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Why is the current therapy not perfect?

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

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Why is the current therapy not perfect?

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  1. 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) diasoce3.ppt

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

  3. 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) diasoce3.ppt

  4. 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 3months • 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 diasoce3.ppt

  5. 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 % • Noprogression of complications • IKEM Prague1994 – 2005: 300 diasoce3.ppt

  6. GRAFT SURVIVAL IN PRAGUE diasoce3.ppt

  7. 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 diasoce3.ppt

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  12. Stem cells • Embryonal cells – ethical problem • Adult – rapid progress in the last years. Stem cells for islets can be found among ductal epithel cells • Therapeuticalcloning – 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 diasoce3.ppt

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  15. 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 diasoce3.ppt

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  17. 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 diabeticsis on human insulins • Genetic engineering (exchange of aminacids) rapid and very slow insulin analogues diasoce3.ppt

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  19. Closed loop systemsBioarteficial 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 diasoce3.ppt

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  21. Insulin Delivery Insulin & syringes You are here Pumps Pens Closed Loop Connectivity Open Loop Data Management Advice/Feedback Monitoring Home Monitors Clinic Monitoring HCP Self Management Automation Convergence Toward Automation diasoce3.ppt

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