Stem Cells and Diabetes: A Website for BI108

1. Stem Cells and Diabetes:A Website for BI108 David Keyzer Nicholas Marcantonio Lesley Rabach Morgan Rabach Sannon Watkins

2. Diabetes is a syndrome characterized by hyperglycemia and glucose intolerance. This is due to either insulin deficiency or impaired effectiveness of insulin action. There are two main classes of diabetes Class I-”juevenile diabetes”, arises due to autoimmune destruction of pancreatic beta cells that secrete insulin Class II-”adult onset diabetes”, arises due to insufficient insulin production. Symptoms can often be controlled by exercise and dietary restriction. Stem cell therapies hold promise for the treatment of both classes. Diabetes

3. Heart disease/High blood pressure -Diabetics die from heart disease 2 to 4 times as often as diabetes free adults. -60% to 65% of people with diabetes have high blood pressure Stroke -The risk of stroke is 2 to 4 X higher in diabetic people. Blindness -Diabetes is the leading cause of new blindness in adults ages 20 to 74. Kidney disease -Diabetes is the leading cause of end-stage renal disease (ESRD).  It accounts for ~ 40% of new cases. -In 1995, approximately 100,000 diabetic people underwent dialysis or kidney transplantation. Amputations -More than 50% of lower limb amputations in the United States result from diabetes related  problems. Significant Risks are associated with Diabetes

4. Diabetes Impact on Society • About 16 million people (5.9% of the population) in the United States have diabetes mellitus. • Diabetes is one of the leading causes of death and disability. It was listed as the 7th leading cause of death in the US by the CDC in 1996. • Diabetes costs about $98 billion per year [1]. • The incidence of diabetes is rapidly on the rise Source: Journal of the American Medical Association

5. Economics • Of the $98.2 Billion Spent, $52.4 Billion Were Spent on Complications of Diabetes. This Accounts for Over 5% of the US Healthcare Budget. • The Average Cost of Treating Diabetes in the United States is $3,400 per Patient per Year • $170,000 After 50 years

6. Am I Covered? • Most States Require That Insurance Companies Cover Diabetes Treatment to Some Degree • The Patient Still Shoulders A Significant Burden, Often Paying A Percentage

7. Dietary adjustments and exercise is sufficient therapy for milder symptoms Insulin Therapy is the most popular current treatment for diabetes It is an insufficient therapy. It does not allow for effective adaptation to changing levels of blood glucose It is an inconvenience. It requires frequent injections/ the presence of a pump Stem cell therapies, if successful, offer a better life for diabetes sufferers No need for multiple injections and pumps More responsive to changing blood glucose levels Current TreatmentStem Cells and the FUTURE

8. Cells that have the capacity to regenerate themselves for long periods of time, and differentiate into specific tissues Two main sources of stem cells Adult-from adult tissues Embryonic- from early embryos Have the potential to treat diabetes and many other diseases(detail coming later) However, complications include: Maintaining in cell lines in culture Immune rejection Teratoma formation (ES) Difficulties in identifying and isolating, scarcity (Adult SC) Ethical Issues (ES) Stem Cells-Potential Therapy for Diabetes

9. Whole Pancreas Transplants • 1,300 people with type 1 diabetes receive whole-organ pancreas transplants each year • 83 percent of these patients have no symptoms of diabetes and do not have to take insulin to maintain normal glucose concentrations in the blood. [2] • However, two obstacles prevent transplantation from becoming a wide-spread therapy for type 1 diabetes • Shortage of donor supply • Need for Immunosuppressive therapy

10. Islet Cell Transplantation • Potential alternative for whole-organ transplants • Non-invasive • Less expensive • Less morbidity • Enticing, because, if islets can be cultured and replicated in vitro, the donor supply can be greatly increased • But, similar to whole-organ transplants in that immunosuppression would still be needed Source: http://cellbio.utmb.edu/microanatomy/Endocrines/endocrines.htm

11. Edmonton Protocol • "Less than 10% of the almost 300 islet allografts transplanted since 1990 resulted in insulin independence for periods of more than 12 months" [3]. • But in 2000, researchers reported a series of successful transplants according to the “Edmonton protocol” [4] • No cyclosporine, azathioprine, or steroids • Instead, sirolimus, tacrolimus, and daclizumab • About twice as many islets transplanted as compared to earlier protocols

12. Results of Edmonton Protocol • “All patients have been resolved of unstable type 1 diabetes and now have no problems with wide swings of blood glucose or hypoglycemia [5] • Problems include: • Lowered white cell count • Hemorrhage • Immunosuppression • SHORTAGE OF DONOR CELLS!!! • Long term effects need to be evaluated, but, demonstrates that islets can be transplanted such that they maintain sensitivity to glucose, and continue to secrete insulin Source: [4]

13. The Promise of Stem Cells • Edmonton protocol shows that cell-based therapies may serve as viable alternative to whole-organ transplant. • And, in the longer term, perhaps insulin therapy • But, for cell-based therapies to become clinically applicable • Donor supply needs to be increased • Issues regarding immunosuppression must be resolved • Stem cells offer the best way to tackle these issues

14. Cell Populations • It is currently unclear whether treatment would be beneficial with just beta cells or with complete pancreatic islets • Islets contain alpha, beta, and delta cells • Current research indicates that beta cells are less responsive to changes in glucose concentration than complete pancreatic islets. • Many researchers believe that a system in which the stem cells will become complete islet cluster will prove most beneficial.

15. Increasing Donor Supply? • Fetal Tissue • Already differentiated • No need for upstream specification • However: • Small donor supply, ethical issues, difficult to culture • Adult Tissue • Harvested from cadavers, cells lining pancreatic ducts, cells in pancreatic tissue • Isolated patient-specific • No ethical concerns • Greater tissue supply • But, difficulty with proliferating and culturing already differentiated beta cells from all cadaver/live patient tissue

16. Increasing Donor Supply II • Embryonic Stem Cells • Multipotent • Limitless capacity to replicate • Easiest to genetically manipulate • Embryoid bodies contain a subset of cells that function like beta cells. • Implantation may lead to teratoma formation • But, ethical concerns. Source: http://www.time.com/time/2001/stemcells/#

17. Graft Rejection/Immunology • Ultimate goal: create a line of donor cells that can be transplanted to diabetic patients that will not be destroyed by a recipient’s immune system • Thus, patients would not require immunosuppressive drugs • But, these cells must evade rejection for being non-self, as well as autoimmune antibodies • Research has shown that patients who receive pancreas transplants generate anti-islet antibodies to allogeneic islet cells

18. Graft Rejection/Immunology 2 • Immunoisolation • Encapsulation must: • allow uptake oxygen and other nutrients • allow bi-directional flow of glucose and insulin • Biocompatible [6].  • Problems caused by • Difficult diffusion kinetics • Issues with mechanical stability • Genetic Engineering? • Removing/Matching HLA antigens • Automimmunity? Source: [7]

19. A Word On Ethics • Patients Urge Research • Potentiality What Constitutes A Person? • Government Funding Limited President Limits Research on Embryonic Stem Cells • Past Precedents Where to Draw the Line? Source: http://www.specialchildren.about.com/library/weekly/aa073101b.htm

20. Interview with a Type I Diabetic Insurance Case Example Covers Part of the Insulin Pump Cost $700 Deductible, then 80% of Treatment Cost ------------------------------------------------------------------ Given that a cure for diabetes were offered which entailed some level of risk, what level of risk would you consider acceptable? “I would be willing to take almost no risk.  Studies have shown a very strong correlation between control of blood glucose and the incidence of complications.  Because I control my diabetes very tightly, I am not at risk of any complications, at least not for a long time. “ Type I Diabetic Age 21 Diagnosed 9 Years Ago

21. Interview (continued) If a cure could be offered with little to no risk, what would you be willing to pay? “Well, I would have to think about the cumulative cost of my disease over my lifetime, as well as the punitive effects of having it.  It's hard to say.  At this stage of my life, this is a disease that I can live with, even though it's a hassle.” . . . “The sentiment in the diabetes community is that a cure could almost come any day now.  With all of the diabetics I know, the feeling is positive.” Bradley Naylor, Brown ’03

22. Future Outlook • Ultimate goal • Unlimited supply of insulin-secreting cells that will not be destroyed via alloreactivity or auto-antibodies • In the meantime, expect stem cell research to lead to supply of donor cells that can be used in cell-based therapies • 1st Gen: Islet transplantation with immunosuppressive drugs as replacement for whole-organ transplants, but not insulin therapy • Improved drugs(tolerance inducing drugs) may increase number of recipients • 2nd Gen?: Encapsulated islets that do not require immunosuppressive drugs? • If this is viable, perhaps it will begin to replace insulin therapy • Type II Diabetes • New evidence suggests transplantation has benefits

23. Acknowledgements • Sincere thanks to Dr. E  Ed Baetge, Ph.D., the Chief Scientific Officer of CyThera Inc.  His knowledge, insight, and experience made our website possible.  Please take some time to visit www.cytheraco.com to learn about CyThera, and it's research of stem cells for use in the treatment of type 1 diabetes.

24. Works Cited [1] http://www.cdc.gov/diabetes/pubs/facts98.htm#top [2] National Institutes of Health (US) [NIH]. Stem Cells: Scientific Progress and Future Research Directions. Bethesda (MD): NIH; 2001 Jun. Available from: http://www.nih.gov/news/stemcell/scireport.htm. [3] Berná G, León-Quinto T, Enseñat-Waser R, Montanya E, Martín F, Soria B. Stem cells and diabetes. Biomedicine and Pharmacotherapy 2001;55:206-12. [4] Shapiro AMJ, Lakey JRT, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. The New England Journal of Medicine 2000;343(4):230-8. [5] Ryan EA, Lakey JRT, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001;50:710-9. [6] Berney T, Ricordi C. Islet cell transplantation: the future? Langenbeck's Archive of Surgery 2000;385:373-8. [7]  Lembert N, Petersen P, Wesche J, et al. In vitro test of new biomaterials for the development of a bioartificial pancreas. Annals of the New York Academy of Sciences 2001;944:271-6.