actabiomedicaActa Biomedica ScientificaActa Biomedica Scientifica2541-94202587-9596Scientific Centre for Family Health and Human Reproduction Problems10.29413/ABS.2025-10.3.3actabiomedica-4807Research ArticleБИОЛОГИЯ И МЕДИЦИНСКАЯ БИОЛОГИЯBIOLOGY AND MEDICAL BIOLOGYГлюкокиназа: эволюция, регуляторные свойства, роль в патогенезе сахарного диабетаGlucokinase: evolution, regulatory properties, role in the pathogenesis of type 2 diabetes mellitushttps://orcid.org/0000-0001-9215-6018КузнецоваЛ. А.KuznetsovaL. A.

Кузнецова Людмила Александровна – доктор биологических наук, ведущий научный сотрудник лаборатории молекулярной эндокринологии и нейрохимии 

194223, г. Санкт-Петербург, пр. Тореза, 44

 

Lyudmila A. Kuznetsova – Dr. Sc. (Biol.), Leading Research Officer at the laboratory of molecular endocrinology and neurochemistry 

pr. Thorez 44, Saint-Petersburg 194223

praskovia1231@mail.ruhttps://orcid.org/0000-0002-7316-2882БасоваН. Е.BasovaN. E.

Басова Наталия Евгеньевна – кандидат биологических наук, старший научный сотрудник лаборатории молекулярной эндокринологии и нейрохимии 

194223, г. Санкт-Петербург, пр. Тореза, 44

Nataliia E. Basova – Cand. Sc. (Biol.), Senior Research Officer at the laboratory of molecular endocrinology and neurochemistry 

pr. Thorez 44, Saint-Petersburg 194223

basovnat@mail.ruhttps://orcid.org/0000-0002-4293-3162ШпаковА. О.ShpakovA. O.

Шпаков Александр Олегович – доктор биологических наук, заместитель директора по научной работе, заведующий лабораторией молекулярной эндокринологии и нейрохимии 

194223, г. Санкт-Петербург, пр. Тореза, 44

Alexander O. Shpakov – Dr. Sc. (Biol.), Head of the laboratory of molecular endocrinology and neurochemistry, deputy director 

pr. Thorez 44, Saint-Petersburg 194223

alex_shpakov@list.ruФедеральное государственное бюджетное учреждение науки Институт эволюционной физиологии и биохимии им. И.М. Сеченова Российской академии наук (ИЭФБ РАН)Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences2025220720251032236Copyright © Кузнецова Л.А., Басова Н.Е., Шпаков А.О., 20252025Кузнецова Л.А., Басова Н.Е., Шпаков А.О.Kuznetsova L.A., Basova N.E., Shpakov A.O.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.actabiomedica.ru/jour/article/view/4807

В обзоре рассмотрены вопросы эволюции, структурно-функциональной организации и регуляторные свойства глюкокиназы, которая преимущественно экспрессируется в β-клетках поджелудочной железы и в гепатоцитах печени. Значительное внимание уделено возможной роли глюкокиназы в этиологии и патогенезе сахарного диабета 2 типа (СД2), и разработке подходов для нормализации секреции инсулина, глюкозного гомеостаза, углеводного и липидного обмена с помощью регуляторов активности глюкокиназы. Представлены данные о влиянии вариантов в гене глюкокиназы и регуляторного белка глюкокиназы в развитии нарушений инсулин-секретирующей функции поджелудочной железы. Так инактивирующие мутации в гене глюкокиназы вызывают СД2, в то время как активирующие мутации приводят к врожденному гиперинсулинизму. Обсуждаются данные, что L-аргинин, аллостерически взаимодействуя с глюкокиназой, стимулирует секрецию инсулина и ингибирует деградацию фермента, защищая его от убиквитинирования. Сделан вывод, что глюкокиназа и функционально связанные с ней белки являются перспективными мишенями при разработке подходов для нормализации чувствительности панкреатических β-клеток к глюкозе, восстановления секреции инсулина и глюкозного гомеостаза при СД2 и других метаболических расстройствах. Данные для этого обзора были определены путем поиска в MEDLINE, PubMed и ссылках на статьи, опубликованные на английском и русском языках в период с 1966 по 2024 год.

The review examines the evolution, structural and functional organization and regulatory properties of glucokinase, which is predominantly expressed in β-cells of the pancreas and in liver hepatocytes. Considerable attention is paid to the possible role of glucokinase in the etiology and pathogenesis of type 2 diabetes mellitus (T2DM), and the development of approaches to normalize insulin secretion, glucose homeostasis, carbohydrate and lipid metabolism using regulators of glucokinase activity. Data are presented on the influence of variants in the glucokinase gene and glucokinase regulatory protein in the development of disorders of the insulin-secreting function of the pancreas. Thus, inactivating mutations in the glucokinase gene cause T2DM, while activating mutations lead to congenital hyperinsulinism. Data are discussed that L-arginine, allosterically interacting with glucokinase, stimulates insulin secretion and inhibits the degradation of the enzyme, protecting it from ubiquitination. It is concluded that glucokinase and functionally related proteins are promising targets when developing approaches to normalize the sensitivity of pancreatic β-cells to glucose, restore insulin secretion and glucose homeostasis in T2DM and other metabolic disorders. Data for this review were identified by searching MEDLINE, PubMed, and references of articles published in English and Russian between 1966 and 2024.

глюкокиназаэволюциясахарный диабетрегуляторный белок глюкокиназыS-нитрозилированиеglucokinaseevolutiondiabetes mellitusglucokinase regulatory proteinS-nitrosylationРабота выполнена в рамках государственного задания ИЭФБ РАН № 075-00263-25-00.ReferencesLenzen S. A fresh view of glycolysis and glucokinase regulation: history and current status. J. Biol. Chem. 2014; 289: 12189–94. doi: 10.1074/jbc.R114.557314Lenzen S. A fresh view of glycolysis and glucokinase regulation: history and current status. J. Biol. Chem. 2014; 289: 12189–94. doi: 10.1074/jbc.R114.557314Wilson JE. Isozymes of mammalian hexokinase: Structure, subcellular localization and metabolic function. J. Exp. Biol. 2003; 206(Pt12): 2049–2057. doi: 10.1242/jeb.00241Wilson JE. Isozymes of mammalian hexokinase: Structure, subcellular localization and metabolic function. J. Exp. Biol. 2003; 206(Pt12): 2049–2057. doi: 10.1242/jeb.00241Cardenas ML, Cornish-Bowden A, Ureta T. Evolution and regulatory role of the hexo-kinases. Biochim. Biophys. Acta. 1998; 1401(3): 242-64. doi: 10.1016/s0167-4889(97)00150-xCardenas ML, Cornish-Bowden A, Ureta T. Evolution and regulatory role of the hexo-kinases. Biochim. Biophys. Acta. 1998; 1401(3): 242-64. doi: 10.1016/s0167-4889(97)00150-xIrwin DM, Tan H. Evolution of glucose utilization: glucokinase and glucokinase regulator protein. Mol. Phylogenet. Evol. 2014; 70: 195-203. doi: 10.1016/j.ympev.2013.09.016Irwin DM, Tan H. Evolution of glucose utilization: glucokinase and glucokinase regulator protein. Mol. Phylogenet. Evol. 2014; 70: 195-203. doi: 10.1016/j.ympev.2013.09.016Guo D, Meng Y, Jiang X, Lu Z. Hexokinases in cancer and other pathologies. Cell Insight. 2023; 2(1): 100077. doi: 10.1016/j.cellin.2023.100077Guo D, Meng Y, Jiang X, Lu Z. Hexokinases in cancer and other pathologies. Cell Insight. 2023; 2(1): 100077. doi: 10.1016/j.cellin.2023.100077Перцева М.Н. О некоторых свойствах гексокиназы мышц кур в онтогенезе. Журнал эв. биохимии и физиол. 1966; 2(5): 419-422.Pertseva MN. On some properties of muscle hexokinase in ontogenesis of hen. Journal of Evolutional Biochemistry and Physiology. 1966; 2(5): 419-422. (In Russ.).Farooq Z, Ismail H, Bhat SA, Layden BT, Khan MW. Aiding Cancer’s “Sweet Tooth”: Role of Hexokinases in Metabolic Reprogramming. Life (Basel). 2023; 13(4): 946. doi: 10.3390/life13040946Farooq Z, Ismail H, Bhat SA, Layden BT, Khan MW. Aiding Cancer’s “Sweet Tooth”: Role of Hexokinases in Metabolic Reprogramming. Life (Basel). 2023; 13(4): 946. doi: 10.3390/life13040946Griffin LD, Gelb BD, Wheeler D, Davison V, McCabe ER. Mammalian hexokinase 1: evolutionary conservation and structure to function analysis. Genomics. 1991; 11(4): 1014-1024. doi: 10.1016/0888-7543(91)90027-cGriffin LD, Gelb BD, Wheeler D, Davison V, McCabe ER. Mammalian hexokinase 1: evolutionary conservation and structure to function analysis. Genomics. 1991; 11(4): 1014-1024. doi: 10.1016/0888-7543(91)90027-cTsai HJ. Functional organization and evolution of mammalian hexokinases: mutations that caused the loss of catalytic activity in N-terminal halves if type I and type III isozymes. Arch. Biochem. Biophys. 1999; 369(1): 149-156. doi: 10.1006/abbi.19999.1326Tsai HJ. Functional organization and evolution of mammalian hexokinases: mutations that caused the loss of catalytic activity in N-terminal halves if type I and type III isozymes. Arch. Biochem. Biophys. 1999; 369(1): 149-156. doi: 10.1006/abbi.19999.1326Choi JM, Seo MH, Kyeong HH, Kim E, Kim HS. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc. Natl. Acad. Sci. USA. 2013; 110(25): 10171-10176. doi: 10.1073/pnas.1300457110Choi JM, Seo MH, Kyeong HH, Kim E, Kim HS. Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc. Natl. Acad. Sci. USA. 2013; 110(25): 10171-10176. doi: 10.1073/pnas.1300457110Zapater JL, Lednovich KR, Khan MW, Pusec CM, Layden BT. Hexokinase domain-containing protein-1 in metabolic diseases and beyond. Trends in Endocrinology and Metabolism. 2022; 33: 72–84. doi: 0.1016/j.tem.2021.10006Zapater JL, Lednovich KR, Khan MW, Pusec CM, Layden BT. Hexokinase domain-containing protein-1 in metabolic diseases and beyond. Trends in Endocrinology and Metabolism. 2022; 33: 72–84. doi: 0.1016/j.tem.2021.10006Ciscato F, Filadi R, Masgras I, Pizzi M, Marin O, Damiano N, et al. Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells. EMBO Reports. 2020; 21(7): e49117. doi: 10.15252/embr.201948117Ciscato F, Filadi R, Masgras I, Pizzi M, Marin O, Damiano N, et al. Hexokinase 2 displacement from mitochondria-associated membranes prompts Ca2+-dependent death of cancer cells. EMBO Reports. 2020; 21(7): e49117. doi: 10.15252/embr.201948117Ashcroft FM, Lloyd M, Haythorne EA. Glucokinase activity in diabetes: Too much of a good thing? Trends Endocrinol metabolism. 2023; 34(2): 119–30. doi: 10.1016/j.tem.2022.12.007Ashcroft FM, Lloyd M, Haythorne EA. Glucokinase activity in diabetes: Too much of a good thing? Trends Endocrinol metabolism. 2023; 34(2): 119–30. doi: 10.1016/j.tem.2022.12.007Matschinsky FM, Wilson DF. The central role of glucokinase in glucose homeostasis: a perspective 50 years after demonstrating the presence of the enzyme in islets of Langerhans. Front. Physiol. 2019; 10: 148. doi: 10.3389/fphys.2019.00148Matschinsky FM, Wilson DF. The central role of glucokinase in glucose homeostasis: a perspective 50 years after demonstrating the presence of the enzyme in islets of Langerhans. Front. Physiol. 2019; 10: 148. doi: 10.3389/fphys.2019.00148Gersing S, Schulze TK, Cagiada M, Stein A, Roth FP, Lindorff-Larsen K, et al. Characterizing glucokinase variant mechanisms using a multiplexed abundance assay. Genome Biol. 2024; 16; 25(1): 98. doi: 10.1186/s13059-024-03238-2Gersing S, Schulze TK, Cagiada M, Stein A, Roth FP, Lindorff-Larsen K, et al. Characterizing glucokinase variant mechanisms using a multiplexed abundance assay. Genome Biol. 2024; 16; 25(1): 98. doi: 10.1186/s13059-024-03238-2Rubtsov PM, Igudin EL, Tiulpakov A.N. Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs. Mol Biol (Mosk). 2015; 49(4): 555-560. doi: 10.7868/S002689841504014XRubtsov PM, Igudin EL, Tiulpakov A.N. Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs. Mol Biol (Mosk). 2015; 49(4): 555-560. doi: 10.7868/S002689841504014XRen Y, Li L, Li W, Huang Y, Cao S. Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists. J. Enzyme Inhib. Med. Chem. 2022; 37(1): 606–615. doi: 10.1080/14756366.2021.2025362Ren Y, Li L, Li W, Huang Y, Cao S. Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists. J. Enzyme Inhib. Med. Chem. 2022; 37(1): 606–615. doi: 10.1080/14756366.2021.2025362Park JM, Kim TH, Jo SH, Kim MY, Ahn YH. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity. Sci Rep. 2015; 5: 17395. doi: 10.1038/srep17395Park JM, Kim TH, Jo SH, Kim MY, Ahn YH. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity. Sci Rep. 2015; 5: 17395. doi: 10.1038/srep17395Jin L, Guo T, Li Z, Lei Z, Li H, Mao Y, et al. Role of Glucokinase in the subcellular localization of glucokinase regulatory protein. Int. J. Mol. Sci. 2015; 16(4): 7377-7393. doi: 10.3390/ijms16047377Jin L, Guo T, Li Z, Lei Z, Li H, Mao Y, et al. Role of Glucokinase in the subcellular localization of glucokinase regulatory protein. Int. J. Mol. Sci. 2015; 16(4): 7377-7393. doi: 10.3390/ijms16047377Agius L. Hormonal and metabolite regulation of hepatic glucokinase. Annu Rev Nutr. 2016; 17; 36: 389-415. doi: 10.1146/annurev-nutr-071715-051145Agius L. Hormonal and metabolite regulation of hepatic glucokinase. Annu Rev Nutr. 2016; 17; 36: 389-415. doi: 10.1146/annurev-nutr-071715-051145Paliwal A, Paliwal V, Jain S, Paliwal S, Sharma S. Current insight on the role of glucokinase and glucokinase regulatory protein in diabetes. Mini Rev Med Chem. 2024; 24(7): 674-688. doi: 10.2174/13895575236662308231519Paliwal A, Paliwal V, Jain S, Paliwal S, Sharma S. Current insight on the role of glucokinase and glucokinase regulatory protein in diabetes. Mini Rev Med Chem. 2024; 24(7): 674-688. doi: 10.2174/13895575236662308231519Kaushik A, Kaushik M. Recent updates on glucokinase activators and glucokinase regulatory protein disrupters for the treatment of Type 2 Diabetes Mellitus. Curr Diabetes Rev. 2019; 15(3): 205-212. doi: 10.2174/1573399814666180724100749Kaushik A, Kaushik M. Recent updates on glucokinase activators and glucokinase regulatory protein disrupters for the treatment of Type 2 Diabetes Mellitus. Curr Diabetes Rev. 2019; 15(3): 205-212. doi: 10.2174/1573399814666180724100749Wang ZY, Jin L, Tan H, Irwin DM. Evolution of hepatic glucose metabolism: liver-specific glucokinase deficiency explained by parallel loss of the gene for Glucokinase Regulatory Protein (GCKR). PLoS One. 2013; 8(4): e60896. doi: 10.1371/journal.pone.0060896Wang ZY, Jin L, Tan H, Irwin DM. Evolution of hepatic glucose metabolism: liver-specific glucokinase deficiency explained by parallel loss of the gene for Glucokinase Regulatory Protein (GCKR). PLoS One. 2013; 8(4): e60896. doi: 10.1371/journal.pone.0060896Veiga-da-Cunha M, Sokolova T, Opperdoes F, Van Schaftingen E. Evolution of vertebrate glucokinase regulatory protein from a bacterial N-acetylmuramate 6-phosphate etherase. Biochem. J. 2009; 423: 323–332. doi: 10.1042/BJ20090986Veiga-da-Cunha M, Sokolova T, Opperdoes F, Van Schaftingen E. Evolution of vertebrate glucokinase regulatory protein from a bacterial N-acetylmuramate 6-phosphate etherase. Biochem. J. 2009; 423: 323–332. doi: 10.1042/BJ20090986Marfori M, Mynott A, Ellis JJ. Mehdi AM, Saunders NF, Curmi PM, et al. Molecular basis for specificity of nuclear import and prediction of nuclear localization. Biochim. Biophys. Acta. 2011; 1813: 1562-1577. doi: 10.1016/j.bbamcr.2010.10.013Marfori M, Mynott A, Ellis JJ. Mehdi AM, Saunders NF, Curmi PM, et al. Molecular basis for specificity of nuclear import and prediction of nuclear localization. Biochim. Biophys. Acta. 2011; 1813: 1562-1577. doi: 10.1016/j.bbamcr.2010.10.013Ford BE, Chachra SS, Rodgers K, Moonira T, Al-Oanzi ZH, Anstee QM, et al. The gckr-P446l gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446l mouse-a model for gckr rs1260326. Mol. Metab. 2023; 72: 101722. doi: 10.1016/j.molmet.2023.101722Ford BE, Chachra SS, Rodgers K, Moonira T, Al-Oanzi ZH, Anstee QM, et al. The gckr-P446l gene variant predisposes to raised blood cholesterol and lower blood glucose in the P446l mouse-a model for gckr rs1260326. Mol. Metab. 2023; 72: 101722. doi: 10.1016/j.molmet.2023.101722Zhang Z, Ji G, Li M. Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD. Front Endocrinol. (Lausanne). 2023; 14: 1247611. doi: 10.3389/fendo.2023.1247611Zhang Z, Ji G, Li M. Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD. Front Endocrinol. (Lausanne). 2023; 14: 1247611. doi: 10.3389/fendo.2023.1247611Barosa C, Ribeiro RT, Andrade R, Raposo JF, Jones JG. Effects of Meal Fructose/Glucose composition on postprandial glucose appearance and hepatic glycogen synthesis in healthy subjects. J. Clin. Med. 2021; 10(4): 596. doi: 10.3390/jcm10040596Barosa C, Ribeiro RT, Andrade R, Raposo JF, Jones JG. Effects of Meal Fructose/Glucose composition on postprandial glucose appearance and hepatic glycogen synthesis in healthy subjects. J. Clin. Med. 2021; 10(4): 596. doi: 10.3390/jcm10040596Smith EVL, Dyson RM, Weth FR, Berry MJ, Gray C. Maternal fructose intake, programmed mitochondrial function and predisposition to adult disease. Int. J. Mol. Sci. 2022; 23(20): 12215. doi: 10.3390/ijms232012215Smith EVL, Dyson RM, Weth FR, Berry MJ, Gray C. Maternal fructose intake, programmed mitochondrial function and predisposition to adult disease. Int. J. Mol. Sci. 2022; 23(20): 12215. doi: 10.3390/ijms232012215Sternisha SM, Miller BG. Molecular and cellular regulation of human glucokinase. Arch. Biochem. Biophys. 2019; 663: 199-213. doi: 10.1016/j.abb.2019.01.011Sternisha SM, Miller BG. Molecular and cellular regulation of human glucokinase. Arch. Biochem. Biophys. 2019; 663: 199-213. doi: 10.1016/j.abb.2019.01.011Zhou HL, Premont RT, Stamler JS. The manifold roles of protein S-nitrosylation in the life of insulin. Nat. Rev. Endocrinol. 2022; 18(2): 111-128. doi: 10.1038/s41574-021-00583-1Zhou HL, Premont RT, Stamler JS. The manifold roles of protein S-nitrosylation in the life of insulin. Nat. Rev. Endocrinol. 2022; 18(2): 111-128. doi: 10.1038/s41574-021-00583-1Sternisha SM, Liu P, Marshall AG, Miller BG. Mechanistic Origins of Enzyme Activation in human glucokinase variants associated with Congenital Hyperinsulinism. Biochemistry. 2018; 57(10): 1632-1639. doi: 10.1021/acs.biochem.8b00022Sternisha SM, Liu P, Marshall AG, Miller BG. Mechanistic Origins of Enzyme Activation in human glucokinase variants associated with Congenital Hyperinsulinism. Biochemistry. 2018; 57(10): 1632-1639. doi: 10.1021/acs.biochem.8b00022Seckinger KM, Rao VP, Snell NE, Mancini AE, Markwardt ML, Rizzo MA. Nitric Oxide Activates β-Cell Glucokinase by Promoting Formation of the “Glucose-Activated” State. Biochemistry. 2018; 57(34): 5136–5144. doi: 10.1021/acs.biochem.8b00333Seckinger KM, Rao VP, Snell NE, Mancini AE, Markwardt ML, Rizzo MA. Nitric Oxide Activates β-Cell Glucokinase by Promoting Formation of the “Glucose-Activated” State. Biochemistry. 2018; 57(34): 5136–5144. doi: 10.1021/acs.biochem.8b00333Markwardt ML, Seckinger KM, Rizzo MA. β-Regulation of glucokinase by intracellular calcium levels in pancreatic β-Cells. J. Biol. Chem. 2016; 291: 3000-3009. doi: 10.1074/jbc.M115.692160Markwardt ML, Seckinger KM, Rizzo MA. β-Regulation of glucokinase by intracellular calcium levels in pancreatic β-Cells. J. Biol. Chem. 2016; 291: 3000-3009. doi: 10.1074/jbc.M115.692160Gheibi S, Ghasemi A. Insulin secretion: The nitric oxide controversy. EXCLI J. 2020; 19: 1227-1245. doi: 10.17179/excli2020-2711Gheibi S, Ghasemi A. Insulin secretion: The nitric oxide controversy. EXCLI J. 2020; 19: 1227-1245. doi: 10.17179/excli2020-2711Bahadoran Z, Mirmiran P, Ghasemi A. Role of nitric oxide in insulin secretion and glucose metabolism. Trends Endocrinol. Metab. 2020; 31: 118-130. doi: 10.1016/j.tem.2019.10.001Bahadoran Z, Mirmiran P, Ghasemi A. Role of nitric oxide in insulin secretion and glucose metabolism. Trends Endocrinol. Metab. 2020; 31: 118-130. doi: 10.1016/j.tem.2019.10.001Lajoix AD, Reggio H, Chardes T, Peraldi-Roux S, Tribillac F, Roye M, et al. A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion. Diabetes. 2001; 50: 1311-1323. doi: 10.2337/diabetes.50.6.1311Lajoix AD, Reggio H, Chardes T, Peraldi-Roux S, Tribillac F, Roye M, et al. A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion. Diabetes. 2001; 50: 1311-1323. doi: 10.2337/diabetes.50.6.1311Rizzo MA, Piston DW. Regulation of β-cell glucokinase by S-nitrosylation and association with nitric oxide synthase. J. Cell Biol. 2003; 161: 243–248. doi: 10.1083/jcb.200301063Rizzo MA, Piston DW. Regulation of β-cell glucokinase by S-nitrosylation and association with nitric oxide synthase. J. Cell Biol. 2003; 161: 243–248. doi: 10.1083/jcb.200301063Basu L, Bhagat V, Ching MEA, Di Giandomenico A, Dostie S, Greenberg D, et al. Recent developments in islet biology: a review with patient perspectives. Can J Diabetes. 2023; 47(2): 207-221. doi: 10.1016/j.jcjd.2022.11.003Basu L, Bhagat V, Ching MEA, Di Giandomenico A, Dostie S, Greenberg D, et al. Recent developments in islet biology: a review with patient perspectives. Can J Diabetes. 2023; 47(2): 207-221. doi: 10.1016/j.jcjd.2022.11.003Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 2015; 95: 513-548. doi: 10.1152/physrev.00013.2014Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 2015; 95: 513-548. doi: 10.1152/physrev.00013.2014Takeda Y. Theoretical investigations into the quantitative mechanisms underlying the regulation of [cAMP]i, membrane excitability and [Ca(2+)]i during GLP-1 Stimulation in Pancreatic β Cells. Yakugaku Zasshi. 2016; 136(3): 467-471. doi: 10.1248/yakushi.15-00246-2Takeda Y. Theoretical investigations into the quantitative mechanisms underlying the regulation of [cAMP]i, membrane excitability and [Ca(2+)]i during GLP-1 Stimulation in Pancreatic β Cells. Yakugaku Zasshi. 2016; 136(3): 467-471. doi: 10.1248/yakushi.15-00246-2Langer S, Waterstradt R, Hillebrand G, Santer R, Baltrusch S. The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes. Diabetologia. 2021; 64(12): 2687-2700. doi: 10.1007/s00125-021-05553-wLanger S, Waterstradt R, Hillebrand G, Santer R, Baltrusch S. The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes. Diabetologia. 2021; 64(12): 2687-2700. doi: 10.1007/s00125-021-05553-wVieira R, Souto SB, Sánchez-López E, Machado AL, Severino P, Jose S, et al. Sugar-lowering drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome-Review of Classical and New Compounds: Part-I. Pharmaceuticals. 2019; 12(4): 152. doi: 10.3390/ph12040152Vieira R, Souto SB, Sánchez-López E, Machado AL, Severino P, Jose S, et al. Sugar-lowering drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome-Review of Classical and New Compounds: Part-I. Pharmaceuticals. 2019; 12(4): 152. doi: 10.3390/ph12040152Vivot K, Pasquier A, Goginashvili A, Ricci R. Breaking Bad and Breaking Good: Beta-Cell Autophagy Pathways in Diabetes. j. mol. biol. 2020; 432(5): 1494-1513. doi: 10.1016/j.jmb.2019.07.030Vivot K, Pasquier A, Goginashvili A, Ricci R. Breaking Bad and Breaking Good: Beta-Cell Autophagy Pathways in Diabetes. j. mol. biol. 2020; 432(5): 1494-1513. doi: 10.1016/j.jmb.2019.07.030Timper K, Donath MY. Diabetes mellitus Type 2 – The new face of an old lady. Swiss Med. Wkly. 2012; 142: w13635. doi: 10.4414/smw.2012.13635Timper K, Donath MY. Diabetes mellitus Type 2 – The new face of an old lady. Swiss Med. Wkly. 2012; 142: w13635. doi: 10.4414/smw.2012.13635Retnakaran R, Pu J, Emery A, Harris SB, Reichert SM, Gerstein HC, et al. Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes. Nat. Commun. 2023; 14: 4514. doi: 10.1038/s41467-023-40287-wRetnakaran R, Pu J, Emery A, Harris SB, Reichert SM, Gerstein HC, et al. Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes. Nat. Commun. 2023; 14: 4514. doi: 10.1038/s41467-023-40287-wCampbell JE, Newgard CB. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat. Rev. Mol. Cell Biol. 2021; 22: 142–158. doi: 10.1038/s41580-020-00317-7Campbell JE, Newgard CB. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat. Rev. Mol. Cell Biol. 2021; 22: 142–158. doi: 10.1038/s41580-020-00317-7Hou J, Li Z, Zhong W, Hao Q, Lei L, Wang L, et al. Temporal transcriptomic and proteomic landscapes of deteriorating pancreatic islets in type 2 diabetic rats. Diabetes. 2017; 66: 2188-2200. doi: 10.2337/db16-1305Hou J, Li Z, Zhong W, Hao Q, Lei L, Wang L, et al. Temporal transcriptomic and proteomic landscapes of deteriorating pancreatic islets in type 2 diabetic rats. Diabetes. 2017; 66: 2188-2200. doi: 10.2337/db16-1305Moede T, Leibiger B, Sanchez PV, Dare E, Kohler M, Muhandiramlage TP, et al. Glucokinase intrinsically regulates glucose sensing and glucagon secretion in pancreatic alpha cells. Sci. Rep. 2020; 10: 20145. doi: 10.1038/s41598-020-76863-zMoede T, Leibiger B, Sanchez PV, Dare E, Kohler M, Muhandiramlage TP, et al. Glucokinase intrinsically regulates glucose sensing and glucagon secretion in pancreatic alpha cells. Sci. Rep. 2020; 10: 20145. doi: 10.1038/s41598-020-76863-zBahl V, May CL, Perez A, Glaser B, Kaestner KH. Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states. Mol. Metab. 2021; 49101193. doi: 10.1016/j.molmet.2021.101193Bahl V, May CL, Perez A, Glaser B, Kaestner KH. Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states. Mol. Metab. 2021; 49101193. doi: 10.1016/j.molmet.2021.101193Haddad D, Dsouza VS, Al-Mulla F, Al Madhoun A. New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment. Int J Mol Sci. 2024; 25(1): 571. doi: 10.3390/ijms25010571Haddad D, Dsouza VS, Al-Mulla F, Al Madhoun A. New-Generation Glucokinase Activators: Potential Game-Changers in Type 2 Diabetes Treatment. Int J Mol Sci. 2024; 25(1): 571. doi: 10.3390/ijms25010571Hussain S, Richardson E, Ma Y, Holton C, Backer ID, Buckley N, et al. Glucokinase activity in the arcuate nucleus regulates glucose intake. J. Clin. Invest. 2015; 125: 337-349. doi: 10.1172/JCI77172Hussain S, Richardson E, Ma Y, Holton C, Backer ID, Buckley N, et al. Glucokinase activity in the arcuate nucleus regulates glucose intake. J. Clin. Invest. 2015; 125: 337-349. doi: 10.1172/JCI77172Nakamura A, Omori K, Terauchi Y. Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes? Diabetes Obes. Metab. 2021; 23: 2199–2206. doi: 10.1111/dom.14459Nakamura A, Omori K, Terauchi Y. Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes? Diabetes Obes. Metab. 2021; 23: 2199–2206. doi: 10.1111/dom.14459Liu J, Fu H, Kang F, Ning G, Ni Q, Wang W, et al. β-Cell glucokinase expression was increased in type 2 diabetes subjects with better glycemic control. J. Diabetes. 2023; 15: 409-418. doi: 10.1111/1753-0407.13380Liu J, Fu H, Kang F, Ning G, Ni Q, Wang W, et al. β-Cell glucokinase expression was increased in type 2 diabetes subjects with better glycemic control. J. Diabetes. 2023; 15: 409-418. doi: 10.1111/1753-0407.13380Nakamura A, Terauchi Y. Present status of clinical deployment of glucokinase activators. J. Diabetes Investig. 2015; 6: 124–132. doi: 10.1111/jdi.12294Nakamura A, Terauchi Y. Present status of clinical deployment of glucokinase activators. J. Diabetes Investig. 2015; 6: 124–132. doi: 10.1111/jdi.12294Li C, Juliana CA, Yuan Y, Li M, Lu M, Chen P, et al. Phenotypic characterization of congenital hyperinsulinism due to novel activating glucokinase mutations. Diabetes. 2023; 72(12): 1809-1819. doi: 10.2337/db23-0465Li C, Juliana CA, Yuan Y, Li M, Lu M, Chen P, et al. Phenotypic characterization of congenital hyperinsulinism due to novel activating glucokinase mutations. Diabetes. 2023; 72(12): 1809-1819. doi: 10.2337/db23-0465Sarabu R, Berthel SJ, Kester RF, Tilley JW. Novel glucokinase activators: a patent review (2008– 2010). Expert Opin. Ther. Pat. 2011; 21: 13-33. doi: 10.1517/13543776.2011.542413Sarabu R, Berthel SJ, Kester RF, Tilley JW. Novel glucokinase activators: a patent review (2008– 2010). Expert Opin. Ther. Pat. 2011; 21: 13-33. doi: 10.1517/13543776.2011.542413Xu J, Lin S, Myers RW, Addona G, Berger JP, Campbell B, et al. Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus. Bioorg Med Chem Lett. 2017; 27(9): 2069-2073. doi: 10.1016/j.bmcl.2016.10.085Xu J, Lin S, Myers RW, Addona G, Berger JP, Campbell B, et al. Novel, highly potent systemic glucokinase activators for the treatment of Type 2 Diabetes Mellitus. Bioorg Med Chem Lett. 2017; 27(9): 2069-2073. doi: 10.1016/j.bmcl.2016.10.085Li W, Zhang X, Sun Y, Liu Z. Recent clinical advances of glucokinase activators in the treatment of diabetes mellitus type 2. Pharmazie. 2020; 75(6): 230-235. doi: 10.1691/ph.2020.0409Li W, Zhang X, Sun Y, Liu Z. Recent clinical advances of glucokinase activators in the treatment of diabetes mellitus type 2. Pharmazie. 2020; 75(6): 230-235. doi: 10.1691/ph.2020.0409Bloomgarden Z. Glucokinase and the potential of glucokinase activation in type 2 diabetes. J Diabetes. 2019; 11(8): 626-627. doi: 10.1111/1753-0407.12937Bloomgarden Z. Glucokinase and the potential of glucokinase activation in type 2 diabetes. J Diabetes. 2019; 11(8): 626-627. doi: 10.1111/1753-0407.12937Whitticar NV, Nunemaker CS. Reducing glucokinase activity to enhance insulin secretion: a counterintuitive theory to preserve cellular function and glucose homeostasis. Front Endocrinol. 2020; 11: 378. doi: 10.3389/fendo.2020.00378Whitticar NV, Nunemaker CS. Reducing glucokinase activity to enhance insulin secretion: a counterintuitive theory to preserve cellular function and glucose homeostasis. Front Endocrinol. 2020; 11: 378. doi: 10.3389/fendo.2020.00378Xu H, Sheng L, Chen W, Yuan F, Yang M, Li H, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: Results from a first-in-human single ascending dose study. Drug Des. Dev. Ther. 2016; 10: 1619–1626. doi: 10.2147/DDDT.S105021Xu H, Sheng L, Chen W, Yuan F, Yang M, Li H, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of novel glucokinase activator HMS5552: Results from a first-in-human single ascending dose study. Drug Des. Dev. Ther. 2016; 10: 1619–1626. doi: 10.2147/DDDT.S105021Yu Y, Yang X, Tong K, Yin S, Hu G, Zhang F, et al. Efficacy and safety of dorzagliatin for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis. Front. Cardiovasc. Med. 2022; 9: 1041044. doi: 10.3389/fcvm.2022.1041044Yu Y, Yang X, Tong K, Yin S, Hu G, Zhang F, et al. Efficacy and safety of dorzagliatin for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis. Front. Cardiovasc. Med. 2022; 9: 1041044. doi: 10.3389/fcvm.2022.1041044Zhu D, Zhang Y, Chen L. 182-OR: A novel dual-acting glucokinase activator (GKA) dorzagliatin (HMS5552) achieved primary efficacy endpoint with good safety profiles in T2DM patients after 24 weeks of treatment in a phase III monotherapy trial. Diabetes. 2020; 69(Suppl. S1): 182-OR. doi: 10.2337/db20-182-ORZhu D, Zhang Y, Chen L. 182-OR: A novel dual-acting glucokinase activator (GKA) dorzagliatin (HMS5552) achieved primary efficacy endpoint with good safety profiles in T2DM patients after 24 weeks of treatment in a phase III monotherapy trial. Diabetes. 2020; 69(Suppl. S1): 182-OR. doi: 10.2337/db20-182-ORZhu D, Li X, Ma J, Zeng J, Gan S, Dong X, et al. Dorzagliatin in drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 2022; 28: 965–973. doi: 10.1038/s41591-022-01802-6Zhu D, Li X, Ma J, Zeng J, Gan S, Dong X, et al. Dorzagliatin in drug-naive patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 2022; 28: 965–973. doi: 10.1038/s41591-022-01802-6Syed YY. Dorzagliatin: First Approval. Drugs. 2022; 82: 1745–1750. doi: 10.1007/s40265-022-01813-0Syed YY. Dorzagliatin: First Approval. Drugs. 2022; 82: 1745–1750. doi: 10.1007/s40265-022-01813-0Satin LS, Butler PC, Ha J, Sherman AS. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. Mol Aspects Med. 2015; 42: 61-77. doi: 10.1016/j.mam.2015.01.003Satin LS, Butler PC, Ha J, Sherman AS. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes. Mol Aspects Med. 2015; 42: 61-77. doi: 10.1016/j.mam.2015.01.003Cho J, Horikawa Y, Enya M, Takeda J, Imai Y, Handa H, et al. Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells. Commun Biol. 2020; 3: 497. doi: 10.1038/s42003-020-01226-3Cho J, Horikawa Y, Enya M, Takeda J, Imai Y, Handa H, et al. Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells. Commun Biol. 2020; 3: 497. doi: 10.1038/s42003-020-01226-3Cho J, Miyagawa A, Yamaguchi K, Abe W, Tsugawa Y, Yamamura H, et al. UDP-Glucose: A cereblon-dependent glucokinase protein degrader. Int. J. Mol. Sci. 2022; 23: 9094. doi: 10.3390/ijms23169094Cho J, Miyagawa A, Yamaguchi K, Abe W, Tsugawa Y, Yamamura H, et al. UDP-Glucose: A cereblon-dependent glucokinase protein degrader. Int. J. Mol. Sci. 2022; 23: 9094. doi: 10.3390/ijms23169094Yuan C, Zhang X, He Q, Li J, Lu J, Zou X. L-arginine stimulates CAT-1-mediated arginine uptake and regulation of inducible nitric oxide synthase for the growth of chick intestinal epithelial cells. Mol Cell Biochem. 2015; 399(1-2): 229-36. doi: 10.1007/s11010-014-2249-2Yuan C, Zhang X, He Q, Li J, Lu J, Zou X. L-arginine stimulates CAT-1-mediated arginine uptake and regulation of inducible nitric oxide synthase for the growth of chick intestinal epithelial cells. Mol Cell Biochem. 2015; 399(1-2): 229-36. doi: 10.1007/s11010-014-2249-2Bekes M, Langley DR, Crews CM. PROTAC targeted protein degraders: The past is prologue. Nat. Rev. Drug Dis. 2022; 21: 181–200. doi: 10.1038/s41573-021-00371-6Bekes M, Langley DR, Crews CM. PROTAC targeted protein degraders: The past is prologue. Nat. Rev. Drug Dis. 2022; 21: 181–200. doi: 10.1038/s41573-021-00371-6

The authors declare that there are no conflicts of interest present.