Rethinking Dogmas That Define Our Knowledge of Type 1 Diabetes

Mark AtkinsonThe University of Florida

Duration of diabetes in young patients (0-31yrs)

Number of patients with

insulitis

Number of beta-cells* / cm2

Acute (<6 months) 15/22378

(0-1919)

Normal controls 0/263104

(950-13060)

*median (range)

Myth # 1

Type 1 diabetes occurs when 90% of the beta cells have been destroyed.

Gepts, Diabetes 14:619, 1965

Myth # 2

The disease occurs due to the exclusive loss of pancreatic beta cells by white blood cells

of the immune system.

InsulitisInsulitis Loss of beta cellsLoss of beta cells ‘‘Hydropic” change, Hydropic” change,

hypertrophyhypertrophy RegenerationRegeneration FibrosisFibrosis Age, BMI, etc.Age, BMI, etc.

• Atrophy of dorsal pancreas

• Pancreatic infiltrates• Psedoatrophic islets• Lobular loss of beta

cells

Myth # 3

Type 1 diabetes is, well…type 1 diabetes

Potential Heterogeneity of Potential Heterogeneity of Type 1 DiabetesType 1 Diabetes

Age (years)

b-cellfunction(%)

10 20 30 40

100LADA

AdultJuvenile

Earlychild-hood

T lymphocytesInsulinaction etc.

1.1. Establish a network to procure and characterize, in a Establish a network to procure and characterize, in a collaborative manner, pancreata and related tissues collaborative manner, pancreata and related tissues (spleen, lymph node, pancreatic lymph node, peripheral (spleen, lymph node, pancreatic lymph node, peripheral blood) from cadaveric organ donors with type 1 diabetes, blood) from cadaveric organ donors with type 1 diabetes, those with long-standing (>50yr) disease, as well as non-those with long-standing (>50yr) disease, as well as non-type 1 diabetic persons whom are islet autoantibody type 1 diabetic persons whom are islet autoantibody positive positive

2.2. Utilizing these tissues, investigators will address key Utilizing these tissues, investigators will address key immunological, histological, viral, and metabolicimmunological, histological, viral, and metabolic questions questions related to how type 1 diabetes developsrelated to how type 1 diabetes develops

Mission:

Program Supported by the Juvenile Diabetes Research Foundation (JDRF)

www.jdrfnpod.org

Disease Diversity – Long Standing Type 1

Ki67+Insulin

Amyloid

Insulin+ Medalist (6065)76 yo FC T1D for 56 yrs

Insulin- Medalist (6066)78 yo MC T1D for 74 yrs

Islets are large and ~100% non-beta cells

Glucagon

Myth # 4

Within a few weeks to months after symptomatic onset, there are no more beta

cells in those with type 1 diabetes.

78 yr male Medalist (4 at onset) IA2+Most islets have no insulin+ but half of sections have scattered insulin+ cells (small clusters, singlets or doublets); no TUNEL+ insulin+ cells seen.

insulin

TUNEL

C peptide undetectable

Beta Cells – Long Standing Type 1

Myth # 5

Obesity is driving the increase in Type 1 Diabetes

EnvironmentEnvironment

Accelerating Incidence Type 1 Diabetes Finland: Lancet 371:1778

Harjutsalo et al May 2008

Finland Type 1 Diabetes Incidence 1965-1996 (32 years)Relative Percent Increase

Diabetes Care: 22:1066-1070, 2008

Myth # 6

Type 1 Diabetes is caused by a an inciting event, likely a viral infection

EnvironmentEnvironment What is “it”?What is “it”?

Omega-3 Fatty AcidsN

utra

swee

t

Myth # 7

The immune response against the insulin producing cells ends shortly after the

months to few years after onset

Insulin- Insulitis+ T1D (6062)10 yo MAA, T1D for 6 yrs

Genotype: DRB1 1/7, DQA1 1/3Histopath: Ins- islets, CD3+ infiltrates.

CD3+Glucagon

Insulitis Can Persist Long After Disease Onset (but rare)

Myth # 8

Beta cells cannot replicate.

Beta Cell Replication by Ki67+Insulin (6052)

Ki67+Insulin

The Islet of Hope

Myth # 9

NOD mice serve as an effective means for finding a way to prevent and/or cure type 1

diabetes.

The List – NOD miceAAV murine IL-10AAV rat preproinsulin gene (vLP-1)Adenovirus expressing mIL-4AerosolinsulinAllogenic thymic macrophagesAlpha GalactosylceramideAlpha-interferon (rIFN-alpha)Alpha/beta T cell receptor thymocytes AminoguanidineAndrogensAnesthesiaAntioxidant 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-human Interleukin-12Intrathymic administration of mycobacterial heat shock protein 65 Intrathymic 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 water Tumor necrosis factor-alphaTX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))Vitamin EAnti-VLA-4

ThymoglobulinAnti-CD3ALS + Exendin-4LSF + Exendin-4EGF + GastrinRegulatory T CellsIslet TransplantationMicrospheresFTY720sICAM-Ig (Adenovirus Vector)

Early 2011 est. - ~400Early 2011 est. - ~400

N=193 as of 2004

The List – Humans

2011 Estimate - 02011 Estimate - 0

BUT – 2011 a Year of Promise

A Sampling of Large clinical trials seeking to reverse T1D whose results are due for reporting in 2011Drug Compound Type of Trial Abatacept CTLA4-Ig Phase II (NIH TrialNet)Diamyd GAD-alum Phase III (Diaprevent)

Phase III (European)Phase II (NIH TrialNet)

DiaPep277 HSP peptide Phase IIIProchymal Mesenchymal stem Phase II Teplizumab Anti-CD3 Phase II/III (Protégé)

Phase II (Protégé encoure)Phase II (NIH, AbATE)

Otelixizumab Anti-CD3 Phase III (Defend-1)

Myth # 10

Most of what we can learn about type 1 diabetes can be determined in mouse

models…and most of the important questions about human disease have been answered.

Diabetes 14:619-633, 1965

Courtesy Peter In’t Veld

In’t Veld and Atkinson, Diabetes (Submitted)

Pipeleers and Ling, Diabetes/Metabolism Reviews 8:209, 1992.Gepts et al, 1965, 1978; ,Doniach et al, 1973; Klöppel et al, 1984; Bottazzo et al, 1985; Foulis et al, 1986; Hänninen et al, 1992; Somoza et al, 1994; Lernmark et al, 1995; Shimada et al, 1999; Dotta et al, 2007; Uno et al, 2007; Butler et al, 2007, Gianani and Atkinson, 2010.

Duration of disease

≤1 week >1 week - ≤1 year

>1 year total

Onset childhood (0-14 yrs)

22/23 37/42 3/32 62/97

Onset young adult(15-39 yrs)

8/14 17/26 1/23 26/63

Insulitis – T1D Patients Stratified to Age at Onset and Duration of Disease

One Bottom Line Message…..

At our current level of diagnosis and classification, type 1 Diabetes is a VERY heterogeneous disease AND one that needs much more in the way of research, to bring a cure.

The JDRF is vital to this cause

THANK YOU

• Anastasia Albanese-O'Neil, Martha Campbell Thompson, Desmond Schatz

• Roberto Gianani & George Eisenbarth• Teo Stavea, Marie Nierras, Dick Insel & the JDRF for their

support• nPOD leadership (Executive Committee members, Chairs,

Committee members)• Scientists• Our Cores and their staff• Our partners (Kronus, OPO)• George King, Susan Bonner-Weir, Al Powers• NDRI and IIAM• Organ donors & their families