Loss of β-Cell Identity Occurs in Type 2 Diabetes and Is Associated With Islet Amyloid Deposits

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 8; pp. 2928 - 2938
• Main Authors: Spijker, H. Siebe, Song, Heein, Ellenbroek, Johanne H., Roefs, Maaike M., Engelse, Marten A., Bos, Erik, Koster, Abraham J., Rabelink, Ton J., Hansen, Barbara C., Clark, Anne, Carlotti, Françoise, de Koning, Eelco J.P.
• Format: Journal Article
• Language: English
• Published: United States 01.08.2015
• Subjects: Animals; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - physiopathology; Glucagon - metabolism; Glucagon-Secreting Cells - metabolism; Glucagon-Secreting Cells - pathology; Humans; Insulin - metabolism; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Islets of Langerhans - physiopathology; Macaca fascicularis; Macaca mulatta; Male; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Plaque, Amyloid - physiopathology
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db14-1752

Loss of pancreatic islet β-cell mass and β-cell dysfunction are central in the development of type 2 diabetes (T2DM). We recently showed that mature human insulin-containing β-cells can convert into glucagon-containing α-cells ex vivo. This loss of β-cell identity was characterized by the presence of β-cell transcription factors (Nkx6.1, Pdx1) in glucagon+ cells. Here, we investigated whether the loss of β-cell identity also occurs in vivo, and whether it is related to the presence of (pre)diabetes in humans and nonhuman primates. We observed an eight times increased frequency of insulin+ cells coexpressing glucagon in donors with diabetes. Up to 5% of the cells that were Nkx6.1+ but insulin− coexpressed glucagon, which represents a five times increased frequency compared with the control group. This increase in bihormonal and Nkx6.1+glucagon+insulin− cells was also found in islets of diabetic macaques. The higher proportion of bihormonal cells and Nkx6.1+glucagon+insulin− cells in macaques and humans with diabetes was correlated with the presence and extent of islet amyloidosis. These data indicate that the loss of β-cell identity occurs in T2DM and could contribute to the decrease of functional β-cell mass. Maintenance of β-cell identity is a potential novel strategy to preserve β-cell function in diabetes.