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Diabetologia
Published in: Diabetologia 1/2012

01-01-2012 | Article

A common variant upstream of the PAX6 gene influences islet function in man

Authors: E. Ahlqvist, F. Turrini, S. T. Lang, J. Taneera, Y. Zhou, P. Almgren, O. Hansson, B. Isomaa, T. Tuomi, K. Eriksson, J. G. Eriksson, V. Lyssenko, L. Groop

Published in: Diabetologia | Issue 1/2012

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Abstract

Aims/hypothesis

Impaired glucose tolerance and impaired insulin secretion have been reported in families with PAX6 mutations and it is suggested that they result from defective proinsulin processing due to lack of prohormone convertase 1/3, encoded by PCSK1. We investigated whether a common PAX6 variant would mimic these findings and explored in detail its effect on islet function in man.

Methods

A PAX6 candidate single nucleotide polymorphism (rs685428) was associated with fasting insulin levels in the Diabetes Genetics Initiative genome-wide association study. We explored its potential association with glucose tolerance and insulin processing and secretion in three Scandinavian cohorts (N = 8,897 individuals). In addition, insulin secretion and the expression of PAX6 and transcriptional target genes were studied in human pancreatic islets.

Results

rs685428 G allele carriers had lower islet mRNA expression of PAX6 (p = 0.01) and PCSK1 (p = 0.001) than AA homozygotes. The G allele was associated with increased fasting insulin (p replication = 0.02, p all = 0.0008) and HOMA-insulin resistance (p replication = 0.02, p all = 0.001) as well as a lower fasting proinsulin/insulin ratio (p all = 0.008) and lower fasting glucagon (p = 0.04) and gastric inhibitory peptide (GIP) (p = 0.05) concentrations. Arginine-stimulated (p = 0.02) insulin secretion was reduced in vivo, which was further reflected by a reduction of glucose- and potassium-stimulated insulin secretion (p = 0.002 and p = 0.04, respectively) in human islets in vitro.

Conclusions/interpretation

A common variant in PAX6 is associated with reduced PAX6 and PCSK1 expression in human islets and reduced insulin response, as well as decreased glucagon and GIP concentrations and decreased insulin sensitivity. These findings emphasise the central role of PAX6 in the regulation of islet function and glucose metabolism in man.
Appendix
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Metadata
Title
A common variant upstream of the PAX6 gene influences islet function in man
Authors
E. Ahlqvist
F. Turrini
S. T. Lang
J. Taneera
Y. Zhou
P. Almgren
O. Hansson
B. Isomaa
T. Tuomi
K. Eriksson
J. G. Eriksson
V. Lyssenko
L. Groop
Publication date
01-01-2012
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 1/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2300-8

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