title: A novel functional polymorphism (-336A/G) in the promoter of the partitioning-defective protein-6alpha gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids.
abstract: OBJECTIVE
  Partitioning-defective protein-6alpha (Par6alpha) has recently been demonstrated to negatively regulate insulin signalling in murine myoblasts. To address whether Par6alpha plays a role in human physiology, the present study investigated whether mutations exist in the Par6alpha gene and whether these mutations, if present, are associated with pre-diabetic phenotypes in non-diabetic subjects.
  
  
  METHODS
  The complete gene (part of the promoter [2.1 kb], all exons/introns and the 3' untranslated region) encoding Par6alpha was analysed in 664 non-diabetic subjects. We investigated possible associations between single nucleotide polymorphisms and percentage of body fat, glucose tolerance (as determined by OGTT), serum NEFA concentrations and whole-body insulin sensitivity (estimated during the OGTT, and for a subgroup of 242 subjects determined by the euglycaemic-hyperinsulinaemic clamp).
  
  
  RESULTS
  A rare A/G polymorphism was found 336-bp upstream of the translational start codon (allele frequency 0.03). The data for subjects homozygous and heterozygous for -336G (R/G, n=43) were combined and compared with those for subjects homozygous for -336A (A/A, n=621). Subjects with the R/G genotype had lower fasting (4.84+/-0.09 mmol/l, means+/-SEM, p=0.049) and 2-h (5.50+/-0.02 mmol/l, p=0.050) plasma glucose concentrations than subjects with the A/A genotype (5.02+/-0.02 and 5.94+/-0.06 mmol/l, respectively). Subjects with the R/G genotype also had lower fasting (448+/-31 micromol/l, p=0.018) and 2-h serum NEFA concentrations (61+/-7 micromol/l, p=0.015) than subjects with the A/A genotype (529+/-9 and 75+/-2 micromol/l, respectively), adjusted for age, sex and percentage of body fat. There were no differences in adiposity or whole-body insulin sensitivity between the two genotype groups (all p>0.36). A luciferase reporter gene assay revealed that the -336G promoter variant had a significantly lower (-22.8%, p=0.006) transcriptional activity in transfected C2C12 murine myoblasts than the -336A promoter variant.
  
  
  CONCLUSIONS
  A novel functional variant in the promoter of the Par6alpha gene is associated with reduced fasting glycaemia, increased glucose tolerance and reduced serum NEFA concentrations.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Metabolism and Pathobiochemistry, University of Tübingen, Otfried-Müller-Str.10, 72076 Tübingen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Weyrich
authors.forename: R
authors.initials: R
authors.lastname: Lammers
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
authors.forename: F
authors.initials: F
authors.lastname: Machicao
authors.forename: H-U
authors.initials: HU
authors.lastname: Häring
authors.forename: N
authors.initials: N
authors.lastname: Stefan
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000235:genetics; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D047495:PPAR gamma; D011506:Proteins
references.citation: Nucleic Acids Res. 2002 Jun 15;30(12):e53
references.pmid: 12060691
references.citation: J Biol Chem. 2004 Jun 11;279(24):25157-63
references.pmid: 15069075
references.citation: Endocr Rev. 1998 Aug;19(4):491-503
references.pmid: 9715377
references.citation: Diabetes Care. 1999 Sep;22(9):1462-70
references.pmid: 10480510
references.citation: Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E1-11
references.pmid: 12067836
references.citation: J Biol Chem. 1990 May 15;265(14):8285-96
references.pmid: 2186040
references.citation: Trends Endocrinol Metab. 2002 Dec;13(10):444-51
references.pmid: 12431841
references.citation: Diabetes. 2001 Jun;50(6):1449-54
references.pmid: 11375347
references.citation: Genes Cells. 2001 Feb;6(2):107-19
references.pmid: 11260256
references.citation: Mol Endocrinol. 2004 May;18(5):1287-300
references.pmid: 14976222
references.citation: Curr Opin Cell Biol. 2003 Feb;15(1):67-72
references.pmid: 12517706
references.citation: FEBS Lett. 2001 Mar 16;492(3):199-203
references.pmid: 11257494
references.citation: EMBO Rep. 2000 Nov;1(5):399-403
references.pmid: 11258478
references.citation: J Cell Biol. 2004 Jan 19;164(2):279-90
references.pmid: 14734537
references.citation: J Mol Biol. 1997 Apr 25;268(1):78-94
references.pmid: 9149143
references.citation: N Engl J Med. 1992 Jan 2;326(1):22-9
references.pmid: 1727062
references.citation: J Biol Chem. 2001 Feb 2;276(5):3543-9
references.pmid: 11063744
references.citation: Diabetes. 2001 Apr;50(4):876-81
references.pmid: 11289055
references.citation: Nat Cell Biol. 2000 Aug;2(8):531-9
references.pmid: 10934474
references.citation: Curr Biol. 2000 Jun 15;10(12):697-707
references.pmid: 10873802
references.citation: Diabetes Care. 2003 Jul;26(7):2126-32
references.pmid: 12832324
references.citation: Nat Cell Biol. 2002 Feb;4(2):E39-44
references.pmid: 11835058
references.citation: Nucleic Acids Res. 2003 Jan 1;31(1):374-8
references.pmid: 12520026
references.citation: J Biol Chem. 2001 Apr 27;276(17):14459-65
references.pmid: 11278339
references.citation: Mol Cell Biol. 2003 Nov;23(21):7794-808
references.pmid: 14560023
references.citation: World Health Organ Tech Rep Ser. 1980;646:1-80
references.pmid: 6771926