advances in diabetes care and prevention - ghc.fiu.edu · advances in diabetes care and prevention...
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Advances in Diabetes Care and Prevention
Camillo Ricordi, MDDirector, Diabetes Research Institute and Cell Transplant Center
University of Miami, Florida, USAwww.DiabetesReseaerch.org
Founding President, The Cure Alliancewww.TheCureAlliance.org
www.CellR4.org
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• Center of Excellence of the University of Miami
• MISSION: To Cure Diabetes in the Fastest, Most Efficient and Safest Way Possible
• Home of the UM Cell Transplant Program and the Division of Cellular Transplantation, Dept . Of Surgery
• First cGMP Human Cell Processing Facility in the USA FDA approved to deliver therapeutic cell products across state barriers
• NIH Cell Distribution Center
• FDA approved, FACT and AABB Certified
• Over 160 Physicians, Scientists and Staff
• Coordinating Center of the DRI Federation
2
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1988 – 2018 30 Years of the Ricordi Chamber
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Biologic License Application
Phase III Clinical Trial(2004-2016)
Clinical Islet
Transplantation
ConsortiumiCClinical Islet
Transplantation
ConsortiumiC• Preclinical data• Manufacturing information• Detailed Clinical protocols• Investigator information• Informed consents• Assurances: IRB, IND
IND 9336
Diabetes Care 2016 Jul; 39(7): 1230-1240
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Alefacept (ITN/TrialNet)
DPT-1 Parenteral
DPT-1 Oral
Pathway to Prevention
MMF/DZB
T Cell Validation
MMTT/GST
Prevention
New-Onset
Pathway to Prevention
Rituximab
NIP
Oral Insulin
Abatacept
GAD
Metabolic Control (TrialNet/DirecNet)
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Methodological
Thymoglobulin (ITN/TrialNet)
IL-2-Rapamycin (ITN/TrialNet)
Canakinumab
Teplizumab
Teplizumab (ITN/TrialNet)
ATG/GCSF
Abatacept
Tocilizumab
LIFT
Long Term Follow-Up
Two Decades of Disappointing Clinical Trials for T1D Prevention/Intervention
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• DPT-1 Parenteral Insulin No effect
• Belgian Parenteral Insulin No effect
• DPT-1 Oral Insulin No effect
• TrialNet Oral Insulin No effect in Primary Stratum
• DIPP Nasal Insulin No effect
• INIT-II Nasal Insulin Ongoing – finishing 2018??
• DIAPREV-IT GAD No effect
• PRE-Point Oral Insulin Immunologic hints
Antigen-Based Prevention Studies
• ENDIT Nicotinamide No effect
• DENIS Nicotinamide No effect
• TrialNet Abatacept Ongoing – finishing 2018
• TrialNet Teplizumab Ongoing – finishing 2018
Immunomodulatory Secondary Prevention Studies
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Antigen-Based New Onset Studies
• Oral Insulin France No effect
• Oral Insulin Italy No effect
• Oral Insulin US No effect
• GAD Pilot No effect (? subgroup)
• TrialNet GAD No effect
• Diamyd EU GAD No effect
• Diamyd US GAD No effect
• Neurocrine Altered Peptide No effect
• Proinsulin-Plasmid No effect
• Proinsulin Peptide Safe
• DiaPep-277 Heat Shock Protein No effect (papers retracted for fraud)
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Ongoing and Planned Antigen-Based Studies
• GPPAD Oral Insulin for Primary Prevention
• DIAPERV-IT 2 – GAD + Vit D for Prevention
• Alpha-methyl-dopa for Prevention
• Proinsulin Plasmid in New Onset
• Proinsulin Peptide in New Onset
• Lactococcus lactis with hProins + IL-10 and anti-CD3 in New Onset
• FINISH Casein hydrolysate Modest effect on abs
• TRIGR Casein hydrolysate No effect
• FINDIA Hydrolysate free of bovine insulin Modest effect on abs
• NIP Docosahexaenoic Acid No effect
Immunomodulatory Primary Prevention Studies
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Immunomodulatory New Onset Studies
• Cyclosporin France Transient effect
• Cyclosporin Canada/EU Transient effect
• Teplizumab Anti-CD3 Pilot Transient effect
• Otelixizumab Anti-CD3 Pilot Transient effect
• Abate Teplizumab Transient effect
• Protégé Teplizumab (2°endpoint) Transient effect
• DEFEND Otelixizumab (2 trials) No effect
• Etanercept ? Effect
• Mycophenylate+Anti-CD25 No effect
• Rituximab Anti-CD20 Transient effect
• Abatacept CTLA4-Ig Transient effect
• Canakinumab Anti-IL1-β No effect
• Anakinra IL-1 trap No effect
• Thymoglobulin No effect
• Alefacept CTLA4-Ig (2°endpoint) Potential effect
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JAMA 2017; 318:1891-1902
On-Study (Months)
Pro
po
rtio
n T
1D
-Fre
e
0 12 24 36 48 60 72 84
00
. 10
. 20
. 30
. 40
. 50
. 60
. 70
. 80
. 91
Rx GroupOral InsulinPlacebo
T1D-Free140122
T1D5862
96
Oral InsulinPlacebo
198184
194179
177165
151142
130117
112102
9187
7565
6057
5148
4741
3332
3029
2324
1814
1511
Annualized rate of diabetes 8.8% oral insulin; 10.2% placeboHazard ratio 0.87 (95% CI: 0.61,1.24) p=0.42
Presented at ADA San Diego June 12 2017
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The Rationale for Combination Strategies: Lessons from Islet Transplantation
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Islet Allograft Survival
0 6 12 18 24 30 36 42 48 54 600
10
20
30
40
50
60
70
80
90
100
ISLE
T G
RA
FT
SU
RV
IVA
L (
%)
MONTHS POST-TRANSPLANT
Edmonton Protocol (2001 - 2004, n = 17)
CIT07 Protocol (2008 - 2011, n = 11)
Rickels … Naji. Unpublished data
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Remaining Challenges
• Delivery system/Transplant Site
• Immuno Protection– Immune Tolerance/Self Tolerance
– Immunoisolation
• Adequate Supply to Transplant >100 Million Subjects
• Cost Efficiency
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OPTIMIZATIONOF
TRANSPLANT SITE
TOLERANCE INDUCTION AND
REVERSAL OF AUTOIMMUNITY
IMMUNOISOLATION
SOURCE OF INSULIN PRODUCING
CELLS
BIOLOGIC CURE
DRI BioHUB Strategy
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Moving from Immunosuppression to TOLEROGENIC IMMUNOMODULATION
MSCs
T regsRegulatory T Cells
Omega 3Vitamin D Low Dose IL-2
DIPIT
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PBMC from Subjects with T1D
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PBMC from Non Diabetic Subjects
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E. Gorham and C Garland, UCSD
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CASE 1
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CASE 1
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CASE 2 and 3
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CASE 2 and 3
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• Subject: 30 year old male
• T1D diagnosis April 16 2017
• 1 week of insulin therapy while in the hospital
• 2 weeks after hospital discharge complete suspension of exogenous insulin
• In June 2017 starts Omega 3 and High-Dose Vit D + other vitamins (COIMBRA)
T1D Dx 04/2017 HbA1c(%)
Fasting C-Peptide(ng/ml)
05/2017 8.4 0.5
07/2017 5.6 0.6
10/2017 5.4 0.7
01/2018 5.4 0.8
04/2018 4.6 1.0
CASE 4
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• 450 million people have DIABETES
• Diabetes caused 5 million deaths in 2017
• Every seven seconds a person dies from
diabetes
• $260 Billion/Year in the US alone
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Dr. Paul Robbins, Department of Metabolism and Aging , Scripps Florida
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Dr. Paul Robbins, Department of Metabolism and Aging , Scripps Florida
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Dr. Paul Robbins, Department of Metabolism and Aging , Scripps Florida
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Prevention, Diet, Lifestyle and Role of Inflammation in
Diabetes and Chronic Degenerative Disease
Conditions
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Events That Turn On
Inflammatory Responses
◼Microbial invasion
◼ Injuries
◼Diet
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Phases of Inflammation
Initiating Event
Pro-inflammatory Initiation Response
Cellular Destruction
Anti-Inflammatory Resolution Response
Cellular Rejuvenation
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Useful Definitions
◼ Pro-inflammatory
◼Promotes initiation of inflammation
◼ Anti-inflammatory
◼ Inhibits initiation of inflammation
◼ Pro-resolution / pro-resoleomic
◼Promotes resolution of inflammation
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What Happens When
Inflammation Is Not Resolved?
Acute Inflammation Resolution
Acute Inflammation ResolutionX
Chronic Cellular
InflammationFibrosis
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Cellular Inflammation Made Simple
Toll-Like Receptors (TLR) and
AGE Receptors (RAGE)
NF-κB
DNA
Inflammatory
Enzymes (COX-2)
And Cytokines
(IL-1, IL-6, TNF)
Cytokine Receptors
AA
(LTB4 and 12-HETE)PPARγ
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Dietary Controls on
NF-κB Activity
Omega-6 Fatty Acids, Saturated Fatty Acids, and Excess Carbs
Omega-3 Fatty Acids and
Polyphenols
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What Causes Cellular
Inflammation?
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The Perfect Nutritional Storm
• Increased Omega-6
• Increased Refined Carbohydrates
• Decreased Omega-3
• Decreased Polyphenols
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Resolvins: Agents of Resolution
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Measuring Cellular Inflammation
◼ AA/EPA ratio in the blood
◼Upstream marker
◼Tipping point for NF-κB activation
◼ Indication of resolution potential
◼ C-reactive protein
◼Downstream marker
◼No indication of resolution potential
◼ Less reliable
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AA/EPA Ratio Indicates Extent of Cellular Inflammation
AA/EPA Comments
< 1 Potential increase in bleeding
1-3 Ideal for resolution of inflammation
3-6 Good
6-10 Beginning to move out of range
10-15 Cellular inflammation beginning to rise
> 15 Cellular inflammation is systemic
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How Much Omega-3 Fatty Acids
Do You Need?
Maintain Wellness 2.5 g/day
Treat Obesity, Diabetes, and CHD 5 g/day
Treat Chronic Pain 7.5 g/day
Treat Neurological Disease >10 g/day
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Other Auto-Immune
Conditions Improved by
Omega-3 Fatty Acids
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Rheumatoid Arthritis
◼ Royal Transactions of the Philosophical
Society (1786)
◼ About 15 grams EPA and DHA per day
◼ Kremer. Del Med J 60:679 (1988)
◼ Kremer et al. Arthritis and Rheum 33:810
(1990)
◼ 3.15 to 6.3 grams EPA and DHA per day
◼ Lee et al. Arch Med Res 43:356 (2012)
◼ > 2.7 grams of EPA and DHA is effective
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Lupus
◼ Westberg and Tarkowski. Scan J Rheum
19:137 (1990)
◼ Short-term benefit
◼ Wright et al. Ann Rheum Dis 67:841
(2008)
◼ 3 g EPA and DHA per day
◼ Halade et al. Exp Bio Med 238:610 (2013)
◼ Strong dose-response (1 vs. 4%) in NZBxNZF
mice
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61
Omega-6 Fatty Acid Metabolism
Linoleic Acid
Dihomo Gamma Linolenic Acid (DGLA)
Delta 6 DesaturaseActivated by Insulin
Inhibited by DHA
Delta 5 DesaturaseActivated by Insulin
Inhibited by EPA
Cellular Inflammation
Arachidonic Acid (AA)
Gamma Linolenic Acid (GLA)
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Omega-6 Fatty Acids
Let’s Make It Simple
Cellular Inflammation
Arachidonic Acid
Activated by InsulinInhibited by Omega-3 Fats
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Dr. Paul Robbins, Department of Metabolism and Aging , Scripps Florida
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100%1% 50%
INFLAMMATORY DIET
ANTI-INFLAMMATORY DIET
Healthy Lifespan Potential
Telomere Shortening:
Age 0 - 40
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100%1% 50%
Telomere Shortening:
Age 40 - 70
INFLAMMATORY DIET
ANTI-INFLAMMATORY DIET
Healthy Lifespan Potential
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Mediterranean Diet and Telomere
Length: Population Based Cohort Study
BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g6674
M Crous-Bou, TT Fung, J Prescott et al.
• In this large study (121,700 subjects followed since 1976), greater adherence to the Mediterranean diet was associated with longer telomeres
• The results further support the benefits of adherence to the Mediterranean diet for promoting health and longevity
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PROLONGING HEALTHY LIFESPAN IS JUST ONE OF THE THE BURNING ISSUES FOR OUR PLANET
• CLIMATE CHANGE
▪ 8-20% reduction in cultivatedsurface area by 2050
▪ 5-25% reduction in production level by 2050
• WATER MANAGEMENT
▪ less water/more needs
▪ 70% of the world water consumption
linked with agriculture
•AGRICULTURAL PRODUCTIVITY
▪ Productivity growthslowed
▪ increase in meat consumption
pressure on grains production
• POPULATION GROWTH▪ 7 billion in 2011
▪ 9 billion in 2050
• URBANIZATION
Total population in urbanareas (%) in 2030:▪ Africa: 55%▪ Asia: 66%▪ South America: 74 %▪ Food deserts
• GLOBAL FOOD PARADOXES
▪ Malnutrition - hunger
▪ Obesity and Diabetes epidemic
▪ Food Waste
• NEW SCIENCE AND FOOD TRENDS
▪ Better food products formulation
▪ More stringent legislations
▪ Food fears
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THE GLOBAL PARADOXES ON FOOD AND NUTRITION
VS.
805MILLION
1,5BILLION
DIE OF HUNGEROR OBESITY?
FEED PEOPLE,ANIMALSOR CARS?
FEED WASTE OR FEED THE
HUNGRY?
WORLD GRAIN PRODUCTIONAND ITS USE
47%Human food
33%Animal fodder
7%Biofuels
=1,3
BILLION TONSARE WASTED EACH YEAR:
4 TIMES WHAT IT WOULD TAKE
TO FEEDTHE 868 MILLION PEOPLE
WHO ARE HUNGRY
THE PLANET’S BALANCE IS NEGATIVE!
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Diabetes Research Institute
Rodolfo Alejandro David BaidalNorma KenyonJay SkylerAlberto PuglieseGiacomo LanzoniJuan Dominguez-BendalaRicardo PastoriPeter BuchwaldChristopher FrakerDora M.BermanArmando J. Medez Diego CorreaElina LinetskyRaj HiraniCITP TeamcGMP TeamRegulatory / QA Team
Acknowledgments
Andrea FabbriFrancesco CadarioSilvia Savastio
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DIABETES RESEARCH INSTITUTE
FEDERATION
EDMONTON
MIAMI
MILAN,
BOLOGNA,
ROME,
PALERMO
STOCKHOLM
TEL AVIV KYOTO
VALENCIA
UMEA
OXFORD
SAN PAULO
GENEVE
BUENOS AIRES
SHANGHAI-
FOUZO
HACKENSACKTIBLISI
SEOULMANAGUA
STANFORD
UCSF
BOGOTA
CALI
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The Cure Alliancewww.TheCureAlliance.orgwww.CellR4.org
An international not-for-profitassociation of scientists, physicians and committed individuals who share the vision to promote international collaborations while overcoming the impediments and barriers to the development of cures
Facebook: The Cure AllianceTwitter: @CureAlliance