Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes

Context: Diabetes is associated with a deficit of insulin-producing beta-cells. Animal studies show that beta-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, beta-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 beta-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, beta-cell-specific transcription factors were ectopically found in glucagon-and somatostatin-producing cells of diabetic subjects. Conclusions: The data support the view that pancreatic beta-cells become dedifferentiated and convert to alpha-and delta-"like" cells in human type 2 diabetes. The findings should prompt a reassessment of goals in the prevention and treatment of beta-cell dysfunction.