title: A common variant upstream of the PAX6 gene influences islet function in man.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, CRC at Skåne University Hospital, 205 02 Malmö, Sweden. Emma.Ahlqvist@med.lu.se
authors.forename: E
authors.initials: E
authors.lastname: Ahlqvist
authors.forename: F
authors.initials: F
authors.lastname: Turrini
authors.forename: S T
authors.initials: ST
authors.lastname: Lang
authors.forename: J
authors.initials: J
authors.lastname: Taneera
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: P
authors.initials: P
authors.lastname: Almgren
authors.forename: O
authors.initials: O
authors.lastname: Hansson
authors.forename: B
authors.initials: B
authors.lastname: Isomaa
authors.forename: T
authors.initials: T
authors.lastname: Tuomi
authors.forename: K
authors.initials: K
authors.lastname: Eriksson
authors.forename: J G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: V
authors.initials: V
authors.lastname: Lyssenko
authors.forename: L
authors.initials: L
authors.lastname: Groop
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D015536:Down-Regulation; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005387:Finland; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D045664:Proprotein Convertase 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D046509:Tissue Culture Techniques; D055815:Young Adult
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D012097:Repressor Proteins; D045664:Proprotein Convertase 1