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1. INTRODUCTION 2. DEVELOPMENT OF THE PANCREAS

1. INTRODUCTION 2. DEVELOPMENT OF THE PANCREAS 3. DEVELOPMENT OF CELL-BASED THERAPIES FOR DIABETES 4. FETAL TISSUE AS SOURCE FOR ISLET CELLS 5. ADULT TISSUE AS SOURCE FOR ISLET CELLS 6. EMBRYONIC STEM CELLS 7. FUTURE DIRECTIONS. INTRODUCTION. Diabetes Mellitus.

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1. INTRODUCTION 2. DEVELOPMENT OF THE PANCREAS

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  1. 1. INTRODUCTION 2. DEVELOPMENT OF THE PANCREAS 3. DEVELOPMENT OF CELL-BASED THERAPIES FOR DIABETES 4. FETAL TISSUE AS SOURCE FOR ISLET CELLS 5. ADULT TISSUE AS SOURCE FOR ISLET CELLS 6. EMBRYONIC STEM CELLS 7. FUTURE DIRECTIONS

  2. INTRODUCTION Diabetes Mellitus • Type 1 DM( beta cell destruction) • - Immune-mediated • - Idiopathic • Type 2 DM( insulin resistance and/or deficiency) Current Treatment of Diabetes • - Control of blood glucose and Symptoms • - Prevention of chronic complications • - Diet • - Exercise • - Pharmacotherapy • - Oral agent • - Insulin • Problem; chronic complications

  3. Complications of DM Heart disease; x2-4 higher Stroke; x4 higher High blood pressure ; 73% of hypertensive pt Blindness; leading cause of new cases Kidney disease; leading cause of end-stage renal disease, 44% of new cases Nervous system disease; About 60 percent to 70 percent of people with diabetes Amputations; More than 60 percent of nontraumatic lower-limb amputations Dental disease; one-third of people with diabetes Complications of pregnancy Other complications

  4. UK Prospective Diabetes Study - multi-centre - randomized controlled trial: of different therapies of Type 2 diabetes UKPDS : need for a long-term study • complications of Type 2 diabetes develop • over decades • Protocol written 1976 • Recruitment 1977-1991 • End of study Sept. 1997 • Clinical Centres 23 • Type 2 diabetic patients 5102 • Person years follow-up 53,000 UKPDSAny Diabetes Related Endpoint (cumulative )

  5. Any Diabetes Related Endpoint • First occurrence of any one of: 1401 of 3867 patients (36%) • - diabetes related death • - non fatal myocardial infarction, heart failure or angina • - non fatal stroke • - amputation • - renal failure • - retinal photocoagulation or vitreous haemorrhage • - cataract extraction or blind in one eye 329:977-986 (1993) Cumulative Incidence of Urinary Albumin Excretion 300 mg per 24 Hours (Dashed Line) and 40 mg per 24 Hours (Solid Line) in Patients with IDDM Receiving Intensive or Conventional Therapy The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus The Diabetes Control and Complications Trial Research Group

  6. New Treatment of Diabetes • - Transplantation • - Whole or segmental pancreas transplantation • - Islet transplantation • - Implantable devices • Closed loop systems • Bio-responsive membrane • Pump, insulin reservoir and glucose sensor • - Hybrid artificial pancreas • - Gene Therapy Islet Cell Transplantation • - Attractive possibility for the treatment of diabetes • - Reversibility of late complication • - More safer and simpler than pancreas transplantation • - Auto-transplantation: Chronic Pancreatitis, trauma • - Allo-transplantation • Type 1 DM with renal problem (Limited indication) • Type 2 DM with kidney transplantation.

  7. The Benefits of Islet Transplant - No need for insulin therapy - Improved glucose control (provided graft function persists) - Elimination of comas, hypoglycemic reactions & metabolic labiality - Normal HbA1C (impossible with intensive insulin therapy) - Prevention/stabilization/reversal of early 2º complications - Better quality of life - Much lower risk than whole (vascularized) pancreas transplant

  8. Cumulative 3 year patient and graft survival in C-peptide Negative type-1 Diabetic Recipients: 1990-1997: n=200 Total Number of Adult islet allografts 1974-2000: 445

  9. Islet Volume 11,547±1,604 EIN/kg Steroid free Immunosuppression Silolimus(Rapamune, Wyeth-Ayerst) tacrolimus(Prograf, Fujisawa) Daclizumab(Zenapax, Roche): IL-2R mAb Blood glucose levels: Before and after islet transplantation

  10. Barriers of Islet Transplantation • - Immunosuppression • - Diabetogenic effects of some immunosuppressants • - Immunological rejection • - Oncogenic effects of long term use of immunosuppressive treatment • - Shortage of donor pancreas and islets Insulin secretion cells from other source • - Genetically designed insulin secreting artificial beta-cells • :- Tumor or transformed cell lines • :- Proliferating islet cells of human origin • :- Fetal pancreatic tissue • :- Pancreatic ductal cell ? • - Stem cells: adult or embryonic • - Xenotransplantation: Animal tissue

  11. Development Of Cell-based Therapies For Diabetes • - Source for Islet Cells • :- Fetal tissue • :- Adult tissue • :- Embryonic stem cells Fetal tissue Diabetes46(2):   244-248 (1997) Molecular Endocrinology 15 (3): 476-483 ß-Cell Differentiation from a Human Pancreatic Cell Line in Vitro and in Vivo Functional beta-Cell Mass After Transplantation of Human Fetal Pancreatic Cells: Differentiation or Proliferation? D. Dufayet de la Tour, T. Halvorsen, C. Demeterco, B. Tyrberg, P. Itkin-Ansari, M. Loy, S.-J. Yoo, E. Hao, S. Bossie & F. Levine Beattie, Gillian M.; Otonkoski, Timo; Lopez, Ana D.; Hayek, Alberto • - transformed pancreatic ß-cell lines • :- expression of dominant oncogenes transcription • factor PDX-1 • - Major problem • :- Balance growth and differentiation • Growth (+) cell: insulin secretion(-) • Insulin secretion(+) cell: no proliferation Comparison of insulin content; fetal islets, freshly isolated islets and ICCs

  12. 20 mM glucose 5 mM glucose Adult tissue • - Islet progenitor cells? • :- Pancreatic ductal cells • :- CHIBs (cultivated human islet buds) • :- Subset of stem-cell like islet progenitor cells • :- Nestin positive cells CHIBs(Cultivated Human Islet Buds) Pancreatic ductal cell culture Cultivated Human Islet Buds(CHIBs) immunostained for pan-cytokeratin (FITC green); Insulin-positive cells (Texas red)

  13. Stem-like Cells Within Islet and Duct Nestin-positive cells are expressed in localized regions of the ducts in the rat pancreas Diabetes 2001 50: 521-533 Expression of the neural stem cell–specific marker nestin in a distinct cell population within pancreatic islets Secretion of pancreatic endocrine hormones from differentiation human NIP cells

  14. Embryonic stem cells Mouse ES cells Diabetes 2000 49:157-162 ES derived insulin secreting cells Changes in blood glucose levels after implantation of IB/3x-99 cells Glucose-induced insulin release in IB/3x-99 cells

  15. Double-immunofluorescence staining for insulin/nestin during and at the end of stage 3, and for insulin-[ beta] -III tubulin at the end of stages 4 and 5.Bar,100 µ m ES cells generate insulin-positive cells that associate with neurons Insulin-producing cells contain different hormone-producing cell types and are organized in three-dimensional clusters with topological organization similar to pancreatic islets

  16. Islet clusters release insulin in response to glucose using normal pancreatic mechanisms

  17. EBs at day 19 after differentiation Normal Human pancreas Human ES cells Insulin secretion at various glucose concentrations and growth conditions Diabetes 2001 50: 1691-1697 Differentiation of hES cells in suspension culture Potential cure for diabetes Insulin-expressing cells in EBs

  18. Summary Primordial Gonads EG Teratocarcinoma EC Inner cell mass ES Adult Brain Bone marrow Muscle Skin Intestinal Epithelia Pluripotent Stem cells • In vitro differentiation • Cell-lineage selection • Maturation Ductal Cells Beta-cell Cell transplantation

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