title: Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor.
abstract: An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal-related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation.
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Stamateris
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Rohit B
authors.initials: RB
authors.lastname: Sharma
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Pantea
authors.initials: P
authors.lastname: Ebrahimpour
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Panday
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Pavana
authors.initials: P
authors.lastname: Ranganath
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Baobo
authors.initials: B
authors.lastname: Zou
authors.affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Helena
authors.initials: H
authors.lastname: Levitt
authors.affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Nisha Abraham
authors.initials: NA
authors.lastname: Parambil
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.affiliation: Diabetes, Obesity and Metabolism Institute, Division of Endocrinology, Diabetes and Bone Disease, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Ocaña
authors.affiliation: Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA laura.alonso@umassmed.edu.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Alonso
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D056742:Cyclin D2 / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D055504:Insulin Receptor Substrate Proteins; C546843:mTOR protein, mouse; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases; D005947:Glucose