Why is the current therapy not perfect?

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Presentation transcript:

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) 10.8.2007 diasoce3.ppt

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

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) 10.8.2007 diasoce3.ppt

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 10.8.2007 diasoce3.ppt

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 10.8.2007 diasoce3.ppt

GRAFT SURVIVAL IN PRAGUE 10.8.2007 diasoce3.ppt

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 10.8.2007 diasoce3.ppt

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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 10.8.2007 diasoce3.ppt

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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 10.8.2007 diasoce3.ppt

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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 10.8.2007 diasoce3.ppt

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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 10.8.2007 diasoce3.ppt

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Convergence Toward Automation I n s u l i n D e l i v e r y Insulin & syringes You are here Pumps Pens Closed Loop Connectivity Open Loop Data Management Advice/Feedback M o n i t o r i n g Home Monitors We are on a peth to automated blood glucose control. The workload of health care personnel will stay high through the current “self-management” stage. Only when useful devices which assist the user in making critical day to day control decisions become widely available will the medical workload begin to diminish. Clinic Monitoring HCP Self Management Automation Convergence Toward Automation 10.8.2007 diasoce3.ppt