Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes

• Published in: The journal of clinical endocrinology and metabolism Vol. 101; no. 3; pp. 1044 - 1054
• Main Authors: Cinti, Francesca, Bouchi, Ryotaro, Kim-Muller, Ja Young, Ohmura, Yoshiaki, Sandoval, P. R., Masini, Matilde, Marselli, Lorella, Suleiman, Mara, Ratner, Lloyd E., Marchetti, Piero, Accili, Domenico
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2016; Copyright by The Endocrine Society; Endocrine Society
• Subjects: 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
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2015-2860

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.