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

Protein kinase CP (PKC beta) 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 PKC beta promoter and investigated their relation to glucose metabolism in humans. We found that the gene variant in the PKC13 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 PKC beta 2-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 polyrnorphism in the PKC beta promoter reduces promoter activity, which leads to a decreased expression of PKC beta 2 and subsequently is associated with decreased peripheral insulin-dependent glucose uptake. (C) 2007 Elsevier Inc. All rights reserved.