Pancreatic β Cells Require NeuroD to Achieve and Maintain Functional Maturity

Abstract

Summary NeuroD, an insulin transactivator, is critical for development of the endocrine pancreas, and NeuroD mutations cause MODY6 in humans. To investigate the role of NeuroD in differentiated β cells, we generated mice in which neuroD is deleted in insulin-expressing cells. These mice exhibit severe glucose intolerance. Islets lacking NeuroD respond poorly to glucose and display a glucose metabolic profile similar to immature β cells, featuring increased expression of glycolytic genes and LDH-A, elevated basal insulin secretion and O2 consumption, and overexpression of NPY. Moreover, the mutant islets appear to have defective KATP channel-mediated insulin secretion. Unexpectedly, virtually all insulin in the mutant mice is derived from ins2, whereas ins1 expression is almost extinguished. Overall, these results indicate that NeuroD is required for β cell maturation and demonstrate the importance of NeuroD in the acquisition and maintenance of fully functional glucose responsive β cells.