient admitted to GRH with acute abdomen 1 patient admitted to Moreton in the Marsh with chest pain 1 patient admitted to Cheltenham with chest pain 1 patient joint care with obstetrics 1 patient joint care with urology 3 patients referred for gastroenterology opinion 1 patient referred to pain clinic (peripheral neuropathy)

17. Summary of tests to assess function FPG/RBG/HbA1c 75g Oral Glucose Tolerance Test Mixed Meal Tolerance Test Arginine Intravenous Glucose Tolerance Test

19. PatientOGTTHbA1c (%)Fasting Glucose (mmol/L) 3 m12 m3 m12 m3 m12 m 1 (SPK)5.55.65.85.1 2 (PAK)4.45.14.74.6 3 (PTA)5.1 4.54.7 4 (PTA)5.25.34.04.1 5 (SPK)5.65.76.25.5 6 (PAK)5.86.04.85.8 Outcomes: Glycaemic control

20. PatientOGTTHbA1c (%)Fasting Glucose (mmol/L) 3 m12 m3 m12 m3 m12 m 1 (SPK)NGT 5.55.65.85.1 2 (PAK)NGT 4.45.14.74.6 3 (PTA)NGT 5.1 4.54.7 4 (PTA)NGT 5.25.34.04.1 5 (SPK)IGT 5.65.76.25.5 6 (PAK)DGT 5.86.04.85.8 85% of patients have normal OGTT at 1 year post transplant Outcomes: Glycaemic control

21. NGT Outcomes: Glycaemic control

23. Outcomes: Beta cell function Acute insulin response to glucose Acute insulin response to arginine Arginine intravenous glucose tolerance test 3 months post transplant

24. Islet Dysfunction Islet Dysfunction Functioning Islets Pancreas Dysfunction Functioning Pancreas Diabetes Insulin Independence Baidal et al, Transplantation 2009, 87(5): 689-697. Miami IsletsPancreas MMTTDysF (n=9)F (n=5)AbNGT (n=3)NGT (n= 15) Basal Glucose6.15.75.14.7 Basal C-peptide456486357526 90 min Glucose8.56.97.55.8 90 min C-peptide999103814771470 IVGTT AIR glucose10.320.534.458.7 AIR arginine21.624.439.853.4

25. Miami IsletsBristol Islets MMTTF (n=5)DysF 2 (n=9)Patient 2Patient 3 Basal Glucose5.76.165.8 Basal C-peptide486456218148 90 min Glucose6.98.512.27.7 90 min C-peptide1038999828531 IVGTT AIR glucose20.510.3-0.73.2 AIR arginine24.421.614.212.4

26. ArginineGlucose

27. Pancreas Transplantation ?

28. Islet Transplantation ? May not work!

29. International and UK outcomes support whole pancreas transplantation International results support islet transplantation UK results support islet transplantation also Patients presented clearly benefitted These results are from early phase of program At this time not ticking boxes associated with good outcome

30. Islet versus whole pancreas transplant ? Risk aversity Comorbidity Whole PancreasIslet

31. Neither whole pancreas or islet transplantation are best for all patients Choice is predicated on being able to achieve successful islet transplantation UK islet transplant outcomes are now good enough to justify islet transplantation’s place alongside whole pancreas transplantation

32. Primary indication the same: severe hypoglycaemia Islet transplant for the more risk averse patient or patient with comorbidity precluding whole pancreas transplantation Whole pancreas transplantation may be preferable for the patient in whom additional benefit might accrue from better more sustained glycaemic control

33. Further information Diapedia Islet transplantation – an overview 2014 Diapedia 81040851399 Rev no 4 Available from http://dx.doi.org/10.14496/dia.81040851399.4 http://dx.doi.org/10.14496/dia.81040851399.4 Pancreas transplantation 2014 Diapedia 81040851381 Rev no 6 Available from http://dx.doi.org/10.14496/dia.81040851381.6 http://dx.doi.org/10.14496/dia.81040851381.6 Also: www.clinimeded.co.uk