title: Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes.
abstract: BACKGROUND
  Diabetes is associated with a deficit of insulin-producing β-cells. Animal studies show that β-cells become dedifferentiated in diabetes, reverting to a progenitor-like stage, and partly converting to other endocrine cell types.
  
  
  OBJECTIVE
  To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors.
  
  
  METHODS
  We scored dedifferentiation using markers of endocrine lineage, β-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3.
  
  
  RESULTS
  By these criteria, dedifferentiated cells accounted for 31.9% of β-cells in type 2 diabetics vs 8.7% in controls, and for 16.8% vs 6.5% of all endocrine cells (P < .001). The number of aldehyde dehydrogenase 1A3-positive/hormone-negative cells was 3-fold higher in diabetics compared with controls. Moreover, β-cell-specific transcription factors were ectopically found in glucagon- and somatostatin-producing cells of diabetic subjects.
  
  
  CONCLUSIONS
  The data support the view that pancreatic β-cells become dedifferentiated and convert to α- and δ-"like" cells in human type 2 diabetes. The findings should prompt a reassessment of goals in the prevention and treatment of β-cell dysfunction.
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cinti
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Bouchi
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ohmura
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: P R
authors.initials: PR
authors.lastname: Sandoval
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Masini
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Suleiman
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Lloyd E
authors.initials: LE
authors.lastname: Ratner
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) and Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Clinical and Experimental Medicine (F.C.), Università Politecnica delle Marche, Ancona, Italy; and Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D054337:Cell Dedifferentiation; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000032:analysis; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000502:physiology; D018398:Homeodomain Proteins / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D008854:Microscopy, Electron; D013004:Somatostatin / Q000378:metabolism; D019864:Somatostatin-Secreting Cells / Q000502:physiology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D007328:Insulin; C105201:NKX6-1 protein, human; D013004:Somatostatin; D005934:Glucagon