Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes
Context: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...
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| Published in | The journal of clinical endocrinology and metabolism Vol. 101; no. 3; pp. 1044 - 1054 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Oxford University Press
01.03.2016
Copyright by The Endocrine Society Endocrine Society |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Context: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.Design: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. |
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| AbstractList | CONTEXT: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.
DESIGN: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. Context: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.Design: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. 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.CONTEXTDiabetes 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.To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors.OBJECTIVETo determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors.We scored dedifferentiation using markers of endocrine lineage, β-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3.DESIGNWe scored dedifferentiation using markers of endocrine lineage, β-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3.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.RESULTSBy 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.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.CONCLUSIONSThe 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. 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. To determine whether similar processes occur in human type 2 diabetes, we surveyed pancreatic islets from 15 diabetic and 15 nondiabetic organ donors. We scored dedifferentiation using markers of endocrine lineage, β-cell-specific transcription factors, and a newly identified endocrine progenitor cell marker, aldehyde dehydrogenase 1A3. 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. 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. |
| Author | Cinti, Francesca Suleiman, Mara Ratner, Lloyd E. Ohmura, Yoshiaki Marselli, Lorella Accili, Domenico Sandoval, P. R. Masini, Matilde Marchetti, Piero Kim-Muller, Ja Young Bouchi, Ryotaro |
| AuthorAffiliation | 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 |
| AuthorAffiliation_xml | – name: 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 |
| Author_xml | – sequence: 1 givenname: Francesca surname: Cinti fullname: Cinti, Francesca organization: 1Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) New York, New York 10032 – sequence: 2 givenname: Ryotaro surname: Bouchi fullname: Bouchi, Ryotaro organization: 1Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) New York, New York 10032 – sequence: 3 givenname: Ja Young surname: Kim-Muller fullname: Kim-Muller, Ja Young organization: 1Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) New York, New York 10032 – sequence: 4 givenname: Yoshiaki surname: Ohmura fullname: Ohmura, Yoshiaki organization: 2Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032 – sequence: 5 givenname: P. R. surname: Sandoval fullname: Sandoval, P. R. organization: 2Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032 – sequence: 6 givenname: Matilde surname: Masini fullname: Masini, Matilde organization: 4Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy – sequence: 7 givenname: Lorella surname: Marselli fullname: Marselli, Lorella organization: 4Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy – sequence: 8 givenname: Mara surname: Suleiman fullname: Suleiman, Mara organization: 4Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy – sequence: 9 givenname: Lloyd E. surname: Ratner fullname: Ratner, Lloyd E. organization: 2Surgery (Y.O., P.R.S., L.E.R.), Columbia University College of Physicians and Surgeons, New York, New York 10032 – sequence: 10 givenname: Piero surname: Marchetti fullname: Marchetti, Piero organization: 4Department of Clinical and Experimental Medicine (M.M., L.M., M.S., P.M.), Islet Cell Laboratory, University of Pisa, 56100 Pisa, Italy – sequence: 11 givenname: Domenico surname: Accili fullname: Accili, Domenico email: da230@columbia.edu organization: 1Departments of Medicine (F.C., R.B., J.Y.K.-M., D.A.) New York, New York 10032 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26713822$$D View this record in MEDLINE/PubMed |
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| Snippet | Context:Diabetes is associated with a deficit of insulin-producing β-cells. Animal studies show that β-cells become dedifferentiated in diabetes, reverting to... CONTEXT:Diabetes is associated with a deficit of insulin-producing β-cells. Animal studies show that β-cells become dedifferentiated in diabetes, reverting to... Diabetes is associated with a deficit of insulin-producing β-cells. Animal studies show that β-cells become dedifferentiated in diabetes, reverting to a... |
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| SubjectTerms | Aldehyde dehydrogenase Aldehydes Beta cells Cell Dedifferentiation Dehydrogenases Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - pathology Forkhead Box Protein O1 Forkhead Transcription Factors - analysis Glucagon Glucagon - metabolism Glucagon-Secreting Cells - physiology Homeodomain Proteins - analysis Humans Immunohistochemistry Insulin - metabolism Insulin Secretion Insulin-Secreting Cells - chemistry Insulin-Secreting Cells - pathology Insulin-Secreting Cells - physiology Microscopy, Electron Organ donors Original Pancreas Progenitor cells Somatostatin Somatostatin - metabolism Somatostatin-Secreting Cells - physiology Transcription factors |
| Title | Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes |
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