1. Oliver Rácz Dedicated to prof. Korec and doc. Šofranková
Twists in the tale of diabetes history and the role of our people in it
Oliver Rácz
Dedicated to prof. Korec and doc. Šofranková
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2. Twists in the tale of diabetes history “Serendipity”
The Ebers papyrus, ancient oriental medicine
Rare and mysterious disease
Arateus, Demetrios, Galenos, Avicenna
Terminology, symptomatology
Johann Konrad Brunner, 1683
Pancreas extirpation in dogs, transient polyuria
Langerhans
Doctoral thesis on pancreas histology
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3. Twists in the tale of diabetes history “Serendipity”
Mehring and Minkowski, 1889
Pancreas extirpation in dogs to study the lipid metabolism – polyuria, glucosuria!!!
Banting (surgeon without patients) and Best (student after his biochemistry exam) 1921
But also Züelzer, Paulesco, MacLeod
And finally Marjorie, L. Thompson, The Nobel Price – who???
Eli Lilly, Joslin
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4.
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5.
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6.
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7. The glorious tale of diabetes history
sir Frederick Sanger
(a Quaeker)
1945 – 1953 analysis of primary structure of 2 peptide chains (51 AAs)
Lecture in Košice, 1967 about mRNA structure
Sanger Institute in Cambridge
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8. HUMAN INSULIN WITHOUT C-PEPTIDE G I V E Q C C T S I C S L Y Q L E N Y C N F V N Q H L C G S H L V E A L Y L V C G E R G F F Y T
HUMAN INSULIN WITHOUT C-PEPTIDE
DISULPHIDES BETWEEN: A6 – A1,1A7 – B7, A20 – B19 P K T
HUMAN PROINSULIN WITH C-PEPTIDE
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9. The glorious tale of diabetes history also with us
Rosalyn Yalow and Solomon Berson, from 1960
Radioimunoassay of insulin (RIA, NP 1977)
1971 Anna Šofranková from our institute and introduction the method
Oral drugs
Salicylates, alkaloids, guanidin (!)and a lot of...
VK 57, a new sulfonamide. 3 gonorrhea patient died (2nd WW) in coma. Loubatières – reduction of BG but not in pancreatectomized dogs. (NP)
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10. The glorious present – never without us
Genetic engineering
Human and analog insulins
Technology
Glucometers, pens, continuous measurements, pumps
Unusual haemoglobin 1968, Iran
Hb A1c is an integrated long-time restrospective marker of glycaemic compensation
Introduced from 1979 at our institute
DCCT, UKPDS
Milestones in therapy of DM and prevention of chronic complications
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11. An „unusual“ Hb in blood of diabetic patients
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12. Yeasts and bacteria produce insulin
In tanks of Eli Lilly (yeast) and NOVO-NORDISK (E. coli), but not in our body
Majority of diabetics is on human insulins
Genetic engineering (exchange of aminoacids) rapid and very slow insulin analogues
Is it really necessary? Insulin is also a growth factor ! (ILGs)
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13. ANALOGUES Great scientific success Big commercial pressure
Lot of questions
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14. 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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15. 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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16. Transplantation of pancreas and kidney
The beginnings – hard and dissapointing, 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
Later – improvements in surgical skills (autodigestion of pancreas, vessels) and rejection prevention
Current state – 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
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17. GRAFT SURVIVAL IN PRAGUE
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18. Islet transplantation – simple in therory but…
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19. A simple infusion if you have enough islets
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20. Experimental transplantation in 60’s
Prof. Rudolf Korec, 1923 – 2003
Experimental transplantation in 60’s
Persecuted after the Soviet occupation in 1968
“Slavery work” alone in a cellar from 1971
First elected Rector, 1989
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21.
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22. 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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23. 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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24.
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25. We are here Self Management Automation I n s u l i n D e l i v e r y
Insulin & syringes
We are here
Pumps
Pens
Connectivity
Open Loop
Advice/Feedback
Closed Loop
Data Management
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.
Continuous monitoring
Clinic Monitoring
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Self Management
Automation