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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 l.jpg

Injecting Enthusiasm Intothe Future of Type 1 DiabetesResearch

Mark Daniels, MD

CHOC Children’s

Diabetes Symposium

January 29th, 2010


Speaker disclosures l.jpg
Speaker Disclosures

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


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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.


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Points of Discussion affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand.

  • 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


Diabetes is out there l.jpg
Diabetes is out there!!! affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand.

  • 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


Incidence type 1 diabetes per 100 000 per year children 14 as of 2000 l.jpg
Incidence Type 1 Diabetes affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand. per 100,000 per year Children <=14 (As of 2000)

Karvonnen et al., Diabetes Care, 23:1516, 2000


T1d incidence is rising 3 5 per year due to environmental cause s l.jpg
T1D incidence is rising 3-5% per year affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand. Due 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


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Islet affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand.

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


Slide9 l.jpg

Natural History of Type 1 Diabetes affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand.

BETA CELL MASS

GENETIC

PREDISPOSITION

INSULITIS

BETA CELL INJURY

“PRE”-DIABETES

DIABETES

TIME


Slide10 l.jpg

Natural History of Type 1 Diabetes affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand.

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


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NIP affiliates in the United States, Canada, Finland, United Kingdom, Italy, Germany, Australia, and New Zealand.

  • 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


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  • “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/


Trigr l.jpg
TRIGR 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”


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Natural History of Type 1 Diabetes 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”

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


Oral insulin l.jpg

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


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Oral Insulin delayed or prevented in certain high risk individuals with an Insulin Pill

Subjects with Insulin Autoantibody notably Positive

DPT-1 Group Diabetes Care 28:1068–1076, 2005


Slide18 l.jpg

Natural History of Type 1 Diabetes delayed or prevented in certain high risk individuals with an Insulin Pill

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


Diabetes vaccinations under investigation l.jpg
Diabetes Vaccinations Under Investigation delayed or prevented in certain high risk individuals with an Insulin Pill

  • GAD 65-Alum Injection

    • May lead to tolerance/immunomodulation

    • Ludvigsson et al. 359 (18): 1909-20 NEJM October 30, 2008


C peptide levels in gad treated vs placebo l.jpg
C-Peptide Levels in GAD treated vs. Placebo delayed or prevented in certain high risk individuals with an Insulin Pill

GAD n=35

Plac n= 34

Ludvigsson et al. 359 (18): 1909-20 NEJM October 30, 2008


Fasting c peptide levels by duration of diabetes at time of study l.jpg

GAD n= 11 delayed or prevented in certain high risk individuals with an Insulin Pill

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


Use of anti cd3 l.jpg
Use of Anti-CD3 delayed or prevented in certain high risk individuals with an Insulin Pill

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


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The Brazil Experience delayed or prevented in certain high risk individuals with an Insulin Pill

  • 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)


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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.


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Transplantation Complications 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.


The brazil experience concerns l.jpg
The Brazil Experience Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin FreeConcerns

  • 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


Many more studies l.jpg
Many More Studies!!! Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free


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Natural History of Type 1 Diabetes Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free


Pumps l.jpg
Pumps Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free


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Sensors/CGMS Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

  • Embedded in Pump

    • Medtronic

  • Stand Alone

    • Medtronic Guardian RT

    • DexCom

    • FreeStyle Navigator


Super computer l.jpg
Super Computer Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free


How do we close the loop l.jpg
How Do We Close the Loop? Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

From Medtronic UK Website


The path to clinical use l.jpg
The Path to Clinical Use Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

  • Low Glucose Auto-suspend

  • Hypoglycemia Prevention

  • Treat-to-Range – closed-loop control to prevent extremes

  • Full closed-loop

    • Inpatient

    • Outpatient

Buckingham, 2009


A closed loop system should l.jpg
A Closed-Loop System Should: Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

  • 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


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Patient Data from Personal Communication, Dr. Buckingham Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

Buckingham, 2009


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Target Product – Hypo & Hyper Minimizer Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

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


Pharmacokinetics pharmacodynamics aspart novolog l.jpg
Pharmacokinetics & Pharmacodynamics Aspart (NovoLog) Levels During Mixed-Meal Tolerance Test in 12 Patients Continuously Insulin Free and in 8 Patients Transiently Insulin Free

Insulin Pharmacokinetics: Insulin Levels

  • Pharmacodynamics: Insulin bioactivity

Østerberg, J Pharmacokinet Pharmacodyn. 2003 Jun;30(3):221-35.


Effect of age of the infusion set on insulin pharmacodynamics swan diabetes care 2009 l.jpg
Effect Of Age Of The Infusion Set On Insulin PharmacodynamicsSwan, Diabetes Care, 2009


Exercise and nocturnal hypoglycemia glucose 60 mg dl direcnet j pediatr 2005 147 528 34 l.jpg
Exercise and Nocturnal Hypoglycemia(Glucose < 60 mg/dl) DirecNet, J Pediatr 2005;147:528-34



But has someone closed the loop l.jpg
But Has Someone “Closed the Loop?” DirecNet, J Pediatr 2005;147:528-34


Closed loop at uva padova montpellier l.jpg
Closed Loop at UVA/Padova/Montpellier DirecNet, J Pediatr 2005;147:528-34

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)


Sensor vs venous sampling and insulin delivery l.jpg
Sensor Vs. Venous Sampling and Insulin Delivery DirecNet, J Pediatr 2005;147:528-34

Weinzimer et al. Diabetes Care May 2008 vol. 31 no. 5 934-939


Full closed loop vs hybrid l.jpg
Full Closed Loop Vs. Hybrid DirecNet, J Pediatr 2005;147:528-34

Weinzimer et al. Diabetes Care May 2008 vol. 31 no. 5 934-939


Glycemic control parameters l.jpg
Glycemic Control Parameters DirecNet, J Pediatr 2005;147:528-34

Weinzimer et al. Diabetes Care May 2008 vol. 31 no. 5 934-939


Recognizing and treating a missed meal bolus l.jpg
Recognizing and Treating a Missed Meal Bolus DirecNet, J Pediatr 2005;147:528-34

Avoiding missed bolus events

Lunch

Detection < 30 min

2 Hours

13 y.o. male, A1c=8.8, Daily Summary

Buckingham, 2009

Buckingham, 2009


Metabolic control closed loop subject 1 l.jpg
Metabolic Control Closed-loop Subject 1 DirecNet, J Pediatr 2005;147:528-34

Post-DKA

Humalog

And Lantus

Mean 245±111

3-day closed loop

Mean 138±50

At home on Sensor Augmented Pump

Mean 145±50

Buckingham, 2009

Buckingham, 2009


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Pumps and Sensors Communicate to a Shared Platform DirecNet, J Pediatr 2005;147:528-34

Buckingham, 2009


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Islet Cell Encapsulation DirecNet, J Pediatr 2005;147:528-34

From MicroIslet Webpage


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Departures (From Last Years Talk) DirecNet, J Pediatr 2005;147:528-34

  • Exubera Inhaled Insulin

  • Glucowatch

  • Pork Insulin

  • Lente and Ultralente Human Insulin


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Gone, But Not Forgotten DirecNet, J Pediatr 2005;147:528-34


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MannKind And Afresa DirecNet, J Pediatr 2005;147:528-34®


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Studies Are Giving Us HOPE To DirecNet, J Pediatr 2005;147:528-34

  • Identify Triggers and Avoid Them

  • Identify those at risk for DM, and Treat before onset of Symptoms

  • Help those who have just been diagnosed by halting the attack

  • Replacing insulin in a physiologic manner via technology or biology

  • LIVE BETTER


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