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Injecting Enthusiasm Into the Future of Type 1 Diabetes Research

Injecting Enthusiasm Into the Future of Type 1 Diabetes Research. Mark Daniels, MD CHOC Children’s Diabetes Symposium January 29 th , 2010. Speaker Disclosures. Speaker Receives Salary Support from NIH/NIDDK Through TrialNet for work as Site/Local Principal Investigator.

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Injecting Enthusiasm Into the Future of Type 1 Diabetes Research

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  1. Injecting Enthusiasm Intothe Future of Type 1 DiabetesResearch Mark Daniels, MD CHOC Children’s Diabetes Symposium January 29th, 2010

  2. Speaker Disclosures • Speaker Receives Salary Support from NIH/NIDDK Through TrialNet for work as Site/Local Principal Investigator

  3. TrialNet is a network of 18 Clinical Centers and 150 affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand. TrialNet is dedicated to the study, prevention, and early treatment of type 1 diabetes.

  4. Points of Discussion • Note Increasing Incidence of Type 1 Diabetes • Identify Areas to Intervene • Genetic Predisposition + Environmental Triggers • Pre-Diabetes • At Diagnosis • Years Post-Diagnosis • Technological Solutions • Biological Solutions • There is HOPE

  5. Diabetes is out there!!! • Approximately one in 300 children under the age of 18 has type 1 DM. • ~1 million Americans have type 1 DM • Over 30 million annual physician visits for DM related services

  6. Incidence Type 1 Diabetesper 100,000 per year Children <=14 (As of 2000) Karvonnen et al., Diabetes Care, 23:1516, 2000

  7. T1D incidence is rising 3-5% per yearDue to environmental cause(s) Incidence /100,000/ yr in children aged 0-14 REWERS Type 1 Diabetes: Cellular, Molecular & Clinical ImmunologyEdited by George S. Eisenbarth Online Edition Version 3.0

  8. Islet autoantigen Type 1 diabetes is T cell mediated • Infiltrating CD4+, CD8+ T cells • Anti-T cell therapies are effective • Islet cell autoantibodies  disease CD4 T-cell CD8 T-cell TCR CD4 Treg Epitope HLA II Peakman HLA I APC Type 1 Diabetes: Cellular, Molecular & Clinical ImmunologyEdited by George S. EisenbarthOnline Edition Version 3.0

  9. Natural History of Type 1 Diabetes BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY “PRE”-DIABETES DIABETES TIME

  10. Natural History of Type 1 Diabetes Prevention: Oral Insulin Trial, GAD 65 Injection DAISY TEDDY TRIGR NIP CLINICAL ONSET BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY Interventions Anti CD3 Anti CD20 “PRE”-DIABETES DIABETES RESCUE- Transplant TIME

  11. NIP • Nearlyborns and Newborns who have a family member with Type 1 Diabetes Mellitus are eligible • Offered a common Dietary Supplement, DHA (an Omega-3 fatty acid) in hopes of “resetting” the immune system and preventing self-attack

  12. “The long-term goal of the TEDDY study is the identification of infectious agents, dietary factors, or other environmental agents, including psychosocial factors, which trigger type 1 diabetes in genetically susceptible individuals or which protect against the disease” http://teddy.epi.usf.edu/

  13. TRIGR

  14. Natural History of Type 1 Diabetes Prevention: Oral Insulin Trial, GAD 65 Injection TEDDY TRIGGER NIP CLINICAL ONSET Interventions: GAD 65 Anti CD3 Anti CD20 BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY “PRE”-DIABETES DIABETES RESCUE- Transplant TIME

  15. Previous Study (DPT-1) suggested that diabetes could be delayed or prevented in certain high risk individuals with an Insulin Pill This study will look at this group specifically. Insulin pill does not lower blood glucose, but may change immune system attack Oral Insulin

  16. Oral Insulin Subjects with Insulin Autoantibody notably Positive DPT-1 Group Diabetes Care 28:1068–1076, 2005

  17. Natural History of Type 1 Diabetes Prevention: Oral Insulin Trial, GAD 65 Injection TEDDY TRIGGER NIP CLINICAL ONSET Interventions: GAD 65 Anti CD3 Anti CD20 BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY “PRE”-DIABETES DIABETES RESCUE- Transplant TIME

  18. Diabetes Vaccinations Under Investigation • GAD 65-Alum Injection • May lead to tolerance/immunomodulation • Ludvigsson et al. 359 (18): 1909-20 NEJM October 30, 2008

  19. C-Peptide Levels in GAD treated vs. Placebo GAD n=35 Plac n= 34 Ludvigsson et al. 359 (18): 1909-20 NEJM October 30, 2008

  20. GAD n= 11 Plac n= 14 GAD n= 24 Plac n= 20 Fasting C-Peptide Levels by duration of Diabetes at time of study Ludvigsson et al. 359 (18): 1909-20 NEJM October 30, 2008

  21. Use of Anti-CD3 Comparison of Individual Insulin Doses at Baseline and 18 Months in Patients with an Initial Secretory Response at or above the 50th Percentile Keymeulen et al, N. Engl J Med 2005; 352:2598-608

  22. The Brazil Experience • The researchers enrolled 15 patients aged 14 to 31 (mean 19.2) between November 2003 and July 2006. All patients had been diagnosed with type 1 diabetes mellitus within the prior six weeks. • All patients were first given an immune ablative conditioning regimen (Cyclophosphamide and Antithymocyte globulin)

  23. Time Course of Total Area Under the Curve (AUC) of C-Peptide Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free Couri, C. E. B. et al. JAMA 2009;301:1573-1579. Copyright restrictions may apply.

  24. Transplantation Complications Couri, C. E. B. et al. JAMA 2009;301:1573-1579. Copyright restrictions may apply.

  25. The Brazil ExperienceConcerns • Cyclophosphamide – toxic to gonads • 1 patient had Bilateral pneumonia – resolved • Could there be worse side effects –worth it? • Not placebo controlled • Good honeymoon? • Final Results REMAIN TO BE SEEN

  26. Many More Studies!!!

  27. Natural History of Type 1 Diabetes

  28. Pumps

  29. Sensors/CGMS • Embedded in Pump • Medtronic • Stand Alone • Medtronic Guardian RT • DexCom • FreeStyle Navigator

  30. Super Computer

  31. How Do We Close the Loop? From Medtronic UK Website

  32. The Path to Clinical Use • Low Glucose Auto-suspend • Hypoglycemia Prevention • Treat-to-Range – closed-loop control to prevent extremes • Full closed-loop • Inpatient • Outpatient Buckingham, 2009

  33. A Closed-Loop System Should: • Detect the onset of eating • Detect Sensor Failure • Detect Infusion Set Failure • Prevent Hypoglycemia/Hyperglycemia • Be small and lightweight • “Auto-insertion” of sensors and infusion sets • Be user friendly Buckingham, 2009

  34. Patient Data from Personal Communication, Dr. Buckingham Buckingham, 2009

  35. Target Product – Hypo & Hyper Minimizer BG – mm Resume preset basal rate 10 Alarm – impending hypo No response – alarm plus automated insulin push to bring level below threshold No response – alarm plus insulin reduction or off Alarm – impending hyper Minimize time in “Red” zones 3.9 3.0 Time Courtesy B. Buckingham Modified by M.D. 40

  36. Pharmacokinetics & Pharmacodynamics Aspart (NovoLog) Insulin Pharmacokinetics: Insulin Levels • Pharmacodynamics: Insulin bioactivity Østerberg, J Pharmacokinet Pharmacodyn. 2003 Jun;30(3):221-35.

  37. Effect Of Age Of The Infusion Set On Insulin PharmacodynamicsSwan, Diabetes Care, 2009

  38. Exercise and Nocturnal Hypoglycemia(Glucose < 60 mg/dl) DirecNet, J Pediatr 2005;147:528-34

  39. Microneedle Arrays To Deliver Insulin Zahn, DTT 7: 536, 2005

  40. But Has Someone “Closed the Loop?”

  41. Closed Loop at UVA/Padova/Montpellier N=20subjects completed study Primary Outcome:Reduction in Nocturnal Hypoglycemia with better overall glucose control within target range: Overnight percent time within Target range of 70-140 mg/dl Nocturnal Hypoglycemic Episodes (BG<70 mg/dl)

  42. Sensor Vs. Venous Sampling and Insulin Delivery Weinzimer et al. Diabetes Care May 2008 vol. 31 no. 5 934-939

  43. Full Closed Loop Vs. Hybrid Weinzimer et al. Diabetes Care May 2008 vol. 31 no. 5 934-939

  44. Glycemic Control Parameters Weinzimer et al. Diabetes Care May 2008 vol. 31 no. 5 934-939

  45. Recognizing and Treating a Missed Meal Bolus Avoiding missed bolus events Lunch Detection < 30 min 2 Hours 13 y.o. male, A1c=8.8, Daily Summary Buckingham, 2009 Buckingham, 2009

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