10.8.2007diasoce3.ppt1 why is the current therapy not perfect? even slightly elevated blood glucose...
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10.8.2007 diasoce3.ppt 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)
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Possibilities
Pancreas transplantation Islet cell transplantation B cells from stem cells Genetically modified cells producing
insulin Regeneration of B cells Arteficial Langerhans islets
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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)
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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
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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
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GRAFT SURVIVAL IN PRAGUE
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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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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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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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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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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
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10.8.2007 diasoce3.ppt 21Convergence Toward Automation
Insulin
Monitoring
HCP Self Management Automation
Insulin & syringes
Pumps
Pens
Connectivity
Clinic Monitoring
Home Monitors
Data ManagementAdvice/Feedback
Open Loop
Delivery
Closed Loop
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