Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes

作者：Francesca Cinti, Ryotaro Bouchi, Ja Young Kim-Muller, Yoshiaki Ohmura, Pedro Rodrigo Sandoval, Matilde Masini, Lorella Marselli, Mara Suleiman, Lloyd E. Ratner, Piero Marchetti, Domenico Accili · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2015 · DOI：10.1210/jc.2015-2860 · 被引用次数：558 · 研究领域：Pancreatic function and diabetes、Diabetes and associated disorders、Pancreatitis Pathology and Treatment

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.