title: Nor-1, a novel incretin-responsive regulator of insulin genes and insulin secretion.
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.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Germany ; Institute for Diabetes Research and Metabolic Diseases of the Helmholz Centre Munich at the University of Tübingen, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Ordelheide
authors.forename: Felicia
authors.initials: F
authors.lastname: Gerst
authors.forename: Oliver
authors.initials: O
authors.lastname: Rothfuss
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Carina
authors.initials: C
authors.lastname: Haas
authors.forename: Inga
authors.initials: I
authors.lastname: Thielker
authors.forename: Silke
authors.initials: S
authors.lastname: Herzberg-Schäfer
authors.forename: Anja
authors.initials: A
authors.lastname: Böhm
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
keywords: Incretin resistance; Insulin gene expression; Insulin secretion; Nor-1; TCF7L2
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