Abstract
Type 2 diabetes is thought to involve a compromised β cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult β cell identity and function. PAX6 was downregulated in β cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in β cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of β cell function and expansion of α cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of β cell genes, thus maintaining mature β cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human β cells. We conclude that reduced expression of PAX6 in metabolically stressed β cells may contribute to β cell failure and α cell dysfunction in diabetes.
| Original language | English |
|---|---|
| Pages (from-to) | 230-243 |
| Number of pages | 14 |
| Journal | Journal of Clinical Investigation |
| Volume | 127 |
| Issue number | 1 |
| DOIs | |
| State | Published - 3 Jan 2017 |
Bibliographical note
Funding Information:This work was supported by grants from the Juvenile Diabetes Research Foundation (JDRF); the Beta Cell Biology Consortium and the Human Islet Research Network of the NIH (DK104216); the Helmsley Charitable Trust; the European Research Commission (ERC consolidator grant); the Britain Israel Research and Academic Exchange Partnership (BIRAX); the Diabetes Onderzoek Nederland (DON) Foundation; and the Israel Science Foundation and I-CORE Program of The Israel Science Foundation (ISF) (41.11, to YD). Research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by the JDRF. The Organ Procurement Organizations (OPOs) partnering with nPOD to provide research resources are listed on the nPOD/JDRF partners website (http://www.jdrfnpod.org/for-partners/npod-partners/). This work was supported in part by a grant from USAID's American Schools and Hospitals Abroad Program for the upgrading of the Hebrew University Medical School's Flow Cytometry Laboratory. RA-P was supported by the United States-Israel Binational Science Foundation (BSF; grant 2013016) and the ISF (grant 228/14). AS received fellowships from the Adams Foundation and the Ariane de Rothschild Women Doctoral Program
