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.

Islet β-Cell-Specific MafA Transcription Requires the 5′-Flanking Conserved Region 3 Control Domain

“…This result was unexpected, since NeuroD1 bound R3 endogenously and the binding-site mutant profoundly reduced transfected R3-driven activity (Fig. 7), although MafA mRNA levels were also recently found to be unaffected after conditional removal of NeuroD1 from islet ␤ cells in vivo (17). Two interpretations of these results are (i) that NeuroD1 does not directly regulate MafA transcription and (ii) that a closely related bHLH family member acts in a compensatory manner.…”

Pancreas organogenesis: From bud to plexus to gland

“…A late-stage maturation role for NeuroD1 in b-cells was recently proposed by Gu et al (2010). When NeuroD1 was specifically inactivated in mature bcells, the NeuroD1 null islets responded poorly to glucose and displayed a glucose metabolism profile similar to immature b-cells, with the key features of increased expression of glycolytic genes and lactate dehydrogenase (LDHA), elevated basal insulin secretion and oxygen consumption, and neuropeptide Y (NPY) overexpression.…”

The New Generation of Beta-Cells: Replication, Stem Cell Differentiation, and the Role of Small Molecules

“…In humans, mutations in NeuroD expression can predispose individuals to maturity onset diabetes of the young (MODY6), suggesting a role of NeuroD in β-cell function. Mice lacking NeuroD expression in insulin-producing cells respond poorly to glucose, and show a metabolic profile similar to that of immature β-cells [23].…”