The role of Nkx6.1 in maintenance of pancreatic beta cell identity and function

The insulin producing beta cells of the pancreas are essential for maintaining blood glucose levels. With either the destruction or dysfunction of beta cells leading to the onset of diabetes mellitus, it is necessary to understand the factors that maintain beta cells and their function. Nkx6.1 is a homeodomain transcription factor that is required for beta cell development. It is expressed in pancreatic progenitors and once pancreatic development is complete, Nkx6.1 expression becomes restricted to insulin producing beta cells. Although the functional importance of Nkx6.1 during the earliest steps of pancreatic development is known, it is less clear how Nkx6.1 regulates beta cell development and whether Nkx6.1 is required to maintain adult beta cells. Therefore, we developed mice with a conditional Nkx6.1 loss of function allele to examine the spatial and temporal requirements for Nkx6.1.By conditionally ablating Nkx6.1 in pancreatic endocrine progenitors of mice, we found that Nkx6.1 promotes beta cell development at the expense of non-beta endocrine cell subtypes. Nkx6.1 achieves this through direct repression of genetic lineage determinants of non-beta endocrine cells. Once specified, Nkx6.1 continues to be required in beta cells to repress delta cell gene programs. Therefore, Nkx6.1 promotes and maintains beta cell identity through repression of alternative endocrine lineages.In addition to regulating beta cell identity, we determined that Nkx6.1 is also a master regulator of mature beta cell function. By directly regulating genes required for central beta cell functions, Nkx6.1 maintains insulin biosynthesis and glucose import and metabolism. Consequently, deletion of Nkx6.1 in beta cells of adult mice causes the rapid onset of diabetes. By maintaining glucose import, Nkx6.1 also indirectly influences glucose stimulated beta cell proliferation. This role for Nkx6.1 is essential, as loss of Nkx6.1 in neonatal beta cells results in decreased beta cell mass expansion. Finally, we show that Nkx6.1 maintains identity of adult beta cells, as Nkx6.1-deficient beta cells adopt delta cell characteristics over time.Overall, our studies uncover the functional importance of a beta cell specific transcription factor, Nkx6.1, as a central regulator of pancreatic beta cell identity and cellular function