1. 10.8.2007diasoce3.ppt1 Why is the current therapy not perfect?  Even slightly elevated blood glucose is harmful.  The limiting factor of insulin treatment is hypoglycaemia.  The compensation of disease is despite intensified treatment, new insulins (rapid and slow analogues) and pump treatment is often not sufficient – Peripheral/portal insulin – Lack of C-peptide (?!) – Lack of paracrine regulation – The human factor (doctor, patient)

2. 10.8.2007diasoce3.ppt2 Possibilities  Pancreas transplantation  Islet cell transplantation  B cells from stem cells  Genetically modified cells producing insulin  Regeneration of B cells  Arteficial Langerhans islets

3. 10.8.2007diasoce3.ppt3 Real possibilities  Pancreas transplantation (yes)  Islet cell transplantation (yes, but)  B cells from stem cells (research)  Genetically modified cells producing insulin (yes, but not for direct treatment)  Regeneration of B cells (???)  Closed loop system – pump and senzor (yes, but)  Arteficial islets (research)

4. 10.8.2007diasoce3.ppt4 History of transplantations  Soboljev (1902) Allen, 1913 (!!) – future possibility  Carrell Alexis – Nobel price, 1912 – Basic technology of cell culture, short-term success in experiments  Kelly et al., 1966 – 28 y. woman, 9 y T1DM, renal insufficiency. Pancreas and kidney transplantation. Normoglycaemia 6 days, acute pancreatitis, renal insufficiency, exitus after 3 months – Second transplantation – the pancreas worked 2 months – In two years 10 attempts, one-year function: one  and so on  Breakthrough in 1977, Sutherland, Minneapolis – In year 1986 one thousand, one-year graft survival from 3 to 40% – Similar results in Europe

5. 10.8.2007diasoce3.ppt5 Transplantation of pancreas and kidney  The beginnings – hard and dissapointing  Later – surgical skills (autodigestion of pancreas, vessels, rejection)  Current state of the art – effective and safe immunossupression and infection prophylaxis (cytomegalovirus) – Rejection dropped in the last 10 years from 80% to 20% – 5 year graft survival is 70 – 85 % – No progression of complications – IKEM Prague 1994 – 2005: 300

6. 10.8.2007diasoce3.ppt6 GRAFT SURVIVAL IN PRAGUE

7. 10.8.2007diasoce3.ppt7 Transplantation of islets or islet cells  First experiments 1965 – 1972  Basic problem – isolation of islets (collagenase, autodigestion of pancreas tissue).  Korec, Košice (1969 and later) – successful experiments on rats in a cellar without any help from the university  Under renal capsule, into v. renalis or v. portae  Unsufficient clinical results – Isolation and purification of islets – Islets from several donors – The metabolic compensation is worse than after organ transplantation  Clinical experiments were revived in 2000. Edmonton protocoll - Shapiro – hypoglycaemia unawareness patients – Good results of autotransplantations – Minimally invasive surgery (1 day) – Isolated islets can be stored

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12. 10.8.2007diasoce3.ppt12 Stem cells  Embryonal cells – ethical problem  Adult – rapid progress in the last years. Stem cells for islets can be found among ductal epithel cells  Therapeutical cloning – technological problems and legislative hurdles  Study of islet ontogenesis (very complicated)  Exact role of transcription factors – INGAP is a purified protein, in experiment lowers BG, activates other factors of islet development – Pdx1 k.o. mouse is born without pancreas. But Pdx1 is exprimoved also in adult age. K.o. leads to diabetes – more A than B cells, insufficient expression of GLUT2. The cause of MODY 4

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15. 10.8.2007diasoce3.ppt15 Regeneration of pancreas  Brunner  Korec, Šofranková (but also we)  Don’t believe the professors! (the cells of endocrine glands do not divide)  They divide - apoptosis and regeneration of B cells is intensive  Disturbed balance – T1 and T2DM

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17. 10.8.2007diasoce3.ppt17 Yeasts and bacteria produce insulin  In tanks of Eli Lilly (yeast) and NOVO- NORDISK (E. coli), but not in our body  (The problem of regulation)  Majority of diabetics is on human insulins  Genetic engineering (exchange of aminacids) rapid and very slow insulin analogues

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19. 10.8.2007diasoce3.ppt19 Closed loop systems Bioarteficial pancreas  Strips in glucometers produce color or electrical signal  Continuous glucose measurement (3 -5 days)  Insulin pumps are at hand  Connect them together  The first biostator was constructed in 1972  Does not work for long term and safely

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21. 10.8.2007diasoce3.ppt21 Convergence Toward Automation InsulinInsulin MonitoringMonitoring HCPSelf ManagementAutomation Insulin & syringes Pumps Pens Connectivity Clinic Monitoring Home Monitors Data Management Advice/Feedback Open Loop DeliveryDelivery Closed Loop You are here