Editors' ChoiceDiabetes

β Cells Lose Their Identity

Science Signaling  18 Sep 2012:
Vol. 5, Issue 242, pp. ec243
DOI: 10.1126/scisignal.2003615

Some patients with type 2 diabetes exhibit a decreased capacity to produce insulin from pancreatic β cells, which leads to an inability to properly regulate blood glucose concentrations. Although, in response to chronic stress, β cells can become exhausted and undergo apoptotic cell death, resulting in loss of β cell mass, whether this contributes to or is the only mechanism responsible for β cell dysfunction in type 2 diabetes is not clear. Talchai et al. investigated mice with β cells deficient in the transcription factor Foxo1 (IKO mice), which is required for increased β cell mass and the responses of β cells to stress. Under basal conditions, IKO mice exhibited normal β cell function and glucose tolerance; however, under various conditions of stress, IKO mice showed decreased insulin production, reduced glucose tolerance, and increased production of the hormone glucagon. Immunohistochemical analysis and lineage tracing experiments showed that β cells in stressed IKO mice had normal survival but became dedifferentiated, losing β cell markers, as well as transcription factors and enzymes required for insulin production. Analysis of the differentiation state of the Foxo1-deficient β cells showed the presence of markers of progenitor-like cells, including Oct4 and Neurogenin3. Further lineage-tracing experiments showed that the dedifferentiated β cells in IKO pancreatic islets gave rise to other cell types, including glucagon-producing α cells. Analysis of other mouse models of type 2 diabetes showed a similar loss of β cell identity and the increased abundance of markers of progenitor cells. As Puri and Hebrok discuss in commentary, although these findings have yet to be confirmed in humans, the data raise the possibility that therapeutic reversal of β cell dedifferentiation may be effective in preventing the development of type 2 diabetes.

C. Talchai, S. Xuan, H. V. Lin, L. Sussel, D. Accili, Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 150, 1223–1234 (2012). [Online Journal]

S. Puri, M. Hebrok, Diabetic β cells: To be or not to be? Cell 150, 1103–1104 (2012). [Online Journal]