Elsevier

Molecular Metabolism

Volume 2, Issue 3, August 2013, Pages 243-255
Molecular Metabolism

Original article
Nor-1, a novel incretin-responsive regulator of insulin genes and insulin secretion

https://doi.org/10.1016/j.molmet.2013.06.003Get rights and content
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Abstract

B-cell failure at the onset of type 2 diabetes is caused by a decline in β-cell function in the postprandial state and loss of pancreatic β-cell mass. Recently, we showed an association between increased insulin secretion and a single nucleotide polymorphism (SNP), SNP rs12686676, in the NR4A3 gene locus encoding the nuclear receptor Nor-1. Nor-1 is expressed in β-cells, however, not much is known about its function with regard to insulin gene expression and insulin secretion. Nor-1 is induced in a glucose-/incretin-dependent manner via the PKA pathway and directly induces insulin gene expression. Additionally, it stimulates insulin secretion possibly via regulation of potentially important genes in insulin exocytosis. Moreover, we show that the minor allele of NR4A3 SNP rs12686676 fully rescues incretin resistance provoked by a well-described polymorphism in TCF7L2. Thus, Nor-1 represents a promising new target for pharmacological intervention to fight diabetes.

Keywords

Nor-1
Insulin gene expression
Insulin secretion
Incretin resistance
TCF7L2

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