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Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β‐cells, it results in insulin release. Studies of glucokinase‐linked genetically‐modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole‐body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (<jats:styled-content style=\"fixed-case\">GKA</jats:styled-content>s) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that <jats:styled-content style=\"fixed-case\">GKA</jats:styled-content>s also have the effect of stimulating the proliferation of β‐cells. However, the results of recent phase <jats:styled-content style=\"fixed-case\">II</jats:styled-content> trials have shown that <jats:styled-content style=\"fixed-case\">GKA</jats:styled-content>s lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with <jats:styled-content style=\"fixed-case\">GKA</jats:styled-content>s frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1420845751165282432","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"70552420"},{"@type":"NRID","@value":"1000070552420"},{"@type":"NRID","@value":"9000400190462"},{"@type":"NRID","@value":"9000347316744"},{"@type":"NRID","@value":"9000415209262"},{"@type":"NRID","@value":"9000376546777"},{"@type":"NRID","@value":"9000311495123"},{"@type":"NRID","@value":"9000021261024"},{"@type":"NRID","@value":"9000368412205"},{"@type":"NRID","@value":"9000380122588"},{"@type":"NRID","@value":"9000318580605"},{"@type":"NRID","@value":"9000350637169"},{"@type":"NRID","@value":"9000405643499"},{"@type":"NRID","@value":"9000413946920"},{"@type":"NRID","@value":"9000388537027"},{"@type":"NRID","@value":"9000414493455"},{"@type":"NRID","@value":"9000413254426"},{"@type":"NRID","@value":"9000404790758"},{"@type":"NRID","@value":"9000010302404"},{"@type":"NRID","@value":"9000002134646"},{"@type":"NRID","@value":"9000412228736"},{"@type":"NRID","@value":"9000409481138"},{"@type":"NRID","@value":"9000340952778"},{"@type":"NRID","@value":"9000368412194"},{"@type":"NRID","@value":"9000378070688"},{"@type":"NRID","@value":"9000380979073"},{"@type":"NRID","@value":"9000415163320"},{"@type":"NRID","@value":"9000413946905"},{"@type":"NRID","@value":"9000404131450"},{"@type":"NRID","@value":"9000316209388"},{"@type":"NRID","@value":"9000256892756"},{"@type":"NRID","@value":"9000366505323"},{"@type":"NRID","@value":"9000394470708"},{"@type":"NRID","@value":"9000403963354"},{"@type":"NRID","@value":"9000258082962"},{"@type":"NRID","@value":"9000256601746"},{"@type":"NRID","@value":"9000413946926"},{"@type":"NRID","@value":"9000399166297"},{"@type":"NRID","@value":"9000395364177"},{"@type":"NRID","@value":"9000400190451"},{"@type":"NRID","@value":"9000403148322"},{"@type":"NRID","@value":"9000345269306"},{"@type":"NRID","@value":"9000411519827"},{"@type":"NRID","@value":"9000326649173"},{"@type":"NRID","@value":"9000340438914"},{"@type":"NRID","@value":"9000411206415"},{"@type":"NRID","@value":"9000383200636"},{"@type":"NRID","@value":"9000314379161"},{"@type":"NRID","@value":"9000413248301"},{"@type":"NRID","@value":"9000368412224"},{"@type":"NRID","@value":"9000001235333"},{"@type":"NRID","@value":"9000400190440"},{"@type":"NRID","@value":"9000409618613"},{"@type":"NRID","@value":"9000345378507"},{"@type":"NRID","@value":"9000413946958"},{"@type":"NRID","@value":"9000356551015"},{"@type":"NRID","@value":"9000016890472"},{"@type":"NRID","@value":"9000405634571"},{"@type":"NRID","@value":"9000378070600"},{"@type":"NRID","@value":"9000350637473"},{"@type":"NRID","@value":"9000398139164"},{"@type":"NRID","@value":"9000411568250"},{"@type":"NRID","@value":"9000257803255"},{"@type":"NRID","@value":"9000340459179"},{"@type":"NRID","@value":"9000402285886"},{"@type":"NRID","@value":"9000398646598"},{"@type":"NRID","@value":"9000382675291"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/7000002391"}],"foaf:name":[{"@value":"Akinobu 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Terauchi"}],"jpcoar:affiliationName":[{"@value":"Department of Endocrinology and Metabolism Graduate School of Medicine Yokohama City University Yokohama Japan"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"20401116"},{"@type":"EISSN","@value":"20401124"}],"prism:publicationName":[{"@value":"Journal of Diabetes 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Articles"}],"project":[{"@id":"https://cir.nii.ac.jp/crid/1040282257295421312","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"26860683"},{"@type":"JGN","@value":"JP26860683"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-26860683/"}],"notation":[{"@language":"ja","@value":"2型糖尿病病態における膵β細胞量増加への治療戦略"},{"@language":"en","@value":"The treatment strategy of incresing pancreatic beta cell mass"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1050306506452423040","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@language":"en","@value":"The role of glucokinase and insulin receptor substrate-2 in the proliferation of pancreatic beta cells induced by short-term high-fat diet feeding in mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360002216313013632","@type":"Article","resourceType":"学術雑誌論文(journal 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hyperplasia."}]},{"@id":"https://cir.nii.ac.jp/crid/1360292619369525376","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Glucose-Dependent Modulation of Insulin Secretion and Intracellular Calcium Ions by GKA50, a Glucokinase Activator"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292619683518976","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Effects of Increased Glucokinase Gene Copy Number on Glucose Homeostasis and Hepatic Glucose Metabolism"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620337647872","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"By the numbers: New estimates from the IDF Diabetes Atlas Update for 2012"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620468974208","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620699439360","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Characterization of a Novel Glucokinase Activator in Rat and Mouse Models"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620778271744","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"A patent review of glucokinase activators and disruptors of the glucokinase – glucokinase regulatory protein interaction: 2011 – 2014"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292620942867456","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292621220973056","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Transgenic knockouts reveal a critical requirement for pancreatic β cell glucokinase in maintaining glucose homeostasis"}]},{"@id":"https://cir.nii.ac.jp/crid/1360292621238090880","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Disruption of IRS-2 causes type 2 diabetes in mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360306905171513344","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Effects of glucokinase haploinsufficiency on the pancreatic β‐cell mass and function of long‐term high‐fat, high‐sucrose diet‐fed mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574093640433664","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574094244348416","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"A dominant role for glucose in β cell compensation of insulin resistance"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574095028217088","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations."}]},{"@id":"https://cir.nii.ac.jp/crid/1360574095555148800","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Update on mutations in glucokinase (<i>GCK</i>), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574095903280384","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Type 2 Diabetes and Congenital Hyperinsulinism Cause DNA Double-Strand Breaks and p53 Activity in β Cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360576118762499200","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes?"}]},{"@id":"https://cir.nii.ac.jp/crid/1360848656086622720","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions"}]},{"@id":"https://cir.nii.ac.jp/crid/1360855568831094528","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Treatment with glucokinase activator, YH-GKA, increases cell proliferation and decreases glucotoxic apoptosis in INS-1 cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360857593740743424","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Glucokinase is required for high‐starch diet‐induced β‐cell 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