title: Human β-cell proliferation and intracellular signaling: part 3.
abstract: This is the third in a series of Perspectives on intracellular signaling pathways coupled to proliferation in pancreatic β-cells. We contrast the large knowledge base in rodent β-cells with the more limited human database. With the increasing incidence of type 1 diabetes and the recognition that type 2 diabetes is also due in part to a deficiency of functioning β-cells, there is great urgency to identify therapeutic approaches to expand human β-cell numbers. Therapeutic approaches might include stem cell differentiation, transdifferentiation, or expansion of cadaver islets or residual endogenous β-cells. In these Perspectives, we focus on β-cell proliferation. Past Perspectives reviewed fundamental cell cycle regulation and its upstream regulation by insulin/IGF signaling via phosphatidylinositol-3 kinase/mammalian target of rapamycin signaling, glucose, glycogen synthase kinase-3 and liver kinase B1, protein kinase Cζ, calcium-calcineurin-nuclear factor of activated T cells, epidermal growth factor/platelet-derived growth factor family members, Wnt/β-catenin, leptin, and estrogen and progesterone. Here, we emphasize Janus kinase/signal transducers and activators of transcription, Ras/Raf/extracellular signal-related kinase, cadherins and integrins, G-protein-coupled receptors, and transforming growth factor β signaling. We hope these three Perspectives will serve to introduce these pathways to new researchers and will encourage additional investigators to focus on understanding how to harness key intracellular signaling pathways for therapeutic human β-cell regeneration for diabetes.
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY andrew.stewart@mssm.edu rohit.kulkarni@joslin.harvard.edu.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Departments of Medicine and Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Mehboob A
authors.initials: MA
authors.lastname: Hussain
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Ocaña
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Rupangi C
authors.initials: RC
authors.lastname: Vasavada
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA.
authors.forename: Anil
authors.initials: A
authors.lastname: Bhushan
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, and VA Ann Arbor Healthcare System, Ann Arbor, MI.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.affiliation: Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA andrew.stewart@mssm.edu rohit.kulkarni@joslin.harvard.edu.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D003920:Diabetes Mellitus / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin