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White Paper on Human Islet Availability for Diabetes Research

White Paper on Human Islet Availability for Diabetes Research.
Generated Following Discussions with Islet Researchers at the
April 2014 Islet Biology Keystone Meeting

Statement of the Problem:

The need for human islets for diabetes research is pressing and rising.  The pressure on the human islet “pipeline” has increased acutely for several reasons.  First, there is widespread acceptance that, while broadly similar, important functional and morphological differences occur between murine and human islet cells; thus, there is an urgent need to directly address applicability of murine findings to the pathophysiology of all types of diabetes, including type 1, type 2, gestational and others (discussed in 1-3).  Because of these important differences, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has urged researchers to employ human islets more frequently in their diabetes research. This is explicit in the National Institutes of Health’s (NIH) recent call for applications as part of the Human Islet Research Network (HIRN) initiative (4). In parallel, the Juvenile Diabetes Research Foundation (JDRF) also is encouraging diabetes researchers to employ human islets in research as exemplified in recent RFAs (5,6).  Second, as a consequence of the NIDDK HIRN initiative and the general acceptance that murine events should be corroborated in human islet cells, there has been an explosion in the number of investigators requesting human islet tissue for research, either to confirm previously published findings on murine islets, or to generate new data.  Third, both Scientific Grant Review Committees and scientific journals have set the bar higher by demanding data on human islets in grant applications and peer-reviewed manuscripts.

On the other hand, while an urgent need for human islets for research is evident, human islets for research are difficult to obtain from living or cadaveric donors.  This lack of availability stands in contrast to other tissues commonly investigated in diabetes such as adipose or skeletal muscle, and perhaps even the liver, which are more easily obtained by percutaneous biopsy. This is due to poor anatomical access to the needed tissue, and complications inherent in obtaining a biopsy. Nevertheless, the Integrated Islet Distribution Program (IIDP), funded by the NIH as well as the JDRF (until Dec 2011), has been a tremendous boon for the scientific research community, given their organized and concerted approach to obtaining and distributing high quality cadaveric human islet tissues to researchers (7).  Further, since human islets do not grow continuously in culture, have a “shelf-life” of only 7-10 days, and islets from a given cadaver donor must be shared among many investigators, the actual number of available islets in real time is limited. In practical terms these factors translates to teams of investigators obtaining human islets once or twice per month, using them actively for a week, and then waiting idly for the next shipment.  These issues are reflected in the increasing number of new IIDP investigators requesting human islets (increase from 35 in 2010 to 104 in 2014), and the average wait time to obtain human islets of at least two weeks. In theory with a more plentiful islet supply, human beta cell research could be moving twice as fast as it currently is. Also of note, up to 80% of investigators are requesting additional islets from patients with type 1 or type 2 diabetes.

These collective issues have led to informal discussions among the scientific community, which in turn resulted in a “call for action” in a workshop at the recently concluded Keystone Meeting (April 2014). This workshop was specifically designed by the organizers (and enthusiastically approved by the Keystone Advisory Board) in response to popular demand by investigators over the last several years to directly address the issues, limitations and concerns related to availability of human islets for scientific research.  While the need for more islets and the problem of poor availability are now well recognized by researchers (8) and by the NIH, the scientific community as a whole is challenged with crafting a solution, without which research in human islets, and therefore a significant understanding of the pathophysiology of human diabetes, will be severely hampered. Thus, the Keystone Workshop provided an important forum that allowed frank discussions on a variety of issues related to the central concern of availability of human islets for research, and yielded multiple suggestions for potential solutions, as outlined below.

Potential Solutions to Human Islet Availability for Research:
A. There was unanimous agreement that, given the surge in investigators requesting human islets, there is the need to at least double the availability of these human islets. The “doubling” concept is based on the notion that, on average, human islet investigators have access to human islets half as often as needed, and that the “price” for doubling the numbers of human islets distributed by IIDP (estimated at ~$2 million) was minor relative to the overall NIDDK budget. The source of this additional funding was a major topic of discussions.

Given the static number of IIDP Islet Isolation Centers (currently six), one option might be to increase financial support for existing Centers, allowing them to double their efforts rather than open new Centers. One suggestion was to provide the IIDP with a long-term human islet commitment analogous to the NIH-funded Mouse Metabolic Phenotyping Centers (MMPCs) that have been used and appreciated by the scientific community.  It also was suggested that the JDRF and industry provide financial support for the IIDP, given that all stakeholders (NIH, JDRF, industry) share a common long-term goal of islet cell regeneration to enable better therapeutics. Industry has created joint programs in Europe to support diabetes research; perhaps this approach could be organized in the United States as well.  There also was a call to adapt either the JDRF-sponsored nPOD program and/or the IIDP, such that they include an islet distribution arm for type 2 diabetes islets. Again, it is worth noting that Europe has a similar JDRF program, and industry also has contributed to studies focused on type 2 diabetes.

Because the NIDDK-sponsored Clinical Islet Transplant (CIT) program will be ending soon, there was concern that human islet availability may decline just at this time of increasing human islet need.  Further, the supply of pancreata apparently is not rate-limiting; pancreata are not harvested from many cadaver donors of other organs, meaning that these organs that could be used for research are being left on the table.  This realization prompted enthusiasm for a greater involvement of Organ Procurement Organizations (OPOs); along the lines that nPOD has followed to expand human pancreas samples. This would require IIDP and/or JDRF/nPOD educating OPO personnel regarding pancreas isolation to ensure islet resources beyond those currently available via the IIDP.

B. Developing human islet supply-demand Requests for Applications (RFAs) from NIH and JDRF might encourage novel approaches to using, obtaining and conserving human islet cells.  For example, an RFA might challenge investigators to: 1) develop miniaturized assays using human islets, so that each assay would require fewer islets; 2) devise better standardization methods to rapidly and accurately define viability and functional quality of donor islets.  This solution has the potential to reduce the number of required replicates in human islet experiments.  Currently such tests are conducted by individual users, leading to a spectrum of non-standardized methods. If this were completed at the IIDP it would allow for uniform standardized testing results available to all recipients of the same islets. This testing is especially critical when isolating islets from patients with type 1 or type 2 diabetes, to reassure investigators that the donor islets are of good quality, and not compromised due to a poor isolation technique. In addition collection and distribution critical donor characteristics (e.g. HbA1C, age, gender, family history, history of therapy for diabetes or associated diseases that potentially impact glucose homeostasis and other relevant details) would allow investigators to more appropriately interpret the data generated in their experiments.

As noted above, most investigators accept and support the notion that increased human islet availability is critical to advancing human type one and type 2 diabetes research and patient care. We encourage NIH/NIDDK, JDRF, pharma and biotech industries to partner and support greater long-term access to human islets for research towards the ultimate goals of better prevention or reversal of, as well as a cure for, diabetes.

References:
1. Kulkarni RN, Bernal-Mizrachi E, Garcia-Ocana A, Stewart AF. Perspective: Human -cell proliferation and intracellular signaling: driving in the dark without a roadmap. Diabetes 61:2205-2213, 2012 PMID:22751699 PMCID: PMC3425429
2. Bernal-Mizrachi E, Kulkarni RN, Scott DK, Mauvais-Jarvis F, Stewart AF, Garcia-Ocana A. Perspective: Human -cell proliferation and intracellular signaling Part 2: Still Driving in the Dark without a Roadmap. Diabetes 63:819-831, 2014. PMID:24556859
3. Kaddis, JS, Olack BJ, Sowinski J, Cravens J, Contreras JL, Niland JC. Human Pancreatic Islets and Diabetes Research. JAMA 2009:301(15):1580-1587.
4. Human Islet Research Network: National Institutes of Health RFA – DK-13-018, September 26, 2013
5. Optimizing therapeutic strategies for human pancreatic beta cell regeneration. Juvenile Diabetes Research Foundation RFA, May 8, 2014. 
6. Targeting islet cell plasticity for regeneration of beta cell function in T1D.  Juvenile Diabetes Research Foundation RFA, May 8, 2014.
7. Qian D, Kaddis J, Niland J. A matching algorithm for the distribution of human pancreatic islets. Computational Statistics and Data Analysis 2007:51(12):5494-5506.
8. Diabetes researchers fear worsening access to human islets. Nature Medicine 20(6):567, 2014

Rohit N. Kulkarni, MD, PhD (Organizer, Islet Keystone Meeting 2014)
Senior Investigator, Islet Cell and Regenerative Biology, Joslin Diabetes Center;
Associate Professor of Medicine, Harvard Medical School, Boston MA 02215.
Phone: (617)-309-3460; Rohit.Kulkarni@joslin.harvard.edu
 
Andrew F. Stewart, MD
Irene and Dr. Arthur M. Fishberg Professor of Medicine
Director, Diabetes, Obesity and Metabolism Institute
Atran 5, Mount Sinai School of Medicine
One Gustave L. Levy Place, Box 1152, New York, NY 10029
Phone:  (212)-241-7680; andrew.stewart@mssm.edu
http://icahn.mssm.edu/research/institutes/diabetes-obesity-and-metabolism-institute

SIGNATORIES include Co-organizers of the 2014 Islet Keystone Meeting and Senior Researchers in Diabetes and Metabolism (listed alphabetically). All signatories have approved/edited the White Paper.

Ernesto Bernal-Mizrachi, MD.
Larry D. Soderquist Professor
Associate Professor of Medicine
Division of Metabolism, Endocrinology, & Diabetes, University of Michigan.
Brehm Tower Room 5122, 1000 Wall Street
Ann Arbor, MI 48105
Phone: (734) 615-0262; ebernal@umich.edu

Anil Bhushan, PhD
Department of Medicine, Division of Endocrinology, Diabetes & Hypertension
Hillblom Islet Research Center
900A Weyburn Place North
Los Angeles, CA 90095-7345
Phone: (310)-206-5368; ABhushan@mednet.ucla.edu

Susan Bonner-Weir, PhD
Professor of Medicine, Harvard Medical School
Senior Investigator, Joslin Diabetes Center
One Joslin Place, Boston, MA 02215
Phone:617-309-2581; susan.bonner-weir@joslin.harvard.edu

Maureen Gannon, PhD
Vice Chair for Faculty Development and
Associate Professor of Medicine, Molecular Physiology and Biophysics, and
Cell and Developmental Biology
DRTC, Director of Enrichment, Training and Outreach
Vanderbilt University, Division of Diabetes, Endocrinology, and Metabolism
2213 Garland Avenue, MRBIV 7465,Nashville, TN 37232-0475
Phone: (615)-936-2676; maureen.gannon@Vanderbilt.Edu

Adolfo Garcia-Ocana, PhD
Professor of Medicine, Icahn School of Medicine at Mount Sinai
Diabetes, Obesity and Metabolism Institute
Division of Endocrinology, Diabetes and Bone Diseases
One Gustave L. Levy Place  - Box 1152, New York, NY 10029          
adolfo.g.ocana@mssm.edu

Dale L. Greiner, PhD
Professor and Co-Director, Diabetes Center of Excellence
Dr. Eileen L. Berman and Stanley I. Berman
Foundation Chair in Biomedical Research Professor
Program in Molecular Medicine, University of Massachusetts Medical School
368 Plantation Street, AS7-2051, Worcester, MA 01605
Phone: (508)-856-1911; Dale.Greiner@umassmed.edu

George G. Holz, PhD
Professor of Medicine and Pharmacology
SUNY Upstate Medical University
IHP 4310 at 505 Irving Avenue
Syracuse, NY 13210
Phone: (315)-464-9841; holzg@upstate.edu


Mehboob Hussain, MD
Associate Professor, Departments of Medicine, Pediatrics, Biological Chemistry
Diabetes Institute, Johns Hopkins University
600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21218
Phone: (410)-502-5761; mhussai4@jhmi.edu

Klaus H. Kaestner, PhD
Associate Director, Penn Diabetes Research Center
Thomas and Evelyn Suor Butterworth Professor in Genetics
University of Pennsylvania School of Medicine
12-126 Translational Research Center
3400 Civic Center Boulevard, Philadelphia, PA 19104
Phone: (215)-898-8759; kaestner@mail.med.upenn.edu

C. Ronald Kahn, MD
Mary K. Iacocca Professor of Medicine, Harvard Medical School
Chief Academic Officer, Joslin Diabetes Center
One Joslin Place, Boston, MA 02215
Phone: (617)-309-2635; c.ronald.kahn@joslin.harvard.edu

Yogish C. Kudva, MD
Professor, Endocrinology and Metabolism and Pancreas Transplantation
Mayo Clinic College of Medicine
Rochester, MN 55902
Phone: (507)-284-3964; kudva.yogish@mayo.edu

Eckhard Lammert, PhD (Co-organizer, Islet Keystone Meeting 2014)
Professor and Head, Institute of Metabolic Physiology
Heinrich-Heine-University of Duesseldorf
Universitätsstr. 1, D-40225 Duesseldorf, Germany,
Phone: +49-211-81-14990; lammert@uni-duesseldorf.de

Franck Mauvais-Jarvis, MD, PhD
Price-Goldsmith Professor in Nutrition Research
Professor of Medicine, Division of Endocrinology and Metabolism
Director, Tulane Diabetes Research Program
Tulane University Health Sciences Center
1430 Tulane Avenue. SL53, New Orleans, LA 70112
Phone:  (504)-988-5990; fmauvais@tulane.edu

Douglas A. Melton, PhD
Xander University Professor, Harvard University
Thomas Dudley Cabot Professor in the Natural Sciences
Howard Hughes Medical Institute Investigator
SF 358B, Sherman Fairchild, 7 Divinity Ave, Cambridge, MA  02138
Phone: (617)-495-1812; dmelton@harvard.edu

Raghu G. Mirmira, MD, PhD (Co-organizer, Islet Keystone Meeting 2014)
Lilly Professor of Pediatric Diabetes
Professor of Pediatrics, Medicine, Physiology, and Biochemistry
Director, Indiana Diabetes Research Center
Indiana University School of Medicine
635 Barnhill Drive, Room 2031B, Indianapolis, IN 46202
Phone: (317)-274-4145; rmirmira@iu.edu


Christopher B. Newgard, PhD
Director, Sarah W. Stedman Nutrition and Metabolism Center Director, Duke Molecular Physiology Institute.
W. David and Sarah W. Stedman Distinguished Professor,
Duke University Medical Center Durham, NC 27704.
Phone:  (919)-668-6059; chris.newgard@duke.edu

Joyce C. Niland, PhD
Chief Research Information Officer
Chair, Department of Information Sciences
Edward & Estelle Alexander Chaired Professor, Beckman Research Institute
Associate Director for Information Sciences, City of Hope Comprehensive Cancer Center
1500 East Duarte Road, Duarte, CA  910010.
Phone:  (626)-256-4673 ext 63032; jniland@coh.org

Al Powers, MD
Director, Division of Diabetes, Endocrinology and Metabolism
Joe C. Davis Chair in Biomedical Science
Professor of Medicine, and Molecular Physiology and Biophysics
Vanderbilt University, Division of Diabetes, Endocrinology, and Metabolism
2213 Garland Avenue, MRBIV 7465,Nashville, TN 37232-0475
Phone: (615)-936-7678; Al.Powers@Vanderbilt.edu

Aldo A. Rossini, MD
Professor Emeritus, Univ. of Massachusetts Medical School
Visiting Professor, Joslin Diabetes Center
One Joslin Place, Boston MA 02215
Aldo.Rossini@joslin.harvard.edu

Janice Sowinski, MS
Integrarted islet Distribution Program Project Manager
City of Hope, 1500 E. Duarte Rd.Duarte, CA 91010
Phone: (626)-256-4673 x61260; jsowinski@coh.org

Donald K. Scott, PhD
Professor, Icahn School of Medicine at Mount Sinai
Obesity, Diabetes and Metabolism Institute
One Gustave L Levy Place, Box 1152, New York, NY 10029;
Phone: (212)-241-2835; donald.scott@mssm.edu

Doris A. Stoffers, MD, PhD
Professor, Institute for Diabetes, Obesity and Metabolism
Department of Medicine/Endocrinology Diabetes and Metabolism
University of Pennsylvania School of Medicine
Smilow Center for Translational Research SCTR 12-124
3400 Civic Center Blvd, Philadelphia, PA 19104
stoffers@mail.med.upenn.edu

Fumihiko Urano, MD, PhD
Samuel E. Schechter Professor of Medicine
Director, Wolfram Syndrome International Registry
Director, Morphology and Metabolism Core of the Diabetes Research Center
Division of Endocrinology, Metabolism and Lipid Research, and Department of Pathology
Washington University School of Medicine
660 South Euclid, Campus Box 8127, St. Louis, MO 63110; http://wolframsyndrome.dom.wustl.edu/
Phone: (314)-362-8683; urano@dom.wustl.edu;

Rupangi Vasavada, PhD
Associate Professor of Medicine
Icahn School of Medicine at Mount Sinai
Atran 5-02; Box 1152, 1428 Madison Avenue, New York, NY 10029
Phone: (212)-241-2839; rupangi.vasavada@mssm.edu

Bridget K. Wagner, PhD
Director of Pancreatic Cell Biology and Metabolic Disease
Center for the Science of Therapeutics
Broad Institute, 7 Cambridge Center 3027, Cambridge, MA 02142
Phone: (617)-714-7363; bwagner@broadinstitute.org

Gordon C. Weir, MD
Diabetes Research and Wellness Chair, Joslin Diabetes Center
Professor of Medicine, Harvard Medical School
Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center
One Joslin Place, Boston, MA, 02215
Phone:  (617)-309-2581; gordon.weir@joslin.harvard.edu

Page last updated: May 25, 2016