{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Glucokinase regulatory protein (GKRP), encoded by the GCKR gene, is a liver‐specific protein that plays a central role in modulating glucokinase (GCK) activity and, thereby, hepatic glucose and lipid metabolism. In the fasting state, GKRP binds and sequesters GCK in the nucleus, reducing glycolytic flux; conversely, in the fed state the binding is attenuated—partly because of the actions of fructose phosphate effectors (fructose‐6‐phosphate enhances GKRP inhibition, whereas fructose‐1‐phosphate relieves it)—allowing GCK to relocate to the cytosol and catalyze glucose phosphorylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Numerous studies have demonstrated that common genetic variants in GCKR—most notably the P446L substitution—alter the sensitivity of GKRP to these regulatory metabolites. The P446L variant impairs the normal fructose-6-phosphate–mediated enhancement of GKRP inhibitory capacity, resulting in diminished nuclear sequestration of GCK. This leads to increased hepatic glucose uptake and metabolism and a consequent stimulation of de novo lipogenesis, which manifests clinically as lower fasting plasma glucose levels coupled with higher triglyceride concentrations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to influencing glycemic regulation, these reciprocal effects on lipid and glucose parameters have important pathophysiological consequences. Variants in GCKR have been associated with an increased risk for dyslipidemia, nonalcoholic fatty liver disease, and, through interactions with other metabolic pathways, type 2 diabetes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, structural and kinetic investigations have revealed that mutations affecting the GKRP binding interface with GCK—especially those that alter its responsiveness to regulatory fructose phosphates—result in quantitative changes in GCK activity and subcellular localization. These findings clarify the molecular mechanisms by which GCKR modulates hepatic glucose uptake and lipogenesis, thereby linking genetic variation to the clustered metabolic traits observed in common metabolic diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, the available evidence underscores the pivotal role of GKRP in coordinating the liver’s response to fluctuating glucose levels, with genetic variants in GCKR exerting divergent effects on glucose and lipid homeostasis that have significant implications for the development of type 2 diabetes and related metabolic disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nicola L Beer, Nicholas D Tribble, Laura J McCulloch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddp357"}], "href": "https://doi.org/10.1093/hmg/ddp357"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19643913"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19643913"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Maria Veiga-da-Cunha, Emile Van Schaftingen "}, {"type": "b", "children": [{"type": "t", "text": "Identification of fructose 6-phosphate- and fructose 1-phosphate-binding residues in the regulatory protein of glucokinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M105984200"}], "href": "https://doi.org/10.1074/jbc.M105984200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11756407"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11756407"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marju Orho-Melander, Olle Melander, Candace Guiducci, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db08-0516"}], "href": "https://doi.org/10.2337/db08-0516"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18678614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18678614"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Martine Vaxillaire, Christine Cavalcanti-Proença, Aurélie Dechaume, et al. "}, {"type": "b", "children": [{"type": "t", "text": "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."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db07-1807"}], "href": "https://doi.org/10.2337/db07-1807"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18556336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18556336"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "T Sparsø, G Andersen, T Nielsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-007-0865-z"}], "href": "https://doi.org/10.1007/s00125-007-0865-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18008060"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18008060"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "M G Rees, S Wincovitch, J Schultz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetologia (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00125-011-2348-5"}], "href": "https://doi.org/10.1007/s00125-011-2348-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22038520"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22038520"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Claudia H T Tam, Ronald C W Ma, Wing Yee So, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db08-1277"}], "href": "https://doi.org/10.2337/db08-1277"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19073768"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19073768"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Anne Raimondo, Matthew G Rees, Anna L Gloyn "}, {"type": "b", "children": [{"type": "t", "text": "Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Opin Lipidol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MOL.0000000000000155"}], "href": "https://doi.org/10.1097/MOL.0000000000000155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25692341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25692341"}]}]}]}