Identification of a functional protein kinase Cbeta promoter polymorphism in humans related to insulin resistance.
Protein kinase Cbeta (PKCbeta) is known to inhibit insulin production in beta-cells and to support insulin action in skeletal muscle. We therefore searched for functional polymorphisms among already known genetic variants in the PKCbeta promoter and investigated their relation to glucose metabolism in humans. We found that the gene variant in the PKCbeta promoter at position -546 significantly reduced promoter activity in functional assays (P<0.05). Human subjects carrying this variant had a 3.5-fold decrease in PKCbeta2-protein expression in their thrombocytes (P=0.006). Additionally, we tested whether this variant affects parameters of glucose metabolism using 1012 humans included into the MeSyBePo study (Metabolic Syndrome Berlin Potsdam). The -546 variant was highly significant associated with increased homeostasis model assessment for insulin resistance (HOMA-IR, P=0.009) in the cohort. This association was accompanied by significantly increased fasting insulin concentrations in carriers of the homozygous polymorphism (P=0.021). Our results suggest that the -546 polymorphism in the PKCbeta promoter reduces promoter activity, which leads to a decreased expression of PKCbeta2 and subsequently is associated with decreased peripheral insulin-dependent glucose uptake.
Osterhoff
Martin A
MA
German Institute of Human Nutrition, Potsdam-Rehbruecke (DIfE), Department of Clinical Nutrition (KLE), Arthur-Scheunert-Allee 155, D-14558 Nuthetal, Germany. martino@dife.de
Heuer
Susanne
S
Pfeiffer
Michaela
M
Tasic
Jelena
J
Kaiser
Simone
S
Isken
Frank
F
Spranger
Joachim
J
Weickert
Martin O
MO
Möhlig
Matthias
M
Pfeiffer
Andreas F H
AF
D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002460:Cell Line; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D064546:Protein Kinase C beta; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; D011994:Recombinant Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta