Dissecting the transcriptional network of pancreatic islets during development and differentiation

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Abstract
Maturity onset diabetes of the young (MODY) is a heterogenous, monogenic disease that is characterized by an autosomal dominant inheritance and an early disease onset, usually before 25 years of age (1). In contrast to late-onset forms of type 2 diabetes in which β-cell defects develop as a result of insulin resistance, MODY is caused by a primary defect in pancreatic β-cell function and impaired glucose-stimulated insulin secretion (2). Mutations in five genes are associated with different forms of MODY. The MODY2 gene encodes the glycolytic enzyme glucokinase that acts as the glucose sensor of the β cell and when inactivated, leads to impaired sensing of blood glucose levels (3). However, the majority of MODY forms are caused by mutations in transcription factors that are enriched in pancreatic β cells and include hepatocyte nuclear factors 1α (HNF-1α, MODY3), HNF-4α (MODY1), insulin promoter factor 1 (IPF-1/PDX-1, MODY4), and HNF-1β (MODY5) (see Table 1). These forms of diabetes share many pathophysiological features and are known to regulate the expression of genes such as the glucose transporter 2 (GLUT-2) and glycolytic genes that are essential for normal β-cell function (4–6). Studies performed in extrapancreatic tissues such as the liver, gut, and visceral endoderm have shown that HNFs form a hierarchical transcriptional network that regulates differentiation and metabolism in these cells (7–9). Two recent studies, including the paper by Boj et al. in this issue of PNAS (10), significantly advance our understanding of this regulatory circuit in pancreatic β cells. View this table: Table 1 Genetic classification of MODY subtypes The transcriptional cascade of HNFs was first elucidated in hepatocytes where it was shown that HNF-4α, a member of the steroid hormone receptor superfamily, was an essential positive regulator of HNF-1α (11, 12). This was one of the first transcriptional hierarchies that was characterized in …

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