Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland.
Department of Medicine, Kuopio University Hospital, P.O. Box 100 FI 70029 KYS, Kuopio, Finland.
Sci Rep. 2018 Oct 30;8(1):15989. doi: 10.1038/s41598-018-34501-9.
The rs780094 single nucleotide polymorphism (SNP; C/T) of glucokinase regulatory protein gene (GCKR) is a regulatory genetic variant that has been associated with lactate levels in the fasting state. However, the association of this locus with lactate during hyperglycemia, and the mechanisms underlying these associations remain unknown. We investigated the association of rs780094 with lactate levels in a frequently sampled oral glucose tolerance test in humans and evaluated the effect of increasing GCKR expression on lactate production in liver cells. The C allele of rs780094 was associated with lower lactate levels in fasting but increased lactate level during hyperglycemia independently of insulin levels. Increased expression of GKRP induced higher lactate level in HepG2 cells and in human primary hepatocytes (HPH) upon glucose stimulation by increasing the amount of GCK. Glucagon induced the expression of GCKR in HepG2 and HPH cells. Our results suggest that the association of rs780094 with lactate levels may involve differential GCKR expression between the carriers of the C and T alleles.
葡萄糖激酶调节蛋白基因（GCKR）的 rs780094 单核苷酸多态性（SNP；C/T）是一种调节遗传变异，与空腹状态下的乳酸水平有关。然而，该基因座与高血糖期间的乳酸之间的关联以及这些关联的潜在机制尚不清楚。我们在人类频繁采样的口服葡萄糖耐量试验中研究了 rs780094 与乳酸水平的关联，并评估了增加 GCKR 表达对肝细胞中乳酸生成的影响。rs780094 的 C 等位基因与空腹时的乳酸水平较低有关，但在高血糖期间独立于胰岛素水平增加乳酸水平。增加 GKRP 的表达会增加葡萄糖刺激下 HepG2 细胞和人原代肝细胞（HPH）中的乳酸水平，这是通过增加 GCK 的量实现的。胰高血糖素诱导 HepG2 和 HPH 细胞中 GCKR 的表达。我们的结果表明，rs780094 与乳酸水平的关联可能涉及 C 和 T 等位基因携带者之间 GCKR 表达的差异。
