"Insulin Independence" Summit on Capitol Hill

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These slides are from the April 24, 2013 "Insulin Independence" summit at the Canon House Office Building on Capitol Hill in Washington, DC. The event previewed the future of combination therapies to restore insulin production to people living with type 1 diabetes.

Something remarkable happens when some women with type 1 diabetes become pregnant: they start producing completely normal levels of insulin.

You read that correctly: one third of pregnant women, including those who’ve had it for 20 years or more, have reduced insulin needs during pregnancy. Some need no injected insulin at all. This knowledge may soon help everyone living with type 1 diabetes. How is this possible?

Two special things happen during pregnancy. First, the body relaxes the immune system to prevent it from harming the fetus. Second, it floods the body with hormones that promote growth. This causes something that researchers long thought was impossible: brand new islet cells start forming and producing insulin.

The combination therapy approach looks to mimic this effect and transform the treatment of diabetes.

Published in: Health & Medicine

"Insulin Independence" Summit on Capitol Hill

  1. 1. A NEW ROAD FOR TYPE 1 DIABETESIS BEING PAVED TODAYThe International Summit on Insulin Independence
  2. 2. Table of ContentsSlide No. Speaker3 Louis Cocco Jr4-16 Claresa Levetan MD, FACE17-24 Susan Pierce, CDE, MPT25-39 Desmond Schatz, MD40-52 Paolo Pozzilli, MD53-65 Donald Bergman, MD, FACE,MACE66-71 Lois Jovanovic, MD, FACP, FACN,FACE, MACE72-85 Aaron Vinik, MD, PhD, FCP, MACP,FACE
  3. 3. What I Know About Diabetesby Louis Cocco, Jr Age 11 Despite all of the advances, diabetes is the leading cause ofamputations, 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% amongchildren 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 onterrorism combined. 2 I know that this group of doctors will get me off of insulin before I ama grownup.1) http://usatoday30.usatoday.com/news/health/2008-01-23-diabetes-cost_N.html Accessed 4.13.132) http://www.diabetes.org/diabetes-basics/diabetes-statistics/ Accessed 4.13.133) Christopher C et al., Incidence trends for childhood type 1 diabetes in Europe during 1989—2003 and predicted new cases 2005—20: amulticenter prospective registration study The Lancet, (373)9689, Pages 2027 - 2033, 13;20094) Lipman T, et al., Diabetes. March 2013. Population-based Survey of the Prevalence of Type 1 and Type 2 diabetes in School Children inPhiladelphia . [Epub ahead of print]3
  4. 4. • 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 regenerationagent to reverse the underlying mechanisms of diseasein type 1 diabetes• My colleagues will then discuss the therapies we havenow and into the future to reverse type 1 diabetesClaresa Levetan MD, FACE4
  5. 5. 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
  6. 6. What Is an Islet? Islets are small organs within the pancreas that contain 5 different celltypes 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 beenshown necessary for normal glucose metabolism Among both type 1 and 2 diabetes, autopsy studies show not only reducedbeta cells, but also reduced islet numbers Type 1 diabetes will be reversed when 5-celled new islets are generated inan immune protected environment We have the ability to generate new islets that are protected from immuneattack, NOW 6
  7. 7. Distinctions between Isletsof Mice and Men Mice eat continuously and beta cells are constantly turning over duringtheir 1 year lifespan1 Islets in man are designed to regulate glucose based upon emotionalstress and long periods of feast or famine Islets of mice have predominately beta cells, which are centrallyclustered and man has a smaller percentage of beta cells dispersedthroughout the islet, which are in direct contact with the other 4 celltypes The autonomic nervous system in man through innervates islet bloodflow suggesting human islet a have a unique reaction to emotionalstress compared to mice2 100s of immune studies have reversed diabetes in mice, but not inman, because man’s islets have a complex infrastructure that cannotbe 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 arenow available1) 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
  8. 8. Type 1 Diabetes is more than anAutoimmune Disease in Man Humans require both immune protection and generation ofnew islets to reverse the underlying disease process of type1 diabetes Diabetes in mice can be reversed with only an immune agentbecause beta cell turnover is faster in mice than man Islet Regeneration in man is possible, even among patientswith type 1 diabetes for 20 years or longer Type 1 diabetes is not just an autoimmune disease as it is inNOD mice, but is a disease of 1) autoimmunity, 2) beta celldeficiency and 3) lack of beta cell regeneration We have human gene peptides and growth factors thattransform pancreatic ductal cells into new islets that we canuse NOW in type 1 patients8
  9. 9.  One machine pumping both insulin andglucagon Glucose measurements taken and basedupon glucose levels, the correct dosage of bothinsulin and glucagon were automatically givento the patient This is same concept as the “new” artificialpancreas of 2013 now in clinical trials Even the bionic pancreas did not normalizeglucose levels, because it only replaced twomissing and malfunctioning hormones All five cell types generating 6 differenthormones within a functioning islet are requiredfor normal glucose homeostasis Scientific studies show that all 6 hormoneshave a role in glucose metabolismTreatment 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 controlTrans. Am. Soc. Artificial Internal Organs 9. 363. 1963*Kadish AH. Automation control of blood sugar. Biomed Sci. Instr. 1, 172, 1963Available for viewing at the Keck Graduate Institute, Science Heritage Center, Clairemont,CAThe First Successful BionicPancreas was developed in1963 by Dr. Arnold Kadish*9
  10. 10. Regeneration of the Pancreas Clamping of the pancreas resulting in new isletformation has been described for a century Based on a paper in 1920, in which patients withpancreatic stones had new islets, Frederick Bantingclamped the pancreatic ducts of dogs for 10 weeksand collected the pancreatic secretions that becameknown as insulin Before insulin was readily available, surgeons tied offpart of the pancreas among type 1 children, whichtransiently helped their diabetes, but likely the ongoingautoimmune destruction of new islets contributed towhy these surgical successes were only temporary10
  11. 11.  Severely ill diabeticchildren underwentligation of thepancreatic duct toimprove their diabetesbetween 1910 and1930* Benefits were positive,but short-lived likely dueto autoimmunedestruction of newinsulin-producing cells**Cusi 1911; Bierry and Kollman, 1929; DeTakats, 1930 11
  12. 12. In 1983, Dr. Vinik Rediscovered that Wrapping the Pancreaswith Cellophane turned Pancreatic Ducts into Islets New islets were shown by Dr. Vinik by wrapping the pancreatic ducts ofhamsters A peptide was specifically isolated in 1992 by Dr. Vinik’s team that hasbeen 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 within2 months in type 1 patients with a 20 year history of diabetes and nobaseline C-peptide, but without immune protection, these results werenot sustained. A rise in GAD antibodies were seen reflecting theimmune system was seeing new beta cells3 As much as a 75% reduction in insulin requirements was seen after 4weeks of gastrin and epidermal growth factor in type 1 patients21) Dungan KM et al., Diabetes Metab Res Rev 2009; 25: 558–5652) 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, 2013DuctIslet212
  13. 13. Islet Relationship to DuctsDUCTSISLET13
  14. 14. Not until the Early 1980s Was DiabetesConsidered to be an Autoimmune Disease In the 1980s, nearly 100% of patients became insulin-freewhen the immune agent Cyclosporine A was begunimmediately after diagnosis, thus protecting the remainingfew beta cells By 2 years, almost all patients in remission, required insulin,demonstrating that an immune tolerance agent alone, doesNOT mean that there will be generation of beta cells in man It is only now after 100s of studies using a variety ofimmune tolerance agents and immune approaches that wecan look back and see that in man, diabetes is a diseaseNOT only of autoimmunity We now have both immune tolerance agents and betaregeneration agents (some are already FDA-approvedtherapies) that can address the underlying mechanisms ofdisease in type 1 diabetes: 1) autoimmunity 2) beta celldeficiency and 3) lack of beta cell regeneration 14
  15. 15. 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 regenerationagents; a platform for future insulin independence Type 1 Diabetes is a disease of Autoimmunity Beta Cell Deficiency Lack of Beta Cell Regeneration15
  16. 16. ImmuneTolerance AgentProtect newlygenerated and existingbeta cellsPotential for Insulin Independence20152013More potentbetagenerationagentsInsulinIndependenceamong existingand new onsetRegenerationAgentRemissionfollowed bymaintenanceImmuneTolerance AgentProtect newlygenerated and existingbeta cellsInsulinIndependenceamong existingand new onset16
  17. 17. • What are normal A1Cs and glucoses?• Is it patients or the pancreas that are non-compliant?• Current therapy and technology is not enoughSusan Pierce CDE, MPT17
  18. 18. What IS the Normal Glucose Range forSomeone without Diabetes? Continuous Glucose MonitoringShows that out of 288 readings/day 95% of glucose levels < 120 mg/dL 180% of glucose levels 60 - 100 mg/dL 11. 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
  19. 19. In those without diabetes,95% of daily (24 hour) lifeis spent with a glucosesless than 120 mg/dl80% of daily (24 hour) lifeis spent with glucose levelsof 60-100 mg/dlhttp://www.diabetes-symposium.org/index.php?menu=view&id=32219
  20. 20. *Updated mean sA1C adjusted for age, sex, andethnic group.Stratton I, et al. UKPDS 35. BMJ. 2000;321:405-412.0204060800 5 6 7 8 9 10 11MyocardialinfarctionMicrovascularcomplicationsUpdated Mean HbA1c (%)*%Incidenceper1,000Patient-yearsA1Cs Above 5.5% Increase ComplicationRisk in Non-Diabetic Individuals as well as those withType 1 and Type 2 Diabetes20
  21. 21. Can a normal A1C be achievedwithout too many lows? The leading diabetes researchers of theDCCT believed that insulin alone couldrestore a glucose to < 6.05% withouthypoglycemia 1 An A1C of < 6.05% was attained at leastonce during the 10 year study by 44% ofthe patients receiving intensive therapy 1 The intensively managed groupmaintained an average A1C throughoutthe study of 7.2% 11. The DCCT Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86.21
  22. 22. Is New Technology Helping? Sensor-augmented pump studies recently Demonstrated a decrease of A1C levels from 8.3% to7.5% over 12 months (1) With further reduction to 7.4% after an additional 6months on the sensor (2) These achievements were made without associatedweight gain or hypoglycemia Despite advances in sensors and pumps, sensor-augmented pumps did not improve the A1C levelsas much as did the DCCT decades ago1) 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
  23. 23. I need my human pancreas back!Even pumping all 6 missing hormones --- insulin,amylin, glucagon, ghrelin, somatostatin, pancreaticpolypeptide --- would notThere is no computer that can integrate stress andother factors the way the human islet does.23
  24. 24. Restoring Normal Glucose Restoring 5-celled new islets that generate 6hormones that all communicate with oneanother and the brain to maintain glucoselevels < 120mg/dL 95 % of the time In order to maintain new islets immuneprotection must be in place Drs. Vinik and Bergman will describe how wenow have therapies to transform pancreaticducts into 5-celled islets Drs. Pozzilli and Schatz will describe how wecan optimally protect the new islets 244
  25. 25. The need to change the paradigm ofdiabetes simply being an autoimmunedisease.Desmond Schatz, MD25
  26. 26. GeneticRisk“Pre”-DiabetesNew-OnsetEstablished ComplicationsAntibodiesOPPORTUNITIES FOR PREVENTIONAND CUREPREVENTIONINTERVENTIONCUREWITHOUT PREVENTIONTHERE CAN NEVER BE ACURE26
  27. 27. 27
  28. 28. • Concept rejected initially…”lacks evidence, notnovel, too presumptive, etc.”• Based on lessons learned from pastexperiences), efficacy in other disorders(cancer, HIV, transplantation), and mechanismsunderlying type 1 pathogenesisDiabetes Care, 2002THE CONCEPT FOR COMBINATION28
  29. 29. DO WE HAVE CLUES AS TO WHATIS THE “BEST” COMBINATION?Difficult question to answer, based on: Differences in preclincial studies? Potential differences in mouse to man?29
  30. 30. AAV murine IL-10AAV rat preproinsulin gene (vLP-1)Adenovirus expressing mIL-4AerosolinsulinAllogenic thymic macrophagesAlpha GalactosylceramideAlpha-interferon (rIFN-alpha)Alpha/beta T cell receptor thymocytesAminoguanidineAndrogensAnesthesiaAntioxidant MDL 29,311Antisense GAD mRNAAzathioprineAnti-B7-1Bacille Calmette Gue’rin (BCG)BaclofenBee venomBiolistic-mediated IL-4Blocking peptide of MHC class IIBone marrow transplantationCastrationAnti-CD3Anti-CD4CD4+CD25+regulatory T cellsAnti-CD8Anti-CD28 MAbCholera toxin B subunit-insulin proteinClass I derived self-I-A beta(g7) (54-76) peptideCold exposureAnti-complement receptorComplete Freund’s adjuvantAnti-CTLA-4Cyclic nucleotide phosphodiesterases (PDEs)CyclosporinCyclosporin ADC deficient in NF-kappaBDC from pancreatic lymph nodeDC with IL-4DeflazacortDeoxysperogualinDexamethasone/progesterone/growth hormone/estradiolDiazoxide1,25 dihydroxy Vitamin D3, KH10601,25 dihydroxycholecalciferol1,25 dihydroxyl Vitamin D3Elevated temperatureEmotionalityEncephalomyocarditis virus (ECMV)Essential fatty acid deficient dietsFK506FTY720 (myriocin)GAD 65 peptides in uteroAnti-GAD monoclonal antibodyGalactosylceramideGlucose (neonatal)Glutamic acid decarboxylase(intraperitoneal, intrathymic, intravenous, oral)Glutamic acid decarboxylase 65 Th2 cell cloneGlutamic acid decarboxylase peptides(intraperitoneal, intrathymic, intravenous, oral)GonadectomyGuanidinoethyldisulphideHeat shock protein 65Heat shock protein peptide (p277)Hematopoietic stem cells encoding proinsulinHousing aloneHuman IGF-1I-A beta g7(54-76) peptideAnti-I-A monoclonal antibodiesAnti-ICAM-1IgG2a antibodiesImmobilizationInomideAnti-integrin alpha 4Insulin (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-gammaAnti-interferon-gammaInterferon-gamma receptor/IgG1 fusion proteinInterleukin-1Interleukin-4Interleukin-4-Ig fusion proteinInterleukin-4-plasmidInterleukin-10Interleukin-10-plasmid DNAInterleukin-10-viralInterleukin 11-humanInterleukin-12Intrathymic administration of mycobacterial heat shock protein 65Intrathymic administration of mycobacterial heat shock peptide p277Islet cells-intrathymicL-Selectin (MEL-14)Lactate dehydogenase virus (LDH)Large multilamellar liposomeLazaroidAnti-leukocyte function associated antigen (LFA-1)Anti-LFA-1Linomide (quinoline-3-carboxamide)Lipopolysaccharide-activated B cellsLisofyllineLymphocyte choriomeningitis virus (LCMV)Anti-lymphocyte serumLymphoctyte vaccinationLymphocytic choriomeningitis virusAnti-L-selectinLymphotoxinLZ8MC1288 (20-epi-1,25-dihydroxyvitamin D3)MDL 29311Metabolically inactive insulin analogAnti-MHC class IAnti-MHC class IIMHC class II derived cyclic peptideMixed allogeneic chimerismMixed bone marrow chimerasMonosodium glutamateMurine hepatitis virus (MHV)Mycobacterium aviumMycobacterium lepraeNatural antibodiesNatural polyreactive autoantibodiesNeuropeptide calcitonin gene-related peptideNicotinamideNicotineNinjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulationNKT cellsNY4.2 cellsOK432OvercrowdingPancreatectomyPentoxifyllinePertussigenPoly [I:C]Pregestimil dietPrenatal stressPreproinsulin DNAProbucolProlactinRampamycinRecombinant vaccinia virus expressing GADReg proteinReg proteinRolipramSaline (repeated injection)Schistosoma mansoniSemi-purified diet (e.g., AIN-76)Short term chronic stressSilicaSirolimus/tacrolimusSodium fusidateSoluble interferon-gamma receptorSomatostatinNon-specific pathogen free conditionsStreptococcal enterotoxinsStreptozotocinSulfatide (3’sulfogalactosylceramide)SuperantigensSuperoxide dismutase-desferrioxamineAnti-T cell receptorTGF-beta 1 somatic gene therapyTh1 clone specific for hsp60 peptideAnti-thy-1Thymectomy (neonatal)TolbutamideTolerogenic dendritic cells induced by vitamin D receptor ligandsTop of the rackTreatment combined with a 10% w/v sucrose-supplemented drinking waterTumor necrosis factor-alphaTX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))Vitamin EAnti-VLA-4ThymoglobulinAnti-CD3ALS + Exendin-4LSF + Exendin-4EGF + GastrinRegulatory T CellsIslet TransplantationMicrospheresFTY720sICAM-Ig (Adenovirus Vector)IDS 2004, Cambridge (Atkinson & Roep)N=193;Now ~400THERAPIES PREVENTING DIABETES IN NOD MICE30
  31. 31. WHAT CONSIDERATIONS NEED TOGO INTO SELECTIONS FORCOMBINATION RX?Selecting combination therapies should occur,with a combination of thoughts regardingmechanism of action, synergy, safety, andpotential for efficacy31
  32. 32. USE COMBINATIONS THAT IMPROVE EFFICACY0 25 50 75 100 125 150020406080100ControlGCSFATGATG + GCSFDays Post OnsetNormalGlycemia(%)32
  33. 33. USE COMBINATIONS THAT IMPROVEALLOW FOR LOWER DOSING OF DRUGS33
  34. 34. USE COMBINATIONS THATIMPROVE SAFETYp values @ 4 weeks(n is still increasing)ATG vs. A+G = .0128ATG vs. CD3 = .3569ATG vs. 3+G = .2141A+G vs. CD3 = .0005A+G vs. 3+G < .0001CD3 vs. 3+G = .913534
  35. 35. RECENT NEW-ONSET DIABETES STUDIESPublished- * 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; AnakinraCompleted enrollment- Mesenchymal Stem Cells- Cord Blood Phase 2 (+ Vit D + Omega 3 FA)- Meticulous Metabolic Control- GCSF- ATG-GCSFEnrolling- T reg - α-1 antitrypsin 35
  36. 36. WHAT HAVE WE LEARNED?We can do well designed, adequately powered,and carefully conducted intervention andprevention studiesSample sizes require a collaborative,cooperative, multi-center approachIf a response is seen, it is likely to be evidentsoon after therapy begun (3-6 months)Long term benefit largely unknown36
  37. 37. WHY LIMITED SUCCESS TO DATE?BACK TO THE FUTURE…..RETHINKING MECHANISMS LEADING TO TYPE 1DIABETES?1986: Suicide or Homicide of β Cell Bottazzo …..Is the autoimmune/inflammatory process in humans reallyprimary 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
  38. 38. OUR FUTURE CHALLENGESCurrent treatment quite good – but…insulin not a biological curePrimum non nocere (safety)Re-evaluate study design (smaller, shorterstudies in new-onset patients)Define clinical significance (efficacy)- superiority or ease over current treatment ifnew-onset- only do if translatable (therapy or prevention)Better understand triggers (TEDDY)/mechanismsleading to diseaseUse a `cocktail approach’(Immunoregulatory/regenerative)38
  39. 39. PUTATIVEENVIRONMENTALTRIGGERTIMEFUTURE PREVENTIONOF TYPE 1 DIABETESBETACELLMASSMDIABETES“PRE”-DIABETESGENETICPREDISPOSITIONINSULITISBETA CELL INJURYEarly MonotherapyLate CombinationsSAFEMORE TOXIC ?39
  40. 40. Prof. Paolo PozzilliUniversità Campus Bio-Medico, Roma, ItalyBarts and The London Hospital, UKOutcomes with immune tolerance agents inType 1 Diabetesfrom Cyclosporine to Current Therapies40
  41. 41. Roma,1989: First International Meetingon this topicPresident: D AndreaniVice-President: G GambassiScientific Coordinators: P Pozzilli, H KolbScientific Advisors: JF Back, GD Bompiani, PBrunetti, JJ Duprè, GS Eisenbarth, G Ghirlanda,L Harrison, NK Maclaren, J Nerup, G Pozza, CRStillerScientific Secretariat: A Corcos, E Killick, NVisalli“Immunotherapy of Type 1 diabetes”41
  42. 42. Nearly 100% insulin-free remission if used very early in the course of disease within2-3 days of insulin therapy and before weight loss (Eisenbarth GS Immunotherapy ofDiabetes and Selected Autoimmune Diseases CRC Press, 1989)Remissions are not typically sustained more than 2 yearsMaintaining 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 termadverse effects. There was fear of long term adverse effect at kidney levelThere were no beta cell regenerative agents available at the time to use inconjunction with CyA to sustain potential regeneration of beta cell mass, nor was itunderstood that outcomes in man would be different than mice when using immunetolerance agents42CyA for Type 1 diabetes: history(n= 692 treated patients)
  43. 43. Bougneres PF et al. Diabetes 199043
  44. 44. Skyler JS et al. Diabetic Medicine 199344
  45. 45. Disease State Drug Oral InjectableOrgan Transplant Sandimmune 14-18 mg/kg/day, taper to 5-10mg/kg/day in 1-2 weeks5-6mg/kg/dayNeoral or a bioequivalent generic 7-9 mg/kg/day, taper to 5-10mg/kg/day in 1-2 weeksRheumatoid Arthritis Neoral or a bioequivalent generic 2.5–4 mg/kg/day in two divideddosesPsoriasis Neoral or a bioequivalent generic 2.5–4 mg/kg/day in two divideddosesCrohns Disease Sandimmune 4 mg/kg/dayUlcerative Colitis Sandimmune 4 mg/kg/dayNephrotic Syndrome Brand not specified 3.5 mg/kg/day in two divided dosesMultiple sclerosis Brand not specified 7.2 mg/kg/dayLupus Brand not specified 2.5 mg/kg/dayAlopecia Areata Brand not specified 3-5 mg/kg/dayAtopic Dermatitis Brand not specified 5 mg/kg/dayDermatomyositis Brand not specified 3-10 mg/kg/dayLichen Planus Brand not specified 6 mg/kg/dayMyasthenia Gravis Brand not specified 5 mg/kg/dayPolymyositis Brand not specified 2.5 mg/kg/dayPsoriatic Arthritis Brand not specified 3.5 mg/kg/dayPulmonary Sarcoidosis Brand not specified 5-7 mg/kg/dayUveitis Brand not specified 2.5-5 mg/kg/dayToday usage and dosages of CyA45
  46. 46. Minimal renal adverse effects as shown by Assan and others iftrough levels are <300 ng/mlAmong 285 patients on 19.9 months of CyA averaging 6.5mg/kg/day for 19.9 months and followed for 13 years, no longterm renal effects seen. Trough goal of < 300 ng/ml withreductions if creatinine more than 30% above baseline (AssanR, Blanchet F, Feutren G et al., Diabetes Metab Res Rev.2002;18(6):464-72)Minimal renal adverse effects if dosage maintained in a rangeof 5 mg/kg/day after initial dosage of 7.5 mg/kg/day withtrough goal of 300 ng/ml with reduction of dosage ifcreatinine rises above 30% of baselineA direct toxicity effect of CyA on beta cells function has notbeen demonstrated46Renal Effects of CyA in patients with T1D
  47. 47. Modify from Reimann M et al. Pharmacology & Therapeutics 2009GAD65HSP60IL-1 receptor antagonistGAD65HSP60Anti CD3 MoAbCTLA-4Anti CD20 antibodyToday’s main strategies with immune toleranceagents to halt progression towards beta cell failure47
  48. 48. Pozzilli P. Immunotherapy 2012Results of main trials with immune tolerance agents in T1D48
  49. 49.  We know the good and the bad about CyA, so we should befeel confident enough about its use. This is not the case withall the other immune tolerance agents tested so far for lackof long term studies.No long term renal toxicity has been shown with CyA usedat 7.5 mg/kg per day for 1 year The concept of combination therapy using an immunetolerance agent with a beta cell regenerative compoundshould be considered, and among the different immunetolerance agents, CyA still holds a prominent role.49Rationale for reconsidering CyA in patientswith recent onset T1D
  50. 50. Leslie RD. Diabetes 2010The spectrum of autoimmune diabetes extendsacross all ages and varies with age at diagnosis50
  51. 51. Key issues to consider for trialsin type 1 diabetes51
  52. 52. Future directions:combination therapy52
  53. 53. Ability to use proton pump inhibitors toincrease gastrin, which increases beta cellregeneration.Donald Bergman, MD, FACE, MACE53
  54. 54. Gastrin• Gastrin plays a role in pancreatic growth and development infetal life1,2• Pancreatic gastrin expression is suppressed after birth and thenfound as a growth factor in the gastric antrum and duodenum (Gcells) after fetal development1• Excessive gastrin has been associated with new islet and betacell formation since the 1950s3,4• Gastrin hypersecretion results in the formation of new isletscontaining new pools of beta cells5• Gastrin’s mechanism of action is the transformation ofpancreatic ducts to islets51. Tellez N. Endocrinology, 2011, 152(7):2580–25882. 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):3401–340954
  55. 55. The Association betweenGastrin and Insulin• Patients with Zollinger-Ellison Syndrome-- increased gastrinproducing nests of cells found both in the pancreas and GItract have new islets and increased beta cell replication2• Patients infused with gastrin had heightened insulinresponses to glucose compared to those not receiving agastrin infusion.11) Rehfeld JF, Stadil F. 1973. J Clin Invest 52:1415–14262) Zollinger RM and Ellison EH. Ann. Surg., 142:709-728, 1955.55
  56. 56. Gastrin’s Mechanism of ActionGastrin has been shown by specialized studies includingBrdU studies to transform ductal (extraislet) tissue intonew islets*On the left, a single, larger black cell represents the presence of gastrin and the pink cell representing aprogenitor cell within the ductal population. Blue cells indicate beta cells and red cells represent alphacells, with delta cells present to a smaller extent in green.*Telez, et al., Endocrinology, July 2011, 152(7):2580–258856
  57. 57. Gastrin Transforms Human Ducts to Islets• Gastrin alone, has been shown the ability to induce newhuman islets from human duct cells without othergrowth factors (Suarez-Pinzon, J Clin Endocrinol Metab, June 2005, 90(6):3401–3409)• A combination of Gastrin with Epidermal Growth Factorgiven to type 1 patients for 4 weeks resulted in– up to a 75% decrease in insulin requirements when followedfor 3 months post treatment– an A1C from 6.7% at baseline down to 4.7% at 3 monthspost-treatment (Transition Therapeutics, March 5, 2007http://www.transitiontherapeutics.com/media/archive.php Accessed January 1,2013)57
  58. 58. Proton Pump Inhibitors increase Gastrin• Proton pump inhibitors (PPIs) are used extensively for the treatment ofpeptic ulcer and related symptoms and indirectly elevate gastrin levels• Studies have shown a dose- and duration-dependent relationship betweenPPIs 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-druginteractions• Long-term usage among postmenopausal women associated with anincreased risk for hip fracture, infectious diarrhea, particularly amonghospitalized patients1) Hu YM. World J Gastroenterol. 12:4750–47532) Ligumsky M. 2001. J Clin Gastroenterol 33:32–353) Cadiot G,. Gastroenterol Clin Biol 19:811–81758
  59. 59. PPIs• Substitutedbenzimidazole derivatives• Block the terminal step inacid production• Inhibit the function ofhydrogen-potassiumadenosine triphosphataseon the luminal surface ofparietal cell membranesin the stomach.Madanick. Cleveland Clinic JM2011;78:39-4959
  60. 60. 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 patientsnot 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 onPPIs (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.
  61. 61. Randomized Trials Using PPIsAmong Type 2 DiabetesPantoprazole/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 groupEsomerprazole/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 groupcompared 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, 201361
  62. 62. Current Trial with Lansoprazole in Type 1Patients 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 lansoprazolewith 50 mg of Sitigliptin once daily– Subjects age 18-45 years will take 60 mg of lansoprazole once daily with 100 mgof sitigliptin once daily• Primary Outcome Measures: 2 hour C-peptide AUC in response to mixed mealtolerance at 12 months• Secondary Outcomes Measures:– 2 hour C-peptide AUC in response to MMTT [ Time Frame: months 6, 18, and24 ]– 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=362
  63. 63. PPI side effects: clopidogrel• PPIs inhibit a P450enzyme which is requiredfor activation ofclopidogrel• Contradictory data inliterature• One retrospective studyfound no adverse effectand found decreased GIbleeding in combined use• FDA warningRay et al. Ann Int Med 2010;152:337-345 63
  64. 64. PPI side effects: fracture, pneumonia,enteric infection• Fracture risk: conflictingreports. Risk greater inthose with other riskfactors for fracture.FDA: possibleassociation• Pneumonia risk: 4.5times higher in PPIusers but only 18% haddocumentedpneumonia• Enteric infection risk: C.Diff. 127000 patientsodds ratio 2.05.• Enteric infection:bacterial overgrowthand SBP (small studies)Madanick. Cleveland Clinic JM2011;78:39-49 65
  65. 65. PPI side effects: nephritis, iron, B12deficiencesnephritis• 64 cases documented in theworld literature in PPI users• Not enough evidence tosupport a causalrelationshipIron, B12 deficiency• Iron: acid needed todissociate iron salts fromfood• B12: acid needed toseparate B12 from foodproteins• No convincing evidence inthe literatureMadanick. Cleveland Clinic JM2011;78:39-4965
  66. 66. Ability for women with decades of type 1diabetes to become insulin independent withinweeks of pregnancy.Lois Jovanovic MD, FACP, FACN, FACE,MACE66
  67. 67. Normal Pregnancy Associated with a 2-4 fold rise in insulin Among those without diabetes, normal glucose levels areconsiderably lower during pregnancy than in the non-pregnant state Goals Glucose During Pregnancy The American College of Obstetricians and Gynecologistsrecommends the following goals when self-monitoring blood glucoselevels 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 followingglucose 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 meal67
  68. 68. Each Pregnancy is Unique Among pregnant type 1 women, there is often adecline in the need for insulin Often see hypoglycemia among type 1 patients inpregnancy with a peak incidence in the firsttrimester due to new insulin production by themother Some women have been insulin-free throughouttheir pregnancy, only to return to insulinrequirements after delivery New insulin production has been seen among type1 patients with a history of diabetes for more than20 years68
  69. 69. Am J Obsetet Gynecol 1976, 15;125(2):264-5.1976Known Insulin Remissions Among Pregnant Type 1Patients Date Back Decades69
  70. 70. Patients with No Detectable InsulinBefore and Significant Rises During Pregnancy*C-peptide/Endogenous insulin concentration before pregnancyand at 10 weeks of gestation00.050.10.150.20.250.31 2 3 4 5 6 7 8 9 10Patients with Type 1 DiabetesC-peptide(nmol/l)Pre-Pregnancy10 weeks of gestation Patients had a mean duration of diabetes 21.2 years By 10 weeks of gestation, endogenous insulin levels werenot only detectable, but into the normal range Some women have been insulin-free not only during thistime, but throughout pregnancy*Jovanovic L, et all.,Diabetologia. 2000 Oct;43(10):1329-30. 70
  71. 71. New Insulin Production OccursQuickly 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 forreplication Most islets are formed by the time of birth Only in rare instances do islets regenerate. These times includeacute pancreatic injury, pancreatitis, pancreatic stones andpregnancy By 10 weeks of pregnancy, new endogenous levels of insulin areseen This is the time similar to the original study by Banting and Bestwhen they collected secretions from clamped pancreatic ducts at10 weeks*Johansson M., et al., Endocrinology 2006. 147(5):2315–2324
  72. 72. Combination Therapies EnhanceProspects of “Curing” DiabetesAaron Vinik MD, PhD, FCP, MACP, FACEMurray Waitzer Chair of DiabetesResearchEastern Virginia Medical School StrelitzDiabetes Center andNeuroendocrine UnitNorfolk Virginia.72
  73. 73. Background (Sarandipity)Saran wrapping reverses streptozotocin-induced (STZ) diabetes in hamsters• Ilotropin, a crude pancreatic extract fromCW, induces new islet formation from ductalepithelium.• Ilotropin reverses streptozotocin-induceddiabetes in hamsters.• mRNA differential display led to• THE DISCOVERY OF INGAPRafaeloff, Quin, Barlow, Rosenberg and VinikFebs Letters378, 219-223, 1996Rafaeloff, Pittenger, Barlow, Qin, Yan, Rosenberg, Duguid, VinikJ Clin Invest 99: 2100-2109, 1997 73
  74. 74. Production of a Biologically Active INGAPPeptide by Biochemical Techniques andEffects on Islet Neogenesis and STZ Diabetes5’UTR Signal peptide Mature peptide 3’UTR1 7835540 6463’UTR766C C C35 46 68C C C146 163 171C= cysteineAA= amino acidN= potential N glycosylationIGLHDPSHGTLPNGSAA 104 AA 118NNN74
  75. 75. Restoration of Normal Blood Glucose in INGAP-treated C57BL/6J STZ Diabetic MiceINGAP/SALINERosenberg, Vinik et al. Ann Surg. 2004 Nov;240(5):875-84.75
  76. 76. 76
  77. 77. INGAP and Human Health and DiseaseIs INGAP present in the human pancreas?Does INGAP affect human pancreatic tissue invivo and in vitro? Will it reverse diabetes?77
  78. 78. Transdifferentiation of Human Islets-TheEffects of INGAP PeptideHuman islets after isolationCK19 –tive and followinginduction of reverse trans-differentiation to a duct-likeepithelial structure CK19 +Effects of INGAP peptideon transdifferentiationof ductal cells (CK19 +)to islet (CK19-)INGAP Peptide inducedtransition from ductal cellsto insulin producing cellsand fully formedislet with expression ofinsulin (brown)78
  79. 79. Accelerating Factors“THE INGAP INDUCERS”AP-1-activatorsSTAT-activatorsPAN-activatorsNEOGENESISINGAPNEWISLETSTaylor Fishwick, Vinik et al J Endocrinol. 2006 Mar;188(3):611-21Hamblet et al Pancrease 36, 17671772, 2008Pittenger, 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, 201179
  80. 80. INGAP is Overexpressed inHuman Islet NeogenesisInsulin RedINGAP GreenSemakula C, Pambucian S, Gruessner R, Kendall D, Pittenger G, Vinik A, Seaquist E JCEM 2003
  81. 81. Recapitulation of Fetal Development ofIslets in NIPHS Syndrome•a) insulin blue/ Ki67 red•B)Proinsulin•C) amylin•D) PDX•E) NKX 6.1•F) Insulin / Ki 67Won Pittenger, Vinik et al Clinical Endocrinology 2006:65, 566-578
  82. 82. HBA1c Response to INGAP in T1 DM per ProtocolTrial0 28 56 84 112 140-0.50+0.5-1.0DaysMeanChangefromBaseline(AUC)Placebo300 mg600 mgINGAP TreatmentDuncan, Buse and Ratner Diabetes Metab Research and Reviews, 25, 558-565.,200982
  83. 83. QuiescentDuct Cells InitiationDifferentiationProliferationApoptosisPro-apoptoticNew isletsAnti-apoptoticIslet NeogenesisGlitazoneGLP analogsAnti inflammatory, Lysophylline,Immunomodulatory,UstekinumabINGAPEGF/gastrin83
  84. 84. 840%10%20%30%40%50%60%70%80%SalineLSFINGAPINGAP/LSFPreTxDelayedPreTXRateofRemission(<200mg/dl)All MiceLow Starters (<350mg/dl)High Starters(>350mg/dl)Hyperglycemia remission rates in INGAP +Lisofylline (LSF) treated NOD MiceTersey et al J of Diabetes 2: 251-257, 201284
  85. 85. Conclusion• It is not beyond the realms of reason to anticipate thatregenerating agents such as INGAP, alone, or incombination with other factors, anti-apoptotic and anti-inflammatory agents, e.g. lisophylline, anti-apoptic agentse.g. GLP-1 or an analog, DPP IV inhibitors or Glitazones,small surrogate molecules that activate the receptor, orgene manipulation will provide a cure for certain forms ofdiabetes in humansThank you for your attention! 85
  86. 86. For Questions, please write us atInsulinIndependence@gmail.comwww.InsulinIndependence.comTHANK YOU!86

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