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Human Pancreatic Islets and Human Pancreatic Islets and Diabetes ResearchDiabetes Research

J.S. Kaddis, B.J. Olack, J. Sowinski, J. Cravens, J.L. Contreras, J.C. Niland

JAMA, April 15, 2009; V 301, No. 15

Presented byJohn S. Kaddis

Support Scientist, Department of Information SciencesCity of Hope National Medical Center

Beckman Research Institute

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Human Islet Based ResearchHuman Islet Based Research

• Goal– One day, cure diabetes mellitus

• Value– Prevent development of the disease– Expand therapeutic options for those with

diabetes – Understand uniqueness of human islet biology

• Challenges– Human islets are difficult to manufacture,

cannot be stored, and are not readily renewable

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Availability of Human Islets Allows Availability of Human Islets Allows Studies Relevant to Human Studies Relevant to Human DiabetesDiabetes

Pancreas

Organ Donations

Human Islets

Pancreas Processing

Ship by overnight courier to scientists Basic Science

Laboratory Research

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Availability of Human Islets Allows Availability of Human Islets Allows Studies Relevant to Human Studies Relevant to Human DiabetesDiabetes

Pancreas

Deliver to Transplant

Center

Human Islets

Clinical Islet Transplantation

Right image adapted from: Naftanel MA, Harlan DM. Pancreatic Islet Transplantation. PLoS Medicine. 2004, 1(3), e58, 198-201

Organ Donations

Pancreas Processing

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Need for Human IsletsNeed for Human Islets

•156 approved studies

•>15% annual increase in production

•>25% annual increase in demand

•Need supplied

•100% in 2004•46% in 2008

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Islet Cell Resource (ICR) Islet Cell Resource (ICR) ConsortiumConsortium

Image Source: http://icr.coh.org/icr_map.asp (accessed April 9, 2009)

ICR Laboratories

•8 currently active •Competitive grant application and renewal process

Facility Qualifications•External Audit Compliance w/ cGMP•Clinical Proficiency

Responsibilities•Provide human islets: Basic Research Clinical Use•Improve human islet isolation and transplantation technologies

Data Coordinating Center•Central Office, Administrative Functions•Biostatistics, Biomedical Informatics

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Studies Using Human IsletsStudies Using Human Islets

• 182 ICR Supported Studies– 26 Transplantation Protocols (Table 1)

• 15 (57%) Islet Alone• 5 (19%) Islet After Kidney• 3 (11%) Simultaneous Islet Kidney• 3 (11%) Double Arm• Data available on 186 of 201 clinical use

pancreata– Multiple transplants per patient

» 99 patients» 170 transplants

– In some cases, greater than 1 pancreas per transplant

– 156 Basic Science Laboratory Studies (Table 2)

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Results Reported By Collaborative Results Reported By Collaborative Islet Transplant RegistryIslet Transplant Registry

Figure Source: Alejandro R et al. Update from the Collaborative Islet Transplant Registry. Transplantation. 2008, 86, 1783-1788.

Insulin Independence Graft Function

Benefits of Transplant• Reduction or

elimination of severe hypoglycemic unawareness

• Stabilization of blood sugar levels

• Alleviation of need for insulin

• Improvement in patient quality of life

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Obstacles in Islet Transplantation Obstacles in Islet Transplantation

• Islet death• Limited engraftment• Chronic immunosuppression• Alloimmunity• Autoimmunity• Limited supply of human islets

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156 Diabetes Research Projects 156 Diabetes Research Projects Supported by the ICR Supported by the ICR Consortium Consortium

Study Type Islets Distributed Extramural Funding

n Number % n Amount %

Prevention and Treatment

86 39,662,677 56 54 $54,713,969 66

Pathophysiology 18 7,056,630 10 11 $5,922,294 7

Both 43 22,289,392 31 25 $21,958,061 26

Data Not Reported 9 2,125,500 3 3 $635,429 1

TOTALS 156 71,134,199

100 93 $83,229,753

100•Certain studies require more islets than others e.g.: Islet/beta-cell imaging and assessment

•Studies requiring fewer islets are greater in number e.g.: Beta cell growth/differentiation, Cell signaling and regulation

•Projects range in cost from: Low of $193,600 (beta-cell regeneration, survival, and death) High of $3.2 million (pharmaceutical research and drug testing)

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Islet Production by ICR ConsortiumIslet Production by ICR Consortium

•Pancreata used predominately in basic science laboratory research (75%)

•Islet yield Clinical transplantation: 91,633,202 / 201 = 455,886 Basic science research: 199,427,452 / 805 = 247,735 Not used: 6,503,022 / 66 = 98,531

•Very little unused

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Organ Donation in the United Organ Donation in the United States 2001-2008States 2001-2008

0 10000 20000 30000 40000 50000 60000

Organ Donors

OPTN data last updated: April 3, 2009 for donations occurring through January 31, 2009

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Organ Donation in the United Organ Donation in the United States 2001-2008States 2001-2008

0 10000 20000 30000 40000 50000 60000

Kidney

Organ Donors

OPTN data last updated: April 3, 2009 for donations occurring through January 31, 2009

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Organ Donation in the United Organ Donation in the United States 2001-2008States 2001-2008

0 10000 20000 30000 40000 50000 60000

Intestine

Lung

Pancreas

Heart

Liver

Kidney

Organ Donors

OPTN data last updated: April 3, 2009 for donations occurring through January 31, 2009

Whole Px ?

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General Measurement Data General Measurement Data from Pancreas Donorsfrom Pancreas Donors

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Gender and Medical History Gender and Medical History of Pancreas Donorsof Pancreas Donors

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Facility OperationsFacility Operations

Image Source: Ricordi C, Strom TM. Clinical Islet Transplantation: Advances and Immunological Challenges. Nature Reviews Immunology. 2004, 4, 259-268.

• $1 million - $7 million to establish facility

• $0.8 million - $3 million annual facility maintenance

• $21,000 estimated direct costs for processing each pancreas*

*Estimation Based on Data From: Frank A et al. Transplantation for Type I Diabetes: Comparison of Vascularized Whole-Organ Pancreas with Isolated Pancreatic Islets. Annals of Surgery. 2004, 240(4), 631-643.

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Standard Acquisition Charges Standard Acquisition Charges for Pancreata Acquired by ICR: 2001-for Pancreata Acquired by ICR: 2001-20082008

Organ Use

Basic Science Research

Clinical Transplant

Not Used

Number of Pancreata

561 86 18

Median Cost (Low, High)

$3000 ($600-

$39,800)

$20,350 ($1,500-$39,800)

$4000($1,600-$16,000)

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Alternatives to Using Human IsletsAlternatives to Using Human Islets

• Surrogates for Human Beta Cells – Main benefit: Restoration of beta cell function – Disadvantages: Pleiotropy, oncogenic

potential, autoimmune properties poorly understood, long term metabolic function

• Cell Lines – Benefits: Low cost, limited variability of

samples, preliminary experiments– Disadvantages: Same

• Nonhuman Islets– Benefits: Easier to isolate, inexpensive

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Using Non-Human IsletsUsing Non-Human Islets

Figure Source: Cabrera O et al. The Unique Cytoarchitecture of Human Pancreatic Islets has Implication for Islet Cell Function. Proceedings of the National Academy of Sciences. 2006, 103 (7), 2334-2339.

Differences seen in:• Number of cells within an

islet • Islet architecture • Beta cell response to

drugs

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ConclusionsConclusions

• Pancreas donations crucial• Islet sharing networks play a key role in

scientific and therapeutic research• Clinical transplantation has proven value• Basic science laboratory research necessary

to understand diabetes mellitus• Human islets play a key role in restoration

of beta cell function• Adequate resources necessary to ensure

local, regional, and national access to human islets9 20

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83

120

158

48

38

37

41

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90

50

100

150

200

250

2002 2003 2004 2005 2006 2007 2008

New Publications

Existing Publications

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AcknowledgementsAcknowledgements

Funding AgenciesFunding AgenciesDepartment of Health and Human Services, National Institutes of Health; National Center for Research Resources National Institute of Diabetes and Digestive and Kidney DiseasesJuvenile Diabetes Research Foundation

Human Islet Isolation Laboratories Human Islet Isolation Laboratories Washington University, T. Mohanakumar; 2001-2006University of Colorado, R.G. Gill; 2001-2006University of Tennessee, A.O. Gaber; 2001-2006Puget Sound Blood Center, J. Reems; 2001-2006Joslin Diabetes Center, G. Weir; 2001-2006Columbia University, M.A. Hardy; 2001-2006University of Minnesota, B.A. Hering; 2001-2009University of Pennsylvania, A. Naji; 2001-2009University of Miami, C. Ricordi; 2001-2009City of Hope (COH) National Medical Center, F. Kandeel; 2001-2009University of Wisconsin, L. Fernandez; 2006-2009Chicago Consortium; University of Illinois at Chicago, J. Oberholzer; 2006-2009 Northwestern University, D. Kaufman; 2006-2009University of Alabama Birmingham, J.L. Contreras; 2006-2009

Organ Donors and their FamiliesOrgan Donors and their Families

People with DiabetesPeople with Diabetes

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AcknowledgementsAcknowledgements

Islet Isolation, Laboratory and Clinical Research DataIslet Isolation, Laboratory and Clinical Research DataIslet Cell Resources Administrative and Bioinformatics Coordinating Center, COH; Martha Antler Tracey Stiller

Clinical Transplant and Organ Donor DataClinical Transplant and Organ Donor DataCollaborative Islet Transplant Registry, EMMES CorporationOrgan Procurement and Transplantation Network United Network for Organ Sharing

OtherOtherVanderbilt University, Alvin PowersUniversity of Pittsburgh, Andrew Stewart

Background Islet ImageBackground Islet ImageInstitute for Molecular Bioscience at the University of Queensland in Australia, Brad Marsh