Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes

J Clin Endocrinol Metab. 2016 Mar;101(3):1044-54. doi: 10.1210/jc.2015-2860. Epub 2015 Dec 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Dedifferentiation*
  • Diabetes Mellitus, Type 2 / pathology*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / analysis
  • 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
  • Somatostatin / metabolism
  • Somatostatin-Secreting Cells / physiology


  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Insulin
  • NKX6-1 protein, human
  • Somatostatin
  • Glucagon