1. Research in T1D Cumming School of Medicine Department of Paediatrics
Carol Huang, MD, PhD, FRCPC
Division of Endocrinology
November 25, 2017

2. Type 1 Diabetes
Nature Rev Gastro 2017

3. Pathology of Type 1 Diabetes
Mononuclear cell infiltration

4. Progression to Type 1 Diabetes
GENETICALLY AT RISK
MULTIPLE ANTIBODY POSITIVE
LOSS OF FIRST PHASE
INSULIN RESPONSE
GENETIC
PREDISPOSITION
BETA CELL MASS
INSULITIS
BETA CELL INJURY
“PRE”-DIABETES
DIABETES
TIME
NEWLY DIAGNOSED DIABETES
Eisenbarth

5. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Stem Cells
Artificial Pancreas
Prevention

6. Nanomedicines and autoimmune disease
Courtesy of Dr. Pere Santamaria

7. Nanomedicines and autoimmune disease
Nature, 2016

8. Nanomedicines and autoimmune disease
Courtesy of Dr. Pere Santamaria

9. Nanomedicines and autoimmune disease
Courtesy of Dr. Pere Santamaria

10. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Stem Cells
Artificial Pancreas
Prevention

11. Islet Transplantation

12. Islet Transplantation

13. Islet transplantation – Edmonton Protocol
NEJM, 2000
Insulin independence is 33%-50% at 5 years

14. Islet transplantation – Challenges
Poor graft survival – alternative sites
Not enough donors – Stem Cells
Toxicity of Immunosuppression

15. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Stem Cells
Artificial Pancreas
Prevention

16. Islet transplantation – under the Skin
collagen cylinders “modules” embedded with endothelial cells
PNAS, 2017

17. Islet transplantation – muscle
Diabetologia, 2017

18. Islet Transplantation – clinical trials of different implantation sites
Current site
Nature Rev Gastro 2017

19. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Stem Cells
Artificial Pancreas
Prevention

20. Stem Cells Are Amenable to Large Scale Production
Courtesy of Dr. Tim Kieffer, UBC

21. Macroencapsulation Courtesy of Dr. Tim Kieffer, UBC
polytetrafluoroethylene (PTFE)
1 million islets, each with 1000 beta cells = 1 billion beta cells.
Therefore need about 10 times this device for human pancreas equivalent.
Islet transplant = 1 ml pellet = 1000 ul = 25 times the volume – but how pure are human islets, and how many survive? Note the function is minimal compared to normal.
Courtesy of Dr. Tim Kieffer, UBC

22. Maturation of Progenitors
Pre-Transplant
Post-Transplant
Courtesy of Dr. Tim Kieffer, UBC

23. Reversal of Diabetes by Macroencapsulated Progenitors
Recipients = SCID-beige mice
Courtesy of Dr. Tim Kieffer, UBC

24. PEC-Direct (ViaCyte)
University of Alberta (Alberta Diabetes Institute), UC san Diego School of Medicine, University of Minnesota
Human Embryonic Stem Cells (hESC) packaged in immunoprotective devices called “sentinels”
Phase 1 clinical trial
safety

25. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Stem Cells
Artificial Pancreas
Prevention

26. MiniMed 670 G: “Artificial Pancreas”

27. “Artificial Pancreas”
Suspend Before Low
Automatically stopping insulin 30 minutes before reaching pre-selected low limits
Automatically restarts insulin when blood glucose level recovers
Auto Mode
Automatically adjusts basal insulin delivery every 5 minutes based on blood glucose levels

28. “Artificial Pancreas”
NEJM, 2013

29. “Artificial Pancreas”
Sensor-augmented insulin pump
NEJM, 2013

30. “Artificial Pancreas”
Sensor-augmented insulin pump
NEJM, 2013

31. “Artificial Pancreas” – Bionic Pancreas
Insulin pump with an automatic adaptive algorithm using information from a continuous glucose monitor to control delivery of insulin and glucagon.

32. “Artificial Pancreas” – Bionic Pancreas
NEJM, 2014

33. “Artificial Pancreas” – Bionic Pancreas
NEJM, 2014

34. “Artificial Pancreas” – Bionic Pancreas
NEJM, 2014

35. “Artificial Pancreas” – Bionic Pancreas
Day time
Lancet, 2017

36. “Artificial Pancreas” – Bionic Pancreas
Night Time
Lancet, 2017

37. “Artificial Pancreas” – Bionic Pancreas
Lancet, 2017

38. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Stem Cells
Artificial Pancreas
Prevention

39. Oral Insulin - TrialNet
JAMA, 2017

40. Abatacept - TrialNet APC T-cell Abatacept Courtesy of TrialNet MHC TCR
CD28
CD80/86
T-cells play a central role in the pathogenesis of autoimmune diseases. T cell activation is thought to involve a “two-signal” model, “signal 1” is the interaction of the T cell receptor (TCR) with the antigen-MHC complex, meanwhile “signal 2” is the engagement of the co-stimulatory receptors. Both signals are required for optimal T cell activation; in the absence of signal 2, T cells fail to activate and became anergic. Abatacept binds to CD80/CD86 receptors on antigen presenting cells, thereby inhibiting their binding to the co-stimulatory molecule CD28 on T-cells. By inhibiting full T-cell activation, Abatacept also affects the downstream inflammatory cascade.
Abatacept
Courtesy of TrialNet

41. Research in Type 1 Diabetes
Nanomedicines
Beta cell replacement/Islet transplantation
Alternative transplant sites
Skin – pre-clinical
Muscle – pre-clinical
Stem Cells
hESC – clinical trial
iPSC – pre-clinical trial
Encapsulation – clinical trial
Artificial Pancreas
miniMED 670g – FDA approved
Bionic pancreas – clinical trial
Prevention
Oral insulin – clinical trial (completed)
Abatacept – clinical trial (recruiting)