Identification of a functional protein kinase Cβ promoter polymorphism in humans related to insulin resistance

Protein kinase Cβ (PKCβ) is known to inhibit insulin production in β-cells and to support insulin action in skeletal muscle. We therefore searched for functional polymorphisms among already known genetic variants in the PKCβ promoter and investigated their relation to glucose metabolism in humans. We found that the gene variant in the PKCβ 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 PKCβ2-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 PKCβ promoter reduces promoter activity, which leads to a decreased expression of PKCβ2 and subsequently is associated with decreased peripheral insulin-dependent glucose uptake.