Postnatal beta-Cell Proliferation and Mass Expansion Is Dependent on the Transcription Factor Nkx6.1

作者：Taylor Brandon L; Benthuysen Jacqueline; Sander Maike^*

来源：Diabetes, 2015, 64(3): 897-903.

DOI：10.2337/db14-0684

All forms of diabetes are characterized by a loss of functional -cell mass, and strategies for expanding -cell mass could have significant therapeutic benefit. We have recently identified the transcription factor Nkx6.1 as an essential maintenance factor of the functional -cell state. In addition, Nkx6.1 has been proposed to control -cell proliferation, but a role for Nkx6.1 in regulating -cell mass has not been demonstrated. Here, we show that Nkx6.1 is required for postnatal -cell mass expansion. Genetic inactivation of Nkx6.1 in newly formed -cells caused a drastic decrease in early postnatal -cell proliferation, leading to reduced -cell mass and glucose intolerance. Interestingly, Nkx6.1 was dispensable for prenatal -cell proliferation. We found that Nkx6.1 regulates the expression of several -cell maturation markers as well as expression of the nutrient sensors Glut2 and Glp1r. Manifestation of the -cell mass defect at the transition to postnatal feeding suggests that Nkx6.1 could regulate -cell growth by enabling -cells to respond to nutrient-dependent proliferation signals, such as glucose and Glp1. Identification of -cell-intrinsic regulators that connect nutrient-sensing and proliferation suggests new therapeutic targets for expanding functional -cell mass.

• 出版日期2015-3