Fig. 6

A model for a combined effect of functional haplotypes in GCKR on glucose metabolism in fasting. The model assumes higher GCKR expression for the CGG haplotype (rs780094-rs780095-rs780096), which is supported by the bias in the transcriptional activity of the haplotypes in response to FOXA2, the H3K27Ac and FOXA2 binding, and the GCKR expression in liver (CGG > TAC). The two most common haplotypes formed by rs780094, rs780095, rs780096, and rs1260326 variants in European populations are CGGC (54%) and TACT (40%) (Visualized with LDlink [55]). The CGGC haplotype encodes a GKRP variant with stronger GCK inhibitory capacity in fasting, which combined with higher GCKR expression (1) may result in increased nuclear sequestration and decreased cytoplasmic activity of GCK (2). In turn, reduced GCK activity results in reduced glucose uptake and higher blood glucose levels (3) and decreased glucose phosphorylation and disposal (4), which in turn results in lower production of the precursors for the synthesis of triglycerides (5). FOXA2 effects on CGGC haplotype expression may be influenced by the interaction with other TFs (represented by a question mark). The TACT haplotype encodes a GKRP protein (P446L) with weaker GCK inhibitory capacity, which combined with lower GCKR expression may result in the opposite effects on GCK activity and glucose metabolism (1*, 2*, 3*, 4*, and 5*). The disruption of MAFK motifs by rs780094-C and rs780095-G may change the haplotype bias in GCKR transcription upon MAFK activating signals