10.8.2007diasoce3.ppt1 Why is the current therapy not perfect? Even slightly elevated blood glucose is harmful. The limiting factor of insulin treatment

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)


Possibilities

Pancreas transplantation Islet cell transplantation B cells from stem cells Genetically modified cells producing

insulin Regeneration of B cells Arteficial Langerhans islets


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)


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


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


GRAFT SURVIVAL IN PRAGUE


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






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




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



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



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


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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10.8.2007diasoce3.ppt1 Why is the current therapy not perfect? Even slightly elevated blood glucose is harmful. The limiting factor of insulin treatment