"Insulin Independence" Summit on Capitol Hill
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Transcript of "Insulin Independence" Summit on Capitol Hill
A NEW ROAD FOR TYPE 1 DIABETES
IS BEING PAVED TODAY
The International Summit on Insulin Independence April 24, 2012
Table of Contents
Slide No. Speaker
3 Louis Cocco Jr
4-16 Claresa Levetan MD, FACE
17-24 Susan Pierce, CDE, MPT
25-39 Desmond Schatz, MD
40-52 Paolo Pozzilli, MD
53-65 Donald Bergman, MD, FACE,MACE
66-71 Lois Jovanovic, MD, FACP, FACN,FACE, MACE
72-85 Aaron Vinik, MD, PhD, FCP, MACP,FACE
What I Know About Diabetes by Louis Cocco, Jr Age 11
Despite all of the advances, diabetes is the leading cause of amputations, blindness and kidney disease requiring dialysis.1
Diabetes killed 284,000 Americans last year.2
Every 17 seconds another American is diagnosed with diabetes.1
10-15% have type 1 diabetes, which has risen by 70% among children under the age of 5 years old.3,4
In 2012, $245 Billion was spent on care of patients with diabetes1
More than the $150 billion in damage caused by Hurricane Katrina. 2
As much the conflicts in Iraq, Afghanistan and the global war on terrorism combined. 2
I know that this group of doctors will get me off of insulin before I am a grownup.
1) http://usatoday30.usatoday.com/news/health/2008-01-23-diabetes-cost_N.html Accessed 4.13.13
2) http://www.diabetes.org/diabetes-basics/diabetes-statistics/ Accessed 4.13.13
3) Christopher C et al., Incidence trends for childhood type 1 diabetes in Europe during 1989—2003 and predicted new cases 2005—20: a
multicenter prospective registration study The Lancet, (373)9689, Pages 2027 - 2033, 13;2009
4) Lipman T, et al., Diabetes. March 2013. Population-based Survey of the Prevalence of Type 1 and Type 2 diabetes in School Children in
Philadelphia . [Epub ahead of print]
3
• Distinctions between Islets of Mice and Men
• Why immune tolerance agents work in mice, but not man
• Why man requires an immune agent and a regeneration agent to reverse the underlying mechanisms of disease in type 1 diabetes
• My colleagues will then discuss the therapies we have now and into the future to reverse type 1 diabetes
Claresa Levetan MD, FACE
4
Islets of Man and Mouse
Red Cells--Beta cells making insulin and amylin
Green Cells---Alpha cells making glucagon
Blue Cells—Delta cells making somatostatin
Black Holes in human islet are blood vessels
>70% of Beta Cells in the human islet direct connect with other cell types
Beta cells are attacked by the immune system in type 1 diabetes resulting in
complete islet dysfunction and destruction of the entire islet
5
What Is an Islet?
Islets are small organs within the pancreas that contain 5 different cell types making 6 different hormones, all necessary for glucose homeostasis
Alpha cells make glucagon
Beta cells make insulin and amylin
Delta cells make somatostatin,
Gamma cells make pancreatic polypeptide
Epsilon cells make ghrelin
In man, 6 islet hormones communicate with one another and all have been shown necessary for normal glucose metabolism
Among both type 1 and 2 diabetes, autopsy studies show not only reduced beta cells, but also reduced islet numbers
Type 1 diabetes will be reversed when 5-celled new islets are generated in an immune protected environment
We have the ability to generate new islets that are protected from immune attack, NOW 6
Distinctions between Islets
of Mice and Men
Mice eat continuously and beta cells are constantly turning over during their 1 year lifespan1
Islets in man are designed to regulate glucose based upon emotional stress and long periods of feast or famine
Islets of mice have predominately beta cells, which are centrally clustered and man has a smaller percentage of beta cells dispersed throughout the islet, which are in direct contact with the other 4 cell types
The autonomic nervous system in man through innervates islet blood flow suggesting human islet a have a unique reaction to emotional stress compared to mice2
100s of immune studies have reversed diabetes in mice, but not in man, because man’s islets have a complex infrastructure that cannot be regenerated simply by blocking the immune attack on the pancreas
In man, in order to generate new islets containing all 5 cell types, requires immune therapy and regeneration therapy, both of which are now available
1) Levetan C and Pierce S .Endocr Pract. 2012 Nov 27:1-36. [Epub ahead of print]
2) Rodriguez-Diaz R et al., Cell Metab. 2011;14:45-54.
7
Type 1 Diabetes is more than an
Autoimmune Disease in Man
Humans require both immune protection and generation of
new islets to reverse the underlying disease process of type
1 diabetes
Diabetes in mice can be reversed with only an immune agent
because beta cell turnover is faster in mice than man
Islet Regeneration in man is possible, even among patients
with type 1 diabetes for 20 years or longer
Type 1 diabetes is not just an autoimmune disease as it is in
NOD mice, but is a disease of 1) autoimmunity, 2) beta cell
deficiency and 3) lack of beta cell regeneration
We have human gene peptides and growth factors that
transform pancreatic ductal cells into new islets that we can
use NOW in type 1 patients 8
One machine pumping both insulin and
glucagon
Glucose measurements taken and based
upon glucose levels, the correct dosage of both
insulin and glucagon were automatically given
to the patient
This is same concept as the “new” artificial
pancreas of 2013 now in clinical trials
Even the bionic pancreas did not normalize
glucose levels, because it only replaced two
missing and malfunctioning hormones
All five cell types generating 6 different
hormones within a functioning islet are required
for normal glucose homeostasis
Scientific studies show that all 6 hormones
have a role in glucose metabolism
Treatment vs. Cure
*http://www.thefreeresource.com/insulin-pump-facts-informtion-and-resources *http://idsa.org/catalyst/LMBVT/case_studies_2010_minimed.pdf *Kadish AH. A servomechanism for glucose monitoring and control
Trans. Am. Soc. Artificial Internal Organs 9. 363. 1963 *Kadish AH. Automation control of blood sugar. Biomed Sci. Instr. 1, 172, 1963 Available for viewing at the Keck Graduate Institute, Science Heritage Center, Clairemont,
CA
The First Successful Bionic
Pancreas was developed in
1963 by Dr. Arnold Kadish*
9
Regeneration of the Pancreas
Clamping of the pancreas resulting in new islet formation has been described for a century
Based on a paper in 1920, in which patients with pancreatic stones had new islets, Frederick Banting clamped the pancreatic ducts of dogs for 10 weeks and collected the pancreatic secretions that became known as insulin
Before insulin was readily available, surgeons tied off part of the pancreas among type 1 children, which transiently helped their diabetes, but likely the ongoing autoimmune destruction of new islets contributed to why these surgical successes were only temporary
10
Severely ill diabetic
children underwent
ligation of the
pancreatic duct to
improve their diabetes
between 1910 and
1930*
Benefits were positive,
but short-lived likely due
to autoimmune
destruction of new
insulin-producing cells*
*Cusi 1911; Bierry and Kollman, 1929; DeTakats, 1930
11
In 1983, Dr. Vinik Rediscovered that Wrapping the Pancreas
with Cellophane turned Pancreatic Ducts into Islets
New islets were shown by Dr. Vinik by wrapping the pancreatic ducts of hamsters
A peptide was specifically isolated in 1992 by Dr. Vinik’s team that has been shown to transform pancreatic ducts into 5-celled new islets
In human trials with Dr. Vinik’s, there was a 27% rise in C-peptide within 2 months in type 1 patients with a 20 year history of diabetes and no baseline C-peptide, but without immune protection, these results were not sustained. A rise in GAD antibodies were seen reflecting the immune system was seeing new beta cells3
As much as a 75% reduction in insulin requirements was seen after 4 weeks of gastrin and epidermal growth factor in type 1 patients2
1) Dungan KM et al., Diabetes Metab Res Rev 2009; 25: 558–565
2) Jamal AM et al., Cell Death and Differentiation (2005) 12, 702–712.
3) Transition Therapeutics, March 5, 2007 http://www.transitiontherapeutics.com/media/archive.php Accessed January 1, 2013
Duct Islet2
12
Islet Relationship to Ducts
DUCTS
ISLET
13
Not until the Early 1980s Was Diabetes
Considered to be an Autoimmune Disease
In the 1980s, nearly 100% of patients became insulin-free when the immune agent Cyclosporine A was begun immediately after diagnosis, thus protecting the remaining few beta cells
By 2 years, almost all patients in remission, required insulin, demonstrating that an immune tolerance agent alone, does NOT mean that there will be generation of beta cells in man
It is only now after 100s of studies using a variety of immune tolerance agents and immune approaches that we can look back and see that in man, diabetes is a disease NOT only of autoimmunity
We now have both immune tolerance agents and beta regeneration agents (some are already FDA-approved therapies) that can address the underlying mechanisms of disease in type 1 diabetes: 1) autoimmunity 2) beta cell deficiency and 3) lack of beta cell regeneration
14
Type 1 Diabetes
“Insulin is not a cure for diabetes; it is a treatment.”
Frederick G. Banting, 1923, Nobel Prize Speech
Merging immune tolerance agents with beta regeneration agents; a platform for future insulin independence
Type 1 Diabetes is a disease of
Autoimmunity
Beta Cell Deficiency
Lack of Beta Cell Regeneration
15
Immune
Tolerance Agent Protect newly
generated and existing
beta cells
Potential for Insulin Independence 2015
2013
More potent
beta
generation
agents
Insulin
Independence among existing
and new onset
Regeneration
Agent
Remission
followed by
maintenance
Immune
Tolerance Agent Protect newly
generated and existing
beta cells
Insulin
Independence among existing
and new onset
16
• What are normal A1Cs and glucoses?
• Is it patients or the pancreas that are non-compliant?
• Current therapy and technology is not enough
Susan Pierce CDE, MPT
17
What IS the Normal Glucose Range for
Someone without Diabetes?
Continuous Glucose Monitoring
Shows that out of 288 readings/day
95% of glucose levels < 120 mg/dL 1
80% of glucose levels 60 - 100 mg/dL 1
1. Christiansen JS. What is normal glucose? – Continuous glucose monitoring data from healthy subjects. Presented at: 42nd Annual Meeting of the EASD; September 14-17, 2006; Copenhagen, Denmark.
18
In those without diabetes, 95% of daily (24 hour) life
is spent with a glucoses less than 120 mg/dl
80% of daily (24 hour) life is spent with glucose levels
of 60-100 mg/dl
http://www.diabetes-symposium.org/index.php?menu=view&id=322
19
*Updated mean sA1C adjusted for age, sex, and
ethnic group.
Stratton I, et al. UKPDS 35. BMJ. 2000;321:405-412.
0
2
0
4
0
6
0
8
0
0 5 6 7 8 9 1 0 1 1
Myocardial
infarction
Microvascular
complications
Updated Mean HbA1c (%)*
% I
ncid
en
ce p
er
1,0
00 P
ati
en
t-years
A1Cs Above 5.5% Increase Complication
Risk in Non-Diabetic Individuals as well as those with
Type 1 and Type 2 Diabetes
20
Can a normal A1C be achieved
without too many lows?
The leading diabetes researchers of the DCCT believed that insulin alone could restore a glucose to < 6.05% without hypoglycemia 1
An A1C of < 6.05% was attained at least once during the 10 year study by 44% of the patients receiving intensive therapy 1
The intensively managed group maintained an average A1C throughout the study of 7.2% 1
1. The DCCT Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86. 21
Is New Technology Helping?
Sensor-augmented pump studies recently
Demonstrated a decrease of A1C levels from 8.3% to
7.5% over 12 months (1)
With further reduction to 7.4% after an additional 6
months on the sensor (2)
These achievements were made without associated
weight gain or hypoglycemia
Despite advances in sensors and pumps, sensor-
augmented pumps did not improve the A1C levels
as much as did the DCCT decades ago
1) Bergenstal RM, Tamborlane WV, Ahmann A, et al. N Engl J Med. 2010;363:311-320.
2) Bergenstal RM, Tamborlane WV, Ahmann A, et al. Diabetes Care. 2011;34:2403-2405. 22
I need my human pancreas back!
Even pumping all 6 missing hormones --- insulin,
amylin, glucagon, ghrelin, somatostatin, pancreatic
polypeptide --- would not
There is no computer that can integrate stress and
other factors the way the human islet does.
23
Restoring Normal Glucose
Restoring 5-celled new islets that generate 6
hormones that all communicate with one
another and the brain to maintain glucose
levels < 120mg/dL 95 % of the time
In order to maintain new islets immune
protection must be in place
Drs. Vinik and Bergman will describe how we
now have therapies to transform pancreatic
ducts into 5-celled islets
Drs. Pozzilli and Schatz will describe how we
can optimally protect the new islets 24
4
The need to change the paradigm of
diabetes simply being an autoimmune
disease.
Desmond Schatz, MD
25
Ge
ne
tic
Ris
k
“P
re”-D
iab
ete
s
New-
Onset Established Complications
A
nti
bo
die
s
OPPORTUNITIES FOR PREVENTION
AND CURE
PREVENTION
INTERVENTION CURE
WITHOUT PREVENTION
THERE CAN NEVER BE A
CURE
26
27
• Concept rejected initially…”lacks evidence, not
novel, too presumptive, etc.”
• Based on lessons learned from past
experiences), efficacy in other disorders
(cancer, HIV, transplantation), and mechanisms
underlying type 1 pathogenesis
Diabetes Care, 2002
THE CONCEPT FOR COMBINATION
28
DO WE HAVE CLUES AS TO WHAT
IS THE “BEST” COMBINATION?
Difficult question to answer, based on:
Differences in preclincial studies?
Potential differences in mouse to man?
29
AAV murine IL-10
AAV rat preproinsulin gene (vLP-1)
Adenovirus expressing mIL-4
Aerosolinsulin
Allogenic thymic macrophages
Alpha Galactosylceramide
Alpha-interferon (rIFN-alpha)
Alpha/beta T cell receptor thymocytes
Aminoguanidine
Androgens
Anesthesia
Antioxidant MDL 29,311
Antisense GAD mRNA
Azathioprine
Anti-B7-1
Bacille Calmette Gue’rin (BCG)
Baclofen
Bee venom
Biolistic-mediated IL-4
Blocking peptide of MHC class II
Bone marrow transplantation
Castration
Anti-CD3
Anti-CD4
CD4+CD25+regulatory T cells
Anti-CD8
Anti-CD28 MAb
Cholera toxin B subunit-insulin protein
Class I derived self-I-A beta(g7) (54-76) peptide
Cold exposure
Anti-complement receptor
Complete Freund’s adjuvant
Anti-CTLA-4
Cyclic nucleotide phosphodiesterases (PDEs)
Cyclosporin
Cyclosporin A
DC deficient in NF-kappaB
DC from pancreatic lymph node
DC with IL-4
Deflazacort
Deoxysperogualin
Dexamethasone/progesterone/growth hormone/estradiol
Diazoxide
1,25 dihydroxy Vitamin D3, KH1060
1,25 dihydroxycholecalciferol
1,25 dihydroxyl Vitamin D3
Elevated temperature
Emotionality
Encephalomyocarditis virus (ECMV)
Essential fatty acid deficient diets
FK506
FTY720 (myriocin)
GAD 65 peptides in utero
Anti-GAD monoclonal antibody
Galactosylceramide
Glucose (neonatal)
Glutamic acid decarboxylase
(intraperitoneal, intrathymic, intravenous, oral)
Glutamic acid decarboxylase 65 Th2 cell clone
Glutamic acid decarboxylase peptides
(intraperitoneal, intrathymic, intravenous, oral)
Gonadectomy
Guanidinoethyldisulphide
Heat shock protein 65
Heat shock protein peptide (p277)
Hematopoietic stem cells encoding proinsulin
Housing alone
Human IGF-1
I-A beta g7(54-76) peptide
Anti-I-A monoclonal antibodies
Anti-ICAM-1
IgG2a antibodies
Immobilization
Inomide
Anti-integrin alpha 4
Insulin (intraperitoneal, oral, subcutaneous, nasal)
Insulin B chain (plasmid)
Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal)
Insulin-like growth factor I (IGF-I)
Anti-intercellular adhesion molecule-1 (ICAM-1)
Interferon-alpha (oral)
Interferon-gamma
Anti-interferon-gamma
Interferon-gamma receptor/IgG1 fusion protein
Interleukin-1
Interleukin-4
Interleukin-4-Ig fusion protein
Interleukin-4-plasmid
Interleukin-10
Interleukin-10-plasmid DNA
Interleukin-10-viral
Interleukin 11-human
Interleukin-12
Intrathymic administration of mycobacterial heat shock protein 65
Intrathymic administration of mycobacterial heat shock peptide p277
Islet cells-intrathymic
L-Selectin (MEL-14)
Lactate dehydogenase virus (LDH)
Large multilamellar liposome
Lazaroid
Anti-leukocyte function associated antigen (LFA-1)
Anti-LFA-1
Linomide (quinoline-3-carboxamide)
Lipopolysaccharide-activated B cells
Lisofylline
Lymphocyte choriomeningitis virus (LCMV)
Anti-lymphocyte serum
Lymphoctyte vaccination
Lymphocytic choriomeningitis virus
Anti-L-selectin
Lymphotoxin
LZ8
MC1288 (20-epi-1,25-dihydroxyvitamin D3)
MDL 29311
Metabolically inactive insulin analog
Anti-MHC class I
Anti-MHC class II
MHC class II derived cyclic peptide
Mixed allogeneic chimerism
Mixed bone marrow chimeras
Monosodium glutamate
Murine hepatitis virus (MHV)
Mycobacterium avium
Mycobacterium leprae
Natural antibodies
Natural polyreactive autoantibodies
Neuropeptide calcitonin gene-related peptide
Nicotinamide
Nicotine
Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation
NKT cells
NY4.2 cells
OK432
Overcrowding
Pancreatectomy
Pentoxifylline
Pertussigen
Poly [I:C]
Pregestimil diet
Prenatal stress
Preproinsulin DNA
Probucol
Prolactin
Rampamycin
Recombinant vaccinia virus expressing GAD
Reg protein
Reg protein
Rolipram
Saline (repeated injection)
Schistosoma mansoni
Semi-purified diet (e.g., AIN-76)
Short term chronic stress
Silica
Sirolimus/tacrolimus
Sodium fusidate
Soluble interferon-gamma receptor
Somatostatin
Non-specific pathogen free conditions
Streptococcal enterotoxins
Streptozotocin
Sulfatide (3’sulfogalactosylceramide)
Superantigens
Superoxide dismutase-desferrioxamine
Anti-T cell receptor
TGF-beta 1 somatic gene therapy
Th1 clone specific for hsp60 peptide
Anti-thy-1
Thymectomy (neonatal)
Tolbutamide
Tolerogenic dendritic cells induced by vitamin D receptor ligands
Top of the rack
Treatment combined with a 10% w/v sucrose-supplemented drinking water
Tumor necrosis factor-alpha
TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))
Vitamin E
Anti-VLA-4
Thymoglobulin
Anti-CD3
ALS + Exendin-4
LSF + Exendin-4
EGF + Gastrin
Regulatory T Cells
Islet Transplantation
Microspheres
FTY720
sICAM-Ig (Adenovirus Vector)
IDS 2004, Cambridge (Atkinson & Roep)
N=193;
Now ~400
THERAPIES PREVENTING DIABETES IN NOD MICE
30
WHAT CONSIDERATIONS NEED TO
GO INTO SELECTIONS FOR
COMBINATION RX?
Selecting combination therapies should occur,
with a combination of thoughts regarding
mechanism of action, synergy, safety, and
potential for efficacy
31
USE COMBINATIONS THAT IMPROVE EFFICACY
0 25 50 75 100 125 1500
20
40
60
80
100Control
GCSF
ATG
ATG + GCSF
Days Post Onset
No
rmal G
lycem
ia (
%)
32
USE COMBINATIONS THAT IMPROVE
ALLOW FOR LOWER DOSING OF DRUGS
33
USE COMBINATIONS THAT
IMPROVE SAFETY
p values @ 4 weeks
(n is still increasing)
ATG vs. A+G = .0128
ATG vs. CD3 = .3569
ATG vs. 3+G = .2141
A+G vs. CD3 = .0005
A+G vs. 3+G < .0001
CD3 vs. 3+G = .9135
34
RECENT NEW-ONSET DIABETES STUDIES
Published - * α-CD3 (x4) - * α-CD20 - Mycophenolic Mofetil + anti-CD25 - GAD x2 - * CTLA-4
- * DiaPep - * Autologous non-myeloablative transplantation - Cord Blood - IL-2 plus Sirolimus (Phase 1) - Canakunimab; Anakinra Completed enrollment - Mesenchymal Stem Cells - Cord Blood Phase 2 (+ Vit D + Omega 3 FA) - Meticulous Metabolic Control - GCSF - ATG-GCSF Enrolling - T reg - α-1 antitrypsin
35
WHAT HAVE WE LEARNED?
We can do well designed, adequately powered, and carefully conducted intervention and prevention studies
Sample sizes require a collaborative, cooperative, multi-center approach
If a response is seen, it is likely to be evident soon after therapy begun (3-6 months)
Long term benefit largely unknown 36
WHY LIMITED SUCCESS TO DATE? BACK TO THE FUTURE…..
RETHINKING MECHANISMS LEADING TO TYPE 1
DIABETES?
1986: Suicide or Homicide of β Cell Bottazzo …..
Is the autoimmune/inflammatory process in humans really
primary or secondary to hitherto unknown β cell defects/killing??
- limited success of immune interventions
- no treatment mediated decrease in islet cell Ab
- what have we really learned from animal models ?
- no markers in humans other than islet Ab
……….of immune dysregulation or β cell killing
- lack of correlation of insulitis with islet Ab (nPOD)
37
OUR FUTURE CHALLENGES
Current treatment quite good – but…insulin not a biological cure
Primum non nocere (safety)
Re-evaluate study design (smaller, shorter studies in new-onset patients)
Define clinical significance (efficacy)
- superiority or ease over current treatment if new-onset
- only do if translatable (therapy or prevention)
Better understand triggers (TEDDY)/mechanisms leading to disease
Use a `cocktail approach’
(Immunoregulatory/regenerative)
38
PUTATIVE
ENVIRONMENTAL
TRIGGER
TIME
FUTURE PREVENTION
OF TYPE 1 DIABETES
BE
TA
CE
LL
MA
SS
M
DIABETES
“PRE”-
DIABETES
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
Early Monotherapy
Late Combinations
SAFE
MORE TOXIC ?
39
Prof. Paolo Pozzilli Università Campus Bio-Medico, Roma, Italy
Barts' and The London Hospital, UK
Outcomes with immune tolerance agents in
Type 1 Diabetes
from Cyclosporine to Current Therapies
40
Roma,1989: First International Meeting
on this topic
President: D Andreani
Vice-President: G Gambassi
Scientific Coordinators: P Pozzilli, H Kolb
Scientific Advisors: JF Back, GD Bompiani, P
Brunetti, JJ Duprè, GS Eisenbarth, G Ghirlanda,
L Harrison, NK Maclaren, J Nerup, G Pozza, CR
Stiller
Scientific Secretariat: A Corcos, E Killick, N
Visalli
“Immunotherapy of Type 1 diabetes”
41
Nearly 100% insulin-free remission if used very early in the course of disease within 2-3 days of insulin therapy and before weight loss (Eisenbarth GS Immunotherapy of Diabetes and Selected Autoimmune Diseases CRC Press, 1989)
Remissions are not typically sustained more than 2 years
Maintaining trough levels of 75-250 ng/ml did not demonstrate significant insulin-free remissions (Miami Study and IMDIAB1)
CyA was abandoned because it was not curative and not because of short term adverse effects. There was fear of long term adverse effect at kidney level
There were no beta cell regenerative agents available at the time to use in conjunction with CyA to sustain potential regeneration of beta cell mass, nor was it understood that outcomes in man would be different than mice when using immune tolerance agents
42
CyA for Type 1 diabetes: history
(n= 692 treated patients)
Bougneres PF et al. Diabetes 1990 43
Skyler JS et al. Diabetic Medicine 1993 44
Disease State Drug Oral Injectable
Organ Transplant Sandimmune 14-18 mg/kg/day, taper to 5-10
mg/kg/day in 1-2 weeks
5-6
mg/kg/day
Neoral or a bioequivalent generic 7-9 mg/kg/day, taper to 5-10
mg/kg/day in 1-2 weeks
Rheumatoid Arthritis Neoral or a bioequivalent generic 2.5–4 mg/kg/day in two divided
doses
Psoriasis Neoral or a bioequivalent generic 2.5–4 mg/kg/day in two divided
doses
Crohn's Disease Sandimmune 4 mg/kg/day
Ulcerative Colitis Sandimmune 4 mg/kg/day
Nephrotic Syndrome Brand not specified 3.5 mg/kg/day in two divided doses
Multiple sclerosis
Brand not specified
7.2 mg/kg/day
Lupus Brand not specified 2.5 mg/kg/day
Alopecia Areata Brand not specified 3-5 mg/kg/day
Atopic Dermatitis Brand not specified 5 mg/kg/day
Dermatomyositis Brand not specified 3-10 mg/kg/day
Lichen Planus Brand not specified 6 mg/kg/day
Myasthenia Gravis Brand not specified 5 mg/kg/day
Polymyositis Brand not specified 2.5 mg/kg/day
Psoriatic Arthritis Brand not specified 3.5 mg/kg/day
Pulmonary Sarcoidosis Brand not specified 5-7 mg/kg/day
Uveitis Brand not specified 2.5-5 mg/kg/day
Today usage and dosages of CyA
45
Minimal renal adverse effects as shown by Assan and others if trough levels are <300 ng/ml
Among 285 patients on 19.9 months of CyA averaging 6.5 mg/kg/day for 19.9 months and followed for 13 years, no long term renal effects seen. Trough goal of < 300 ng/ml with reductions if creatinine more than 30% above baseline (Assan R, Blanchet F, Feutren G et al., Diabetes Metab Res Rev. 2002;18(6):464-72)
Minimal renal adverse effects if dosage maintained in a range of 5 mg/kg/day after initial dosage of 7.5 mg/kg/day with trough goal of 300 ng/ml with reduction of dosage if creatinine rises above 30% of baseline
A direct toxicity effect of CyA on beta cells function has not been demonstrated
46
Renal Effects of CyA in patients with T1D
Modify from Reimann M et al. Pharmacology & Therapeutics 2009
GAD65
HSP60
IL-1 receptor antagonist
GAD65
HSP60
Anti CD3 MoAb
CTLA-4
Anti CD20 antibody
Today’s main strategies with immune tolerance
agents to halt progression towards beta cell failure
47
Pozzilli P. Immunotherapy 2012
Results of main trials with immune tolerance agents in T1D
48
We know the good and the bad about CyA, so we should be
feel confident enough about its use. This is not the case with
all the other immune tolerance agents tested so far for lack
of long term studies.
No long term renal toxicity has been shown with CyA used
at 7.5 mg/kg per day for 1 year
The concept of combination therapy using an immune
tolerance agent with a beta cell regenerative compound
should be considered, and among the different immune
tolerance agents, CyA still holds a prominent role.
49
Rationale for reconsidering CyA in patients
with recent onset T1D
Leslie RD. Diabetes 2010
The spectrum of autoimmune diabetes extends
across all ages and varies with age at diagnosis
50
Key issues to consider for trials
in type 1 diabetes
51
Future directions:
combination therapy
52
Ability to use proton pump inhibitors to
increase gastrin, which increases beta cell
regeneration.
Donald Bergman, MD, FACE, MACE
53
Gastrin
• Gastrin plays a role in pancreatic growth and development in fetal life1,2
• Pancreatic gastrin expression is suppressed after birth and then found as a growth factor in the gastric antrum and duodenum (G cells) after fetal development1
• Excessive gastrin has been associated with new islet and beta cell formation since the 1950s3,4
• Gastrin hypersecretion results in the formation of new islets containing new pools of beta cells5
• Gastrin’s mechanism of action is the transformation of pancreatic ducts to islets5
1. Tellez N. Endocrinology, 2011, 152(7):2580–2588 2. Larsson LI. et al.,1976 Nature 262:609–610. 3. Zollinger RM and Ellison EH. Ann. Surg., 142:709-728, 1955. 4. Bryant JG, Smith JV. Calif Med. 1965 Jan;102:49-52. 5. Suarez-Pinzon WL, et al., The Journal of Clinical Endocrinology & Metabolism 90(6):3401–3409
54
The Association between Gastrin and Insulin
• Patients with Zollinger-Ellison Syndrome-- increased gastrin
producing nests of cells found both in the pancreas and GI tract have new islets and increased beta cell replication2
• Patients infused with gastrin had heightened insulin
responses to glucose compared to those not receiving a gastrin infusion.1
1) Rehfeld JF, Stadil F. 1973. J Clin Invest 52:1415–1426 2) Zollinger RM and Ellison EH. Ann. Surg., 142:709-728, 1955.
55
Gastrin’s Mechanism of Action
Gastrin has been shown by specialized studies including BrdU studies to transform ductal (extraislet) tissue into new islets*
On the left, a single, larger black cell represents the presence of gastrin and the pink cell representing a progenitor cell within the ductal population. Blue cells indicate beta cells and red cells represent alpha cells, with delta cells present to a smaller extent in green. *Telez, et al., Endocrinology, July 2011, 152(7):2580–2588
56
Gastrin Transforms Human Ducts to Islets
• Gastrin alone, has been shown the ability to induce new human islets from human duct cells without other growth factors (Suarez-Pinzon, J Clin Endocrinol Metab, June 2005, 90(6):3401–3409)
• A combination of Gastrin with Epidermal Growth Factor given to type 1 patients for 4 weeks resulted in – up to a 75% decrease in insulin requirements when followed
for 3 months post treatment
– an A1C from 6.7% at baseline down to 4.7% at 3 months post-treatment (Transition Therapeutics, March 5, 2007 http://www.transitiontherapeutics.com/media/archive.php Accessed January 1, 2013)
57
Proton Pump Inhibitors increase Gastrin • Proton pump inhibitors (PPIs) are used extensively for the treatment of
peptic ulcer and related symptoms and indirectly elevate gastrin levels • Studies have shown a dose- and duration-dependent relationship between
PPIs and gastrin levels1,2,3 • Gastrin levels rise significantly with typical dosages for GI disease • PPIs are safe (with some concerns) • Complete hepatic metabolism with some potential for drug-drug
interactions • Long-term usage among postmenopausal women associated with an
increased risk for hip fracture, infectious diarrhea, particularly among hospitalized patients
1) Hu YM. World J Gastroenterol. 12:4750–4753 2) Ligumsky M. 2001. J Clin Gastroenterol 33:32–35 3) Cadiot G,. Gastroenterol Clin Biol 19:811–817
58
PPIs
• Substituted benzimidazole derivatives
• Block the terminal step in acid production
• Inhibit the function of hydrogen-potassium adenosine triphosphatase on the luminal surface of parietal cell membranes in the stomach.
Madanick. Cleveland Clinic JM 2011;78:39-49
59
Studies Confirm Lower A1C on PPI • Retrospective review of 347 type 2 diabetes
– Those taking PPI had lower A1Cs (7.0%) compared to patients not on PPIs (7.6%) (p=0.002) (1)
• Retrospective of 73 type 2 patients – A1C of patients on insulin with PPI was 7.11% compared to 7.70% of patients
not on PPI (p=0.001)
– Patients on multiple oral diabetic agents and PPI had A1C of 7.26% vs. 7.8% (p=.002) (2)
• Cross-sectional study of 97 patients type 2 patients – Those on insulin and PPI had a 0.8% to 1.48% lower A1C than those not on
PPIs (95%, CI: -0.12)
– Those on oral agents and PPI had a 0.6% to 0.83% lower A1C on oral agents (95%, CI: -0.12) (3)
• Retrospective review of 21 type 2s on esomprazole for 12 months – 0.7% lower A1C than those not on PPI (4) 1 )Mefford IN, Wade EU. Med Hypotheses. 2009;73:29-32. 3 3) Boj-Carceller D., et al World J Diabetes 2011 December 15; 2(12): 217-220.
2) MA Crouch. J Am Board Fam Med 2012;25:50 –54. 4) Hove KD, et al.,Diabetes Res Clin Pract. 2010;90(3):e72-4.
Randomized Trials Using PPIs Among Type 2 Diabetes
Pantoprazole/Protonix* • 12 week trial with 31 patients randomized • 38% rise in gastrin • 1.2% drop in A1C from 7.9% to 6.8% in PPI group • Placebo group A1C from rose from 7.5 to 7.9% • Improvement in beta cell function by 30% (HOMA) • The decrease in A1C correlated with an increase in gastrin and insulin • No adverse side effects in Protonix seen over that in the control group. Nausea,
vomiting , headache and myalgia were the same in control and Protonix group Esomerprazole/Nexium** • 12 week trial with 41 patients • Patient further randomized to yogurt or placebo taken with Esomerprazole • There was a 2 kg greater weight gain in those on Esomerprazole and yogurt • Area under the curve for insulin was significantly decreased in the control group
compared to no change in the intervention group (p=0.002)
*Singh PK et al, J Clin Endocrinol Metab 97: E2105–E2108, 2012 **Hove KD et al, Diabetologia 56;22-30, 2013
61
Current Trial with Lansoprazole in Type 1
Patients to Assess Beta Cell Function* • Current Trial with Lansoprazole (Prevacid) in type 1 patients
– ages 11-45 – for 12 months being used with Sitigliptin (Januvia) to assess beta cell function
(no immune tolerance agent being used) – Subjects age 11-17 years will take 30 mg capsule once daily of lansoprazole
with 50 mg of Sitigliptin once daily – Subjects age 18-45 years will take 60 mg of lansoprazole once daily with 100 mg
of sitigliptin once daily
• Primary Outcome Measures: 2 hour C-peptide AUC in response to mixed meal tolerance at 12 months
• Secondary Outcomes Measures:
– 2 hour C-peptide AUC in response to MMTT [ Time Frame: months 6, 18, and 24 ]
– A1C levels – Insulin use in units per kilogram body weight per day – Safety (adverse events frequency, severity)
*http://www.clinicaltrials.gov/ct2/show/NCT01155284?term=lansoprazole+type+1+diabetes&rank=3 62
PPI side effects: clopidogrel
• PPIs inhibit a P450 enzyme which is required for activation of clopidogrel
• Contradictory data in literature
• One retrospective study found no adverse effect and found decreased GI bleeding in combined use
• FDA warning
Ray et al. Ann Int Med 2010; 152:337-345 63
PPI side effects: fracture, pneumonia, enteric infection
• Fracture risk: conflicting reports. Risk greater in those with other risk factors for fracture. FDA: possible association
• Pneumonia risk: 4.5 times higher in PPI users but only 18% had documented pneumonia
• Enteric infection risk: C. Diff. 127000 patients odds ratio 2.05.
• Enteric infection: bacterial overgrowth and SBP (small studies)
Madanick. Cleveland Clinic JM 2011;78:39-49 65
PPI side effects: nephritis, iron, B12 deficiences
nephritis
• 64 cases documented in the world literature in PPI users
• Not enough evidence to support a causal relationship
Iron, B12 deficiency
• Iron: acid needed to dissociate iron salts from food
• B12: acid needed to separate B12 from food proteins
• No convincing evidence in the literature
Madanick. Cleveland Clinic JM 2011;78:39-49
65
Ability for women with decades of type 1
diabetes to become insulin independent within
weeks of pregnancy.
Lois Jovanovic MD, FACP, FACN, FACE,
MACE
66
Normal Pregnancy
Associated with a 2-4 fold rise in insulin
Among those without diabetes, normal glucose levels are considerably lower during pregnancy than in the non-pregnant state
Goals Glucose During Pregnancy The American College of Obstetricians and Gynecologists
recommends the following goals when self-monitoring blood glucose levels during pregnancy: Fasting glucose concentrations ≤95 mg/dL
Premeal glucose concentrations no higher than 100 mg/dL
One-hour postmeal glucose concentrations no higher than 140 mg/dL
Two-hour postmeal glucose concentrations no higher than 120 mg/dL
The American Diabetes Association recommends the following glucose goals: Premeal, bedtime, and overnight glucose concentrations 60 to 99 mg/dL
Peak postmeal glucose concentrations 100 to 129 mg/dL (5.6 to 7.2 mmol/L) one to two hours after the beginning of the meal
67
Each Pregnancy is Unique
Among pregnant type 1 women, there is often a decline in the need for insulin
Often see hypoglycemia among type 1 patients in pregnancy with a peak incidence in the first trimester due to new insulin production by the mother
Some women have been insulin-free throughout their pregnancy, only to return to insulin requirements after delivery
New insulin production has been seen among type 1 patients with a history of diabetes for more than 20 years
68
Am J Obsetet Gynecol 1976, 15;125(2):264-5.
1976
Known Insulin Remissions Among Pregnant Type 1
Patients Date Back Decades
69
Patients with No Detectable Insulin
Before and Significant Rises During Pregnancy*
C-peptide/Endogenous insulin concentration before pregnancy
and at 10 weeks of gestation
0
0.05
0.1
0.15
0.2
0.25
0.3
1 2 3 4 5 6 7 8 9 10
Patients with Type 1 Diabetes
C-p
ep
tid
e (
nm
ol/
l)
Pre-Pregnancy
10 weeks of gestation
Patients had a mean duration of diabetes 21.2 years
By 10 weeks of gestation, endogenous insulin levels were
not only detectable, but into the normal range
Some women have been insulin-free not only during this
time, but throughout pregnancy
*Jovanovic L, et all.,Diabetologia. 2000 Oct;43(10):1329-30. 70
New Insulin Production Occurs
Quickly
Islet Neogenesis Proceeds Beta Cell Regeneration in pregnancy*
Pregnancy is one of the few times postnatally when new islets form
Once new islets form, there are new pools of beta cells for
replication
Most islets are formed by the time of birth
Only in rare instances do islets regenerate. These times include
acute pancreatic injury, pancreatitis, pancreatic stones and
pregnancy
By 10 weeks of pregnancy, new endogenous levels of insulin are
seen
This is the time similar to the original study by Banting and Best
when they collected secretions from clamped pancreatic ducts at
10 weeks
71
*Johansson M., et al., Endocrinology 2006. 147(5):2315–2324
Combination Therapies Enhance
Prospects of “Curing” Diabetes
Aaron Vinik MD, PhD, FCP, MACP, FACE
Murray Waitzer Chair of Diabetes
Research
Eastern Virginia Medical School Strelitz
Diabetes Center and
Neuroendocrine Unit
Norfolk Virginia.
72
Background (Sarandipity) Saran wrapping reverses streptozotocin-
induced (STZ) diabetes in hamsters
• Ilotropin, a crude pancreatic extract from CW, induces new islet formation from ductal epithelium.
• Ilotropin reverses streptozotocin-induced diabetes in hamsters.
• mRNA differential display led to
• THE DISCOVERY OF INGAP
Rafaeloff, Quin, Barlow, Rosenberg and Vinik
Febs Letters378, 219-223, 1996
Rafaeloff, Pittenger, Barlow, Qin, Yan, Rosenberg, Duguid, Vinik
J Clin Invest 99: 2100-2109, 1997 73
Production of a Biologically Active INGAP
Peptide by Biochemical Techniques and
Effects on Islet Neogenesis and STZ Diabetes
5’UTR Signal peptide Mature peptide 3’UTR
1 78 35 540 646
3’UTR
766
C C C
35 46 68
C C C
146 163 171
C= cysteine
AA= amino acid
N= potential N glycosylation
IGLHDPSHGTLPNGS AA 104 AA 118
N N
N
74
Restoration of Normal Blood Glucose in INGAP-
treated C57BL/6J STZ Diabetic Mice
INGAP/SALINE
Rosenberg, Vinik et al. Ann Surg. 2004 Nov;240(5):875-84.
75
76
INGAP and Human Health and Disease
Is INGAP present in the human pancreas?
Does INGAP affect human pancreatic tissue in
vivo and in vitro? Will it reverse diabetes?
77
Transdifferentiation of Human Islets-The
Effects of INGAP Peptide
Human islets after isolation
CK19 –tive and following
induction of reverse trans-
differentiation to a duct-like
epithelial structure CK19 +
Effects of INGAP peptide
on transdifferentiation
of ductal cells (CK19 +)
to islet (CK19-)
INGAP Peptide induced
transition from ductal cells
to insulin producing cells
and fully formed
islet with expression of
insulin (brown) 78
Accelerating Factors
“THE INGAP INDUCERS” AP-1-activators
STAT-activators
PAN-activators
NEOGENESIS INGAP
NEW
ISLETS
Taylor Fishwick, Vinik et al J Endocrinol. 2006 Mar;188(3):611-21
Hamblet et al Pancrease 36, 17671772, 2008
Pittenger, Taylor Fishwick, Vinik Diabetologia 52:735-7382009.
Taylor Fishwick, Hughes, Vinik Pancreas 39(1):64-70, 2009.
Chang et al Molecular and Cellular Endocrinol, 335:104-109, 2011
79
INGAP is Overexpressed in
Human Islet Neogenesis
Insulin Red
INGAP Green
Semakula C, Pambucian S, Gruessner R, Kendall D, Pittenger G, Vinik A, Seaquist E JCEM 2003
Recapitulation of Fetal Development of Islets in NIPHS Syndrome
•a) insulin blue/ Ki
67 red
•B)Proinsulin
•C) amylin
•D) PDX
•E) NKX 6.1
•F) Insulin / Ki 67
Won Pittenger, Vinik et al Clinical Endocrinology 2006:65, 566-578
HBA1c Response to INGAP in T1 DM per Protocol
Trial
0 28 56 84 112 140
-0.5
0
+0.5
-1.0
Days
Me
an
Ch
an
ge
fro
m B
as
elin
e (
AU
C)
Placebo300 mg
600 mg
INGAP Treatment
Duncan, Buse and Ratner Diabetes Metab Research and Reviews, 25, 558-565.,2009
82
Quiescent
Duct Cells Initiation
Differentiation
Proliferation
Apoptosis
Pro-apoptotic New islets
Anti-apoptotic
Islet Neogenesis
Glitazone
GLP analogs
Anti inflammatory, Lysophylline,
Immunomodulatory,Ustekinumab
INGAP
EGF/gastrin
83
84
0%
10%
20%
30%
40%
50%
60%
70%
80%
Saline
LSF
INGAP
INGAP/L
SF
Pre
Tx
Delay
ed P
reTX
Rate
of
Rem
issio
n (
<200m
g/d
l)
All Mice
Low Starters (<350mg/dl)
High Starters(>350mg/dl)
Hyperglycemia remission rates in INGAP +
Lisofylline (LSF) treated NOD Mice
Tersey et al J of Diabetes 2: 251-257, 2012 84
Conclusion
• It is not beyond the realms of reason to anticipate that regenerating agents such as INGAP, alone, or in combination with other factors, anti-apoptotic and anti-inflammatory agents, e.g. lisophylline, anti-apoptic agents e.g. GLP-1 or an analog, DPP IV inhibitors or Glitazones, small surrogate molecules that activate the receptor, or gene manipulation will provide a cure for certain forms of diabetes in humans
Thank you for your attention! 85
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