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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2. 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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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)
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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 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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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 %
No progression of complications
IKEM Prague 1994 – 2005: 300
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6. GRAFT SURVIVAL IN PRAGUE
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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 Edmonton protocoll - Shapiro – hypoglycaemia unawareness patients
Good results of autotransplantations
Minimally invasive surgery (1 day)
Isolated islets can be stored
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8.
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9.
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10.
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11.
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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
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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13.
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14.
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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
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16.
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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 diabetics is on human insulins
Genetic engineering (exchange of aminacids) rapid and very slow insulin analogues
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18.
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19. 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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20.
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21. 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
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