1 Islet transplantation as promising therapy for diabetesNidal Younes MD Professor of Endocrine Surgery and Diabetic foot consultant- Jordan University Hospital

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4 International Diabetes Federation’sDiabetes mellitus chronic metabolic disorder, characterized by chronic hyperglycemia. leading to long-term damage, dysfunction and failure of various organs such as the heart kidneys, eyes and foot ulcers. it affects about 6% of the world’s population International Diabetes Federation’s

5 St Vincent declaration, Italy on 10–12 October 1989. “Diabetes mellitus is a major and growing European health problem, a problem at all ages and in all countries. It causes prolonged ill-health and early death.

6 An increase in prevalence of diabetes mellitus in Jordan over 10 yearsKamel Ajlouni,et al Journal of Diabetes and its Complications Volume 22, Issue 5, 317–324

7 Diabetes epidemic Farag YM, Gaballa MR. Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant Nov 2

8 Types of Diabetes Type I - body does not produce any insulin.Type II -body is not making enough or is losing sensitivity to insulin made. Secondary- a consequence from another disease, pancreatitis or cystic fibrosis. Gestational Diabetes- diabetes during pregnancy. Impaired Glucose Tolerance- an intermediate between normal and diabetes

9 Islet destruction Vs islet exhaustion

10 Treatment of Diabetes Lifestyle changes Diet Drugs Insulin* Sulfonylurea-stimulates insulin production. * Metformin-lowers blood sugar by helping the insulin work better * Thiazolidinediones- increases muscle sensitivity to insulin. * Alpha-glucosidase inhibitors- slow the process of carbohydrate digestion. Insulin Gene therapy Cell replacement therapy

11 Diabetes control & complications trial DCCT1441 adults randomized to conventional (1-2 dose of insulin) Vs Intensive ( >3 doses of insulin) Observed mean 605 years for complications □ Retinopathy First occurrence 67% Progression % □ Nephropathy Microalbuminuria 39% Clinical albuminuria 54% □ Neuropathy Progression 60%

12 Standards of Medical Care in Diabetes—2012A1C<7.0%* Preprandial capillary plasma glucose70–130 mg/dL* (3.9–7.2 mmol/L) Peak postprandial capillary plasma glucose <180 mg/dl

13 How good is the standard of care?Maysaa Khattab, Yousef S. Khader Abdelkarim Al-Khawaldeh Kamel Ajlouni: Factors associated with poor glycemic control among patients with Type 2 diabetes Poor glycemic control (HbA1c >7%) was present in 65.1% of patients Journal of Diabetes and Its Complications 24 (2010) 84–89

14 Conventional Vs intensive insulin Rx

15 Cell replacement therapy3 basic approaches: 1. Islet Cell Transplantation replacement of insulin-producing cells with mature, functioning cells from cadaver organ donors 2. Stem Cell Therapy to Regenerate Islet Function replacement of insulin-producing cells with stem cell-derived insulin-producing cells a. stem cells isolated and differentiated in vitro, then transplanted b. stem cells isolated and transplanted, differentiate in vitro 3. Stem Cell Therapy to Prevent Diabetes Onset modification of host immune system by stem cell-derived immune modulatory cells

16 Sources of Beta Cells Transplantable b-cellsEmbryonic Stem Cells, Allo Transplantable b-cells Adult b-cells, Allo Adult b-cells, Auto Pig Islets, Xeno Pancreatic Stem Cells, or Pancreatic Precursors, Adult, Auto Liver Cells, Transdifferentiation

17 HUMAN ISLET TRANSPLANTATION

18 The Endocrine PancreasFigure 18.18a, b

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20 Methods to treat with insulin-producing cellsPancreas transplant ●Pancreas obtained from cadaver donors, transplanted surgically within 12 hours ● Surgical procedure involves general anesthesia, abdominal surgery, and a 7-10 day hospitalization ● Complications: Thrombosis Pancreatic leak Infection ICT : Islet tissue obtained from cadaver organs by enzyme digestion of the pancreas and purification of islets via density gradients

21 Historical facts 1869- Islet cells described by Langerhansst attempt at pancreatic tissue Tx from animals – Williams 1970s- successful ICT from animal to animal– P.Lacy s- era of organ transplantation- Starzel, Najarian 1990s Minimum # of islets for successful transplantation- Brodzinski Automatic isolation of islet cells from the pancereas- Ricordi

22 Bernhard Hering Giessen/Minnesota Geneva, Milan James Shapiro Camillo Ricordi Automated method (1989) John Najarian Paul Lacy

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27 Final islet preparation

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30 “The road to edmonton” Shapiro AMJ et al, NEJM 2000; 343:230 7 consecutive patients achieved euglycemia during a mean follow-up of 11 months, with normal HgbA1c and GTT 6/7 patients required >1 donor (>1 transplant) a median of 29 days from the first procedure Mean islet equivalents =11,400/kg required to achieve euglycemia Cadaveric pancreata from older donors >45 yo (70% would have been discarded)

31 The Edmonton Protocol: update and follow-upRyan EA, et al, Diabetes 2005; 54:2060 65 patients treated with islet transplantation: 44 completed therapy (defined by insulin independence) Median duration of insulin independence =15 months Mean islets transplanted=799,912 128 procedures: Bleeding in 15, portal vein thrombosis in 5 2+ antihypertensive meds in 42% (6% at entry) Statin use 83% (23% at entry)

32 The 5 year honey period At 5 years, c-peptide secretion preserved but only 11% maintain insulin independence

33 HgbA1c remains improved despite return to insulin useInsulin-free Lost function Primary nonftn

34 ADA guidelines for IST IST performed in the context of researchType -1DM >5 years Absence of endogenous C-peptide Failure of intensive insulin Rx in maintaining glycemic homeostasis ( hypoglycemia/hyperglycemia Medical compliance Psychosocial and financial factors

35 How effective ICT 1990 to 1999; 267 ICT performed worldwide only 8% were free of insulin one year after transplantation. In 2001, the Collaborative Islet Transplant Registry (CITR) 12 transplant centers joined in the first year 19 were participating by September 2005. In July 2005, presented data on 138 patients 40 received only one ICT, 69 received 2, 28 received 3, and one received 4 infusions. 6 months after patients' final infusions, 67 % did not need insulin At one year, 58 % remained insulin independent. The recipients who still needed insulin treatment after one year experienced a reduction of 69 % in insulin needs.

36 ITN Multicenter Trial 9 centers enrolled 3-5 patients to replicate Edmonton trial16/36 patients rendered insulin-independent at one year following final infusion The overall success rate 58% of 1 year Insulin free Center Data presented by AMJ Shapiro at the ATC 2004

37 insulin independence after ISTMiami experience Australia's experience almost 80 %

38 CITR Annual Report Allograft Recipients Allograft Infusions Allograft DonorsFirst (2004) ® (inf) (Don) Second (2005) Third (2006) Fourth (2007) Fifth (2008) Sixth (2009) Seventh (2010) , ,010

39 OBSTACLES TO SUCCESSFUL ISLET TRANSPLANTATION: Low engraftment of isletsThe transplanted b cell mass is ~50% of the mass present in a normal individual The engrafted b cell mass is ~30% of the transplanted b cell mass Islet engraftment takes weeks before revascularization is completed, rendering islets susceptible to: • Hypoxic injury • Nonspecific cell-mediated injury: “IBMIR”, cytokine release, reactive oxygen intermediates elaborated during postoperative healing/wound reaction

40 Islets Possible Reasons for Islet Graft FailureInsufficient islet mass Poor quality of islets Failure to engraft Toxicity of anti- rejection drugs Islets Insulin resistance Disease recurrence Allograft rejection

41 The future of islet transplantationExperimental animal research era 1969 Human islet isolation research era 1990 Edmonton protocol era after 2000 Alternative sources for islet cells era Xenografts Cell cultures Stem cells

42 what are the complications of ICT?Acute complications: Bleeding ~10-15% Thrombosis ~5% Transaminitis ~50% Long-term complications: Renal function Hypertension Hyperlipidemia Mouth ulcers Risk of sensitization Risk of infection (CMV)

43 CONCLUSIONS: Pancreatic ICT represent an up-and –coming means to safely and effectively manage type-1 Innovations in ICT are still needed in reducing toxicity of meds inhibiting early inflammation Enhancing the survival and the function o the islets Organ allocation, patient selection, and payment for islet transplantation will remain controversial topics during the “growth” phase of development of islet transplant programs