Alternative titles; symbols
HGNC Approved Gene Symbol: GCKR
Cytogenetic location: 2p23.3 Genomic coordinates (GRCh38): 2:27,496,839-27,523,684 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p23.3 | [Fasting plasma glucose level QTL 5] | 613463 | 3 |
Glucokinase (GCK; 138079) in the liver and pancreatic beta cells is subject to inhibition by a regulatory protein, GCKR. The inhibitory effect of GCKR depends on the presence of fructose-6-phosphate (F6P) and is antagonized by fructose-1-phosphate (F1P). Warner et al. (1995) noted that mutations in GCKR might be diabetogenic if they resulted in the synthesis of proteins with increased inhibitory activity, perhaps reflecting increased sensitivity to fructose-6-phosphate or reduced susceptibility to antagonism by fructose-1-phosphate. Warner et al. (1995) determined the complete sequence of human GCKR cDNA. The GCKR cDNA encodes a protein of 625 amino acids. Given the role of glucokinase in the causation of maturity-onset diabetes of the young (MODY) type II (125851), GCKR had been considered a candidate gene for a form of MODY.
Hayward et al. (1998) determined that the GCKR gene contains 19 exons and spans 27 kb.
Warner et al. (1995) isolated YAC clones containing human GCKR and localized them to chromosome 2p23 by fluorescence in situ hybridization. Vaxillaire et al. (1994) had previously assigned the GCKR gene to chromosome 2p23-p22.3.
Hayward et al. (1996) demonstrated that the GCKR gene lies within 500 kb of the gene encoding ketohexokinase (KHK; 614058). By high-resolution fluorescence in situ hybridization, they refined the localization of the GCKR gene to chromosome 2p23.3-p23.2.
A common GCKR variant (P446L; rs1260326; 600842.0001) is associated with triglyceride and fasting plasma glucose levels (FGQTL5; 613463) in the general population. In a series of transfection experiments using wildtype and P446L-GKRP, Beer et al. (2009) reported reduced regulation by physiologic concentrations of F6P in the presence of P446L-GKRP, resulting indirectly in increased GCK activity. Assays matched for GKRP activity demonstrated no difference in dose-dependent inhibition of GCK activity or F1P-mediated regulation. Quantitative RT-PCR analysis showed that GCKR is highly expressed relative to GCK in human liver and has very low expression in human pancreatic islets relative to GCK. The authors noted that altered GCK regulation in liver is predicted to enhance glycolytic flux, promoting hepatic glucose metabolism and elevating concentrations of malonyl-CoA (a substrate for de novo lipogenesis). Beer et al. (2009) proposed this as a mutational mechanism for the association of the leu446 allele with raised triglycerides and lower glucose levels.
Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. Suhre et al. (2011) identified rs780094 in the GCKR gene as associated with glucose/mannose ratio with a p value value of 5.5 x 10(-53).
Using in vivo application of Lactobacillus brevis NOX, a bacterial water-forming NADH oxidase, with metabolomics, Goodman et al. (2020) identified circulating alpha-hydroxybutyrate level as a robust marker for elevated hepatic cytosolic NADH/NAD+ ratio, or reductive stress, in mice. The authors noted that elevated circulating alpha-hydroxybutyrate level in human is associated with impaired glucose tolerance, insulin resistance, and mitochondrial disease, and is associated with a common genetic variant in GCKR, rs1260326, that is associated with disparate metabolic traits. Using L. brevis NOX, Goodman et al. (2020) demonstrated that NADH reductive stress mediated the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance, and FGF21 levels. They concluded elevated hepatic NADH/NAD+ ratio is a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.
During fasting, GKRP binds, inactivates, and sequesters GCK in the nucleus, which removes GCK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GCK (GCK activators) lower blood glucose levels but may carry an increased risk of hypoglycemia. To mitigate the risk of hypoglycemia, Lloyd et al. (2013) sought to increase GCK activity by blocking GKRP and described the identification of 2 potent small-molecule GCK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GCK activity and promoted GCK translocation both in vitro and in vivo. A cocrystal structure of full-length human GKRP in complex with AMG-1694 revealed a binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GCK activators), blood glucose lowering was restricted to diabetic and not normoglycemic animals.
To further understand the role of glucokinase regulatory protein, which they symbolized GKRP, Farrelly et al. (1999) inactivated the mouse homolog. With the knockout of the mouse gene, there was a parallel loss of glucokinase protein and activity in mutant mouse liver. The loss was primarily because of posttranscriptional regulation of glucokinase, indicating a positive regulatory role for GKRP in maintaining glucokinase levels and activity. As in rat hepatocytes, both glucokinase and GKRP were localized in the nuclei of mouse hepatocytes cultured in low glucose-containing medium. In the presence of fructose or high concentrations of glucose, conditions known to relieve glucokinase inhibition by GKRP in vitro, only glucokinase was translocated into the cytoplasm. In the GKRP-mutant hepatocytes, glucokinase was not found in the nucleus under any tested conditions. Farrelly et al. (1999) proposed that GKRP functions as an anchor to sequester and inhibit glucokinase in the hepatocyte nucleus, where it is protected from degradation. This ensures that glucose phosphorylation is minimal when the liver is in the fasting, glucose-producing phase. This also enables the hepatocytes rapidly to mobilize glucokinase into the cytoplasm to phosphorylate and store or metabolize glucose after the ingestion of dietary glucose. In GKRP-mutant mice, the disruption of this regulation and the subsequent decrease in GK activity led to altered glucose metabolism and impaired glycemic control.
Grimsby et al. (2000) found that wildtype and Gckr-null mice had comparable glucokinase activity at physiologic glucose concentrations. However, following a glucose tolerance test, the homozygous knockout mice showed impaired glucose clearance, indicating that they could not recruit sufficient glucokinase due to the absence of a nuclear reserve.
Beer et al. (2009) noted that the 1403C-T transition (rs1260326) in the GCKR gene results in a pro446-to-leu (P446L) substitution at a conserved residue in the glucokinase regulatory protein. Residue 446 lies between 2 motifs thought to be directly involved in binding of phosphate esters.
By genomewide association studies, Orho-Melander et al. (2008) showed that the intronic rs780094 variant of the GCKR gene was associated with higher plasma triglyceride levels (p = 3 x 10(-56)) but lower fasting plasma glucose levels (p = 1 x 10(-13)) (FGQTL5; 613463). Fine-mapping by genotyping and imputing SNPs across the GCKR locus identified a common 1403C-T transition, resulting in a pro446-to-leu (P446L; rs1260326) substitution, as the strongest signal for association with triglycerides. The rs1260326 SNP shows strong linkage disequilibrium (r(2) = 0.93) with rs780094 and has a minor allele frequency of 0.34.
In 4,833 middle-aged French individuals, Vaxillaire et al. (2008) found that the minor T allele of the P446L (rs1260326) SNP was strongly associated with lower fasting glucose levels and fasting insulin levels, and conversely, higher triglyceride levels.
Dupuis et al. (2010) performed metaanalyses of 21 genomewide association studies informative for fasting glucose, fasting insulin, and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and 2 loci associated with fasting insulin and HOMA-IR. Dupuis et al. (2010) identified association of elevation of fasting blood glucose (p = 5.6 x 10(-38)) and decreased triglyceride levels (p = 9.6 x 10(-17)) with the C allele of the intronic C-T SNP (rs780094) in the GCKR gene on chromosome 2p23.3-p23.2. This variant was also associated with fasting insulin levels (3.0 x 10(-24)).
In a series of transfection experiments using wildtype and P446L-GKRP, Beer et al. (2009) reported reduced regulation by physiologic concentrations of F6P in the presence of P446L-GKRP, resulting indirectly in increased GCK activity. Assays matched for GKRP activity demonstrated no difference in dose-dependent inhibition of GCK activity or F1P-mediated regulation. Quantitative RT-PCR analysis showed that GCKR is highly expressed relative to GCK in human liver and has very low expression in human pancreatic islets relative to GCK. The authors noted that altered GCK regulation in liver is predicted to enhance glycolytic flux, promoting hepatic glucose metabolism and elevating concentrations of malonyl-CoA (a substrate for de novo lipogenesis). Beer et al. (2009) proposed this as a mutational mechanism for the association of the leu446 allele with raised triglycerides and lower glucose levels.
Beer, N. L., Tribble, N. D., McCulloch, L. J., Roos, C., Johnson, P. R. V., Orho-Melander, M., Gloyn, A. L. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Molec. Genet. 18: 4081-4088, 2009. [PubMed: 19643913] [Full Text: https://doi.org/10.1093/hmg/ddp357]
Dupuis, J., Langenberg, C., Prokopenko, I., Saxena, R., Soranzo, N., Jackson, A. U., Wheeler, E., Glazer, N. L., Bouatia-Naji, N., Gloyn, A. L., Lindgren, C. M., Magi, R., and 295 others. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genet. 42: 105-116, 2010. Note: Erratum: Nature Genet. 42: 464 only, 2010. [PubMed: 20081858] [Full Text: https://doi.org/10.1038/ng.520]
Farrelly, D., Brown, K. S., Tieman, A., Ren, J., Lira, S. A., Hagan, D., Gregg, R., Mookhtiar, K. A., Hariharan, N. Mice mutant for glucokinase regulatory protein exhibit decreased liver glucokinase: a sequestration mechanism in metabolic regulation. Proc. Nat. Acad. Sci. 96: 14511-14516, 1999. [PubMed: 10588736] [Full Text: https://doi.org/10.1073/pnas.96.25.14511]
Goodman, R. P., Markhard, A. L., Shah, H., Sharma, R., Skinner, O. S., Clish, C. B., Deik, A., Patgiri, A., Hsu, Y.-H. H., Masia, R., Noh, H. L., Suk, S., Goldberger, O., Hirschhorn, J. N., Yellen, G., Kim, J. K., Mootha, V. K. Hepatic NADH reductive stress underlies common variation in metabolic traits. Nature 583: 122-126, 2020. [PubMed: 32461692] [Full Text: https://doi.org/10.1038/s41586-020-2337-2]
Grimsby, J., Coffey, J. W., Dvorozniak, M. T., Magram, J., Li, G., Matschinsky, F. M., Shiota, C., Kaur, S., Magnuson, M. A., Grippo, J. F. Characterization of glucokinase regulatory protein-deficient mice. J. Biol. Chem. 275: 7826-7831, 2000. [PubMed: 10713097] [Full Text: https://doi.org/10.1074/jbc.275.11.7826]
Hayward, B. E., Dunlop, N., Intody, S., Leek, J. P., Markham, A. F., Warner, J. P., Bonthron, D. T. Organization of the human glucokinase regulator gene GCKR. Genomics 49: 137-142, 1998. [PubMed: 9570959] [Full Text: https://doi.org/10.1006/geno.1997.5195]
Hayward, B. E., Fantes, J. A., Warner, J. P., Intody, S., Leek, J. P., Markham, A. F., Bonthron, D. T. Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23. Mammalian Genome 7: 454-458, 1996. [PubMed: 8662230] [Full Text: https://doi.org/10.1007/s003359900132]
Lloyd, D. J., St Jean, D. J., Jr., Kurzeja, R. J. M., Wahl, R. C., Michelsen, K., Cupples, R., Chen, M., Wu, J., Sivits, G., Helmering, J., Komorowski, R., Ashton, K. S., and 17 others. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature 504: 437-440, 2013. [PubMed: 24226772] [Full Text: https://doi.org/10.1038/nature12724]
Orho-Melander, M., Melander, O., Guiducci, C., Perez-Martinez, P., Corella, D., Roos, C., Tewhey, R., Rieder, M. J., Hall, J., Abecasis, G., Tai, E. S., Welch, C., and 29 others. Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57: 3112-3121, 2008. [PubMed: 18678614] [Full Text: https://doi.org/10.2337/db08-0516]
Suhre, K., Shin, S.-Y., Petersen, A.-K., Mohney, R. P., Meredith, D., Wagele, B., Altmaier, E., CARDIoGRAM, Deloukas, P., Erdmann, J., Grundberg, E., Hammond, C. J., and 22 others. Human metabolic individuality in biomedical and pharmaceutical research. Nature 477: 54-60, 2011. [PubMed: 21886157] [Full Text: https://doi.org/10.1038/nature10354]
Vaxillaire, M., Cavalcanti-Proenca, C., Dechaume, A., Tichet, J., Marre, M., Balkau, B., Forguel, P., DESIR Study Group. The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes 57: 2253-2257, 2008. [PubMed: 18556336] [Full Text: https://doi.org/10.2337/db07-1807]
Vaxillaire, M., Vionnet, N., Vigouroux, C., Sun, F., Espinosa, R., III, LeBeau, M. M., Stoffel, M., Lehto, M., Beckmann, J. S., Detheux, M., Passa, P., Cohen, D., Van Schaftingen, E., Velho, G., Bell, G. I., Froguel, P. Search for a third susceptibility gene for maturity-onset diabetes of the young: studies with eleven candidate genes. Diabetes 43: 389-395, 1994. [PubMed: 7508874] [Full Text: https://doi.org/10.2337/diab.43.3.389]
Warner, J. P., Leek, J. P., Intody, S., Markham, A. F., Bonthron, D. T. Human glucokinase regulatory protein (GCKR): cDNA and genomic cloning, complete primary structure, and chromosomal localization. Mammalian Genome 6: 532-536, 1995. [PubMed: 8589523] [Full Text: https://doi.org/10.1007/BF00356171]