Beta cell failure is a central feature of type 2 diabetes (T2D), but the molecular underpinnings of the process remain only partly understood. It has been suggested that beta cell failure in T2D involves massive cell death. Other studies ascribe beta cell failure to cell exhaustion, due to chronic oxidative or endoplasmic reticulum stress leading to cellular dysfunction. More recently it was proposed that beta cells in T2D may lose their differentiated identity, possibly even gaining features of other islet cell types. The loss of beta cell identity appears to be driven by glucotoxicity inhibiting the activity of key beta cell transcription factors including Pdx1, Nkx6.1, MafA and Pax6, thereby silencing beta cell genes and derepressing alternative islet cell genes. The loss of beta cell identity is at least partly reversible upon normalization of glycemia, with implications for the reversibility of T2D, although it is not known if beta cell failure reaches eventually a point of no return. In this review we discuss current evidence for metabolism-driven compromised beta cell identity, key knowledge gaps and opportunities for utility in the treatment of T2D.
Bibliographical noteFunding Information:
Supported by grants from the Juvenile Diabetes Research Foundation, the Human Islet Research Network of the NIH (DK104216), The Helmsley Charitable Trust, the European Union (project ELASTISLET), BIRAX, the DON foundation, the Israel Science Foundation and I-CORE Program of The Israel Science Foundation (ISF) #41.11. Research in our group was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners/. Supported in part by a grant from USAID's American Schools and Hospitals Abroad Program for upgrading of the Hebrew University Medical School interdepartmental equipment unit. AS has received fellowships from the Adams foundation and the Ariane de Rothschild Women Doctoral Program.
© 2017 Swisa, Glaser and Dor.
- Beta cell failure
- Oxidative stress
- Type 2 diabetes mellitus