Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas

Huan Wang, Aaron Bender, Peng Wang, Esra Karakose, William B. Inabnet, Steven K. Libutti, Andrew Arnold, Luca Lambertini, Micheal Stang, Herbert Chen, Yumi Kasai, Milind Mahajan, Yayoi Kinoshita, Gustavo Fernandez-Ranvier, Thomas C. Becker, Karen K. Takane, Laura A. Walker, Shira Saul, Rong Chen, Donald K. Scott, Jorge Ferrer, Yevgeniy Antipin, Michael Donovan, Andrew V. Uzilov, Boris Reva, Eric E. Schadt, Bojan Losic, Carmen Argmann and Andrew F. Stewart ()
Additional contact information
Huan Wang: The Icahn School of Medicine at Mount Sinai
Aaron Bender: The Graduate School, The Icahn School of Medicine at Mount Sinai
Peng Wang: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai
Esra Karakose: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai
William B. Inabnet: The Icahn School of Medicine at Mount Sinai
Steven K. Libutti: The Cancer Institute of New Jersey, Rutgers University
Andrew Arnold: Center for Molecular Medicine, University of Connecticut School of Medicine
Luca Lambertini: Gynecology, and Reproductive Sciences, The Icahn School of Medicine at Mount Sinai
Micheal Stang: Duke University School of Medicine
Herbert Chen: University of Alabama at Birmingham
Yumi Kasai: The New York Genome Center
Milind Mahajan: The Icahn School of Medicine at Mount Sinai
Yayoi Kinoshita: The Icahn School of Medicine at Mount Sinai
Gustavo Fernandez-Ranvier: The Icahn School of Medicine at Mount Sinai
Thomas C. Becker: The Sarah W. Stedman Center for Nutrition and Metabolism, Duke University School of Medicine
Karen K. Takane: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai
Laura A. Walker: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai
Shira Saul: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai
Rong Chen: The Icahn School of Medicine at Mount Sinai
Donald K. Scott: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai
Jorge Ferrer: Imperial College
Yevgeniy Antipin: The Icahn School of Medicine at Mount Sinai
Michael Donovan: The Icahn School of Medicine at Mount Sinai
Andrew V. Uzilov: The Icahn School of Medicine at Mount Sinai
Boris Reva: The Icahn School of Medicine at Mount Sinai
Eric E. Schadt: The Icahn School of Medicine at Mount Sinai
Bojan Losic: The Icahn School of Medicine at Mount Sinai
Carmen Argmann: The Icahn School of Medicine at Mount Sinai
Andrew F. Stewart: The Diabetes Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the “genomic recipe” for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.

Date: 2017
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DOI: 10.1038/s41467-017-00992-9

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