Research-Focused Isolation of Human Islets From Donors With and Without Diabetes at the Alberta Diabetes Institute IsletCore.

Recent years have seen an increased focus on human islet biology, and exciting findings in the stem cell and genomic arenas highlight the need to define the key features of mature human islets and β-cells. Donor and organ procurement parameters impact human islet yield, although for research purposes islet yield may be secondary in importance to islet function. We examined the feasibility of a research-only human islet isolation, distribution, and biobanking program and whether key criteria such as cold ischemia time (CIT) and metabolic status may be relaxed and still allow successful research-focused isolations, including from donors with type 1 diabetes and type 2 diabetes. Through 142 isolations over approximately 5 years, we confirm that CIT and glycated hemoglobin each have a weak negative impacts on isolation purity and yield, and extending CIT beyond the typical clinical isolation cutoff of 12 hours (to ≥ 18 h) had only a modest impact on islet function. Age and glycated hemoglobin/type 2 diabetes status negatively impacted secretory function; however, these and other biological (sex, body mass index) and procurement/isolation variables (CIT, time in culture) appear to make only a small contribution to the heterogeneity of human islet function. This work demonstrates the feasibility of extending acceptable CIT for research-focused human islet isolation and highlights the biological variation in function of human islets from donors with and without diabetes.

[1]  P. Neufer,et al.  Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells. , 2015, The Journal of clinical investigation.

[2]  M. Atkinson,et al.  Current Concepts on the Pathogenesis of Type 1 Diabetes—Considerations for Attempts to Prevent and Reverse the Disease , 2015, Diabetes Care.

[3]  M. McCarthy,et al.  Human islet function following 20 years of cryogenic biobanking , 2015, Diabetologia.

[4]  W. Bush,et al.  Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. , 2015, American journal of physiology. Endocrinology and metabolism.

[5]  Emma Ahlqvist,et al.  Identification of novel genes for glucose metabolism based upon expression pattern in human islets and effect on insulin secretion and glycemia. , 2015, Human molecular genetics.

[6]  T. Kieffer,et al.  Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs , 2015, Stem cell reports.

[7]  T. Liang,et al.  Syntaxin-4 mediates exocytosis of pre-docked and newcomer insulin granules underlying biphasic glucose-stimulated insulin secretion in human pancreatic beta cells , 2015, Diabetologia.

[8]  F. Pattou,et al.  Human islet distribution programme for basic research: activity over the last 5 years , 2015, Diabetologia.

[9]  T. Liang,et al.  Munc18c mediates exocytosis of pre-docked and newcomer insulin granules underlying biphasic glucose stimulated insulin secretion in human pancreatic beta-cells , 2015, Molecular metabolism.

[10]  Peng Wang,et al.  Induction of human pancreatic beta cell replication by inhibitors of dual specificity tyrosine regulated kinase , 2015, Nature Medicine.

[11]  M. Grabherr,et al.  Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro , 2015, Diabetes.

[12]  C. Nian,et al.  SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models , 2015, Diabetologia.

[13]  D. Melton,et al.  Generation of Functional Human Pancreatic β Cells In Vitro , 2014, Cell.

[14]  James D. Johnson,et al.  Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells , 2014, Nature Biotechnology.

[15]  L. Groop,et al.  Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism , 2014, Proceedings of the National Academy of Sciences.

[16]  P. J. Marang-van de Mheen,et al.  Effects of Donor-, Pancreas-, and Isolation-Related Variables on Human Islet Isolation Outcome: A Systematic Review , 2014, Cell transplantation.

[17]  I. G. Fantus,et al.  The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. , 2014, Cell metabolism.

[18]  S. Kahn,et al.  Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future , 2014, The Lancet.

[19]  P. Berggren,et al.  Control of Insulin Secretion by Cholinergic Signaling in the Human Pancreatic Islet , 2014, Diabetes.

[20]  U. Boggi,et al.  Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin–proteasome system in pancreatic beta cell dysfunction , 2013, Molecular and Cellular Endocrinology.

[21]  X. Dai,et al.  Functional plasticity of the human infant β-cell exocytotic phenotype. , 2013, Endocrinology.

[22]  A. Wagers,et al.  Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states. , 2013, Cell reports.

[23]  C. Ladenvall,et al.  Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes , 2012, Molecular and Cellular Endocrinology.

[24]  A. M. Shapiro,et al.  Human islet distribution program for basic research at a single center. , 2011, Transplantation proceedings.

[25]  Camillo Ricordi,et al.  Innervation patterns of autonomic axons in the human endocrine pancreas. , 2011, Cell metabolism.

[26]  J. Shapiro,et al.  Surgical aspects of human islet isolation , 2010, Islets.

[27]  D. Scharp,et al.  Islet isolation from human pancreas with extended cold ischemia time. , 2010, Transplantation proceedings.

[28]  J. Niland,et al.  Multicenter Analysis of Novel and Established Variables Associated with Successful Human Islet Isolation Outcomes , 2010, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[29]  R. Planas,et al.  Gene expression profiles for the human pancreas and purified islets in Type 1 diabetes: new findings at clinical onset and in long‐standing diabetes , 2010, Clinical and experimental immunology.

[30]  Joyce C Niland,et al.  Human pancreatic islets and diabetes research. , 2009, JAMA.

[31]  Patrik Rorsman,et al.  Voltage-Gated Ion Channels in Human Pancreatic β-Cells: Electrophysiological Characterization and Role in Insulin Secretion , 2008, Diabetes.

[32]  F Mosca,et al.  Insulin secretion defects of human type 2 diabetic islets are corrected in vitro by a new reactive oxygen species scavenger. , 2007, Diabetes & metabolism.

[33]  C. Ricordi,et al.  The unique cytoarchitecture of human pancreatic islets has implications for islet cell function , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Frank J. Gonzalez,et al.  Loss of ARNT/HIF1β Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes , 2005, Cell.

[35]  U. Boggi,et al.  Functional and molecular defects of pancreatic islets in human type 2 diabetes. , 2005, Diabetes.

[36]  U. Boggi,et al.  Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. , 2004, The Journal of clinical endocrinology and metabolism.

[37]  U. Boggi,et al.  Improved insulin secretory function and reduced chemotactic properties after tissue culture of islets from type 1 diabetic patients , 2004, Diabetes/Metabolism Research Reviews.

[38]  B. Wolf,et al.  Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. , 2004, Diabetes.

[39]  R. Gomis,et al.  Pulsatile insulin release from islets isolated from three subjects with type 2 diabetes. , 2002, Diabetes.

[40]  D. Porte,et al.  beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. , 2001, Diabetes.

[41]  P. Marchetti,et al.  Function of pancreatic islets isolated from a type 1 diabetic patient. , 2000, Diabetes care.

[42]  P. Rorsman,et al.  Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus , 2010, Diabetologia.

[43]  T. Kin.  Islet isolation for clinical transplantation. , 2010, Advances in experimental medicine and biology.

[44]  U. Boggi,et al.  The beta-cell in human type 2 diabetes. , 2010, Advances in experimental medicine and biology.