Human Pancreatic Islets and Diabetes Research

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Human Pancreatic Islets and Diabetes 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 by
• John S. Kaddis
• Support Scientist, Department of Information
  Sciences
• City of Hope National Medical Center
• Beckman Research Institute

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Human 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 Studies
Relevant to Human Diabetes
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Availability of Human Islets Allows Studies
Relevant to Human Diabetes
Organ Donations
Pancreas
Deliver to Transplant Center
Pancreas Processing
Clinical Islet Transplantation
Human Islets
Right image adapted from Naftanel MA, Harlan DM.
Pancreatic Islet Transplantation. PLoS Medicine.
2004, 1(3), e58, 198-201
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Need 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) Consortium

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

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

Image Source http//icr.coh.org/icr_map.asp
(accessed April 9, 2009)
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Studies 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 Islet
Transplant Registry

• 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

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

• 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 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 States 2001-2008
OPTN data last updated April 3, 2009 for
donations occurring through January 31, 2009
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Organ Donation in the United States 2001-2008
OPTN data last updated April 3, 2009 for
donations occurring through January 31, 2009
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Organ Donation in the United States 2001-2008
OPTN data last updated April 3, 2009 for
donations occurring through January 31, 2009
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General Measurement Data from Pancreas Donors
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Gender and Medical History of Pancreas Donors
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Facility Operations

• 1 million - 7 million to establish
  facility
• 0.8 million - 3 million annual facility
  maintenance
• 21,000 estimated direct costs for processing
  each pancreas

Image Source Ricordi C, Strom TM. Clinical Islet
Transplantation Advances and Immunological
Challenges. Nature Reviews Immunology. 2004, 4,
259-268.
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 for Pancreata
Acquired by ICR 2001-2008
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Alternatives 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 Islets

• Differences seen in
• Number of cells within an islet
• Islet architecture
• Beta cell response to drugs

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.
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Conclusions

• 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 islets

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Acknowledgements
Organ Donors and their Families
People with Diabetes
Funding Agencies Department of Health and Human
Services, National Institutes of Health
National Center for Research Resources
National Institute of Diabetes and Digestive and
Kidney Diseases Juvenile Diabetes Research
Foundation
Human Islet Isolation Laboratories Washington
University, T. Mohanakumar 2001-2006 University
of Colorado, R.G. Gill 2001-2006 University of
Tennessee, A.O. Gaber 2001-2006 Puget Sound
Blood Center, J. Reems 2001-2006 Joslin Diabetes
Center, G. Weir 2001-2006 Columbia University,
M.A. Hardy 2001-2006 University of Minnesota,
B.A. Hering 2001-2009 University of
Pennsylvania, A. Naji 2001-2009 University of
Miami, C. Ricordi 2001-2009 City of Hope (COH)
National Medical Center, F. Kandeel
2001-2009 University of Wisconsin, L. Fernandez
2006-2009 Chicago Consortium University of
Illinois at Chicago, J. Oberholzer 2006-2009
Northwestern University, D. Kaufman
2006-2009 University of Alabama Birmingham, J.L.
Contreras 2006-2009
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Acknowledgements
Clinical Transplant and Organ Donor
Data Collaborative Islet Transplant Registry,
EMMES Corporation Organ Procurement and
Transplantation Network United Network for
Organ Sharing
Islet Isolation, Laboratory and Clinical Research
Data Islet Cell Resources Administrative and
Bioinformatics Coordinating Center, COH
Martha Antler Tracey Stiller
Other Vanderbilt University, Alvin
Powers University of Pittsburgh, Andrew Stewart
Background Islet Image Institute for Molecular
Bioscience at the University of Queensland in
Australia, Brad Marsh