葡萄糖激酶激活剂: 一类新型降糖药的最新研究进展

doi:10.5246/jcps.2026.02.008

摘要/Abstract

摘要：

2型糖尿病(T2DM)是一种发病机制复杂的代谢紊乱疾病, 单靶点治疗往往无法有效控制血糖水平。近年来, 抗糖尿病靶点葡萄糖激酶(Glucokinase, GK)引起了研究人员的关注, 它充当葡萄糖传感器, 在葡萄糖水平发生变化后触发反调节反应, 以帮助恢复正常血糖水平。GK的激活诱导葡萄糖代谢并降低葡萄糖水平以治疗2型糖尿病。葡萄糖激酶激活剂(GK activators, GKAs)是一类新型的抗糖尿病药物。本文对GK在糖尿病中的作用机制和GKAs在蛋白质水平上的作用机制, 以及GKAs使用的研究、趋势和前景进行了综述。

关键词: 2型糖尿病, 葡萄糖激酶, 葡萄糖激酶激活剂

Abstract:

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by multifactorial pathogenesis, in which therapies targeting a single mechanism often fail to achieve optimal glycemic control. In recent years, glucokinase (GK), a key regulatory enzyme in glucose homeostasis, has emerged as a promising anti-diabetic target, attracting considerable attention from researchers. Acting as a glucose sensor, GK initiates counter-regulatory responses in response to fluctuations in blood glucose, thereby contributing to the restoration and maintenance of normoglycemia. Activation of GK enhances glucose metabolism and lowers blood glucose levels, representing a potential therapeutic strategy for the management of type 2 diabetes. GK activators (GKAs), a novel class of anti-diabetic agents, have therefore garnered significant interest. This article provides a comprehensive review of the functional role of GK in diabetes, elucidates the mechanistic action of GKAs at the protein level, and summarizes current research progress, emerging trends, and prospects regarding the clinical application of GKAs.

Key words: Type 2 diabetes mellitus, Glucokinase, Glucokinase activators

Supporting:

李文汐, 方功, 张杰, 白娟. 葡萄糖激酶激活剂: 一类新型降糖药的最新研究进展[J]. 中国药学(英文版), 2026, 35(2): 115-130.

Wenxi Li, Gong Fang, Jie Zhang, Juan Bai. Advances in a novel class of hypoglycemic agents: glucokinase activators[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(2): 115-130.

图/表 4

参考文献 100

[1]	International Diabetes Federation. IDF Diabetes Atlas 10th edition [EB/OL]. (2022-12-12) [2023-08-25]. https://diabetesatlas.org/resources/.
[2]	Wang, P.; Liu, H.L.; Chen, L.; Duan, Y.L.; Chen, Q.L.; Xi, S.M. Effects of a novel glucokinase activator, HMS5552, on glucose metabolism in a rat model of type 2 diabetes mellitus. J. Diabetes Res. 2017, 2017, 5812607.
[3]	ElSayed, N.A.; Aleppo, G.; Aroda, V.R.; Bannuru, R.R.; Brown, F.M.; Bruemmer, D.; Collins, B.S.; Cusi, K.; Hilliard, M.E.; Isaacs, D.; Johnson, E.L.; Kahan, S.; Khunti, K.; Leon, J.; Lyons, S.K.; Perry, M.L.; Prahalad, P.; Pratley, R.E.; Seley, J.J.; Stanton, R.C.; Gabbay, R.A.; Association, A.D. Erratum. 4. comprehensive medical evaluation and assessment of comorbidities: Standards of care in diabetes: 2023. Diabetes care. 2023, 46 (suppl. 1) , S49–S67. Diabetes Care. 2023, 46, 1722.
[4]	Deshpande, A.D.; Harris-Hayes, M.; Schootman, M. Epidemiology of diabetes and diabetes-related complications. Phys. Ther. 2008, 88, 1254–1264.
[5]	Ellulu, M.S.; Samouda, H. Clinical and biological risk factors associated with inflammation in patients with type 2 diabetes mellitus. BMC Endocr. Disord. 2022, 22, 16.
[6]	Heller, S.R.; Peyrot, M.; Oates, S.K.; Taylor, A.D. Hypoglycemia in patient with type 2 diabetes treated with insulin: it can happen. BMJ Open Diabetes Res. Care. 2020, 8, e001194.
[7]	Susilawati, E.; Levita, J.; Susilawati, Y.; Sumiwi, S.A. Review of the case reports on metformin, sulfonylurea, and thiazolidinedione therapies in type 2 diabetes mellitus patients. Med. Sci. 2023, 11, 50.
[8]	Di Magno, L.; Di Pastena, F.; Bordone, R.; Coni, S.; Canettieri, G. The mechanism of action of biguanides: new answers to a complex question. Cancers. 2022, 14, 3220.
[9]	Lebovitz, H.E. Thiazolidinediones: the forgotten diabetes medications. Curr. Diabetes Rep. 2019, 19, 151.
[10]	Chiasson, J.L.; Josse, R.G.; Gomis, R.; Hanefeld, M.; Karasik, A.; Laakso, M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002, 359, 2072–2077.
[11]	Minis, E.; Stanford, F.C.; Mahalingaiah, S. Glucagon-like peptide-1 receptor agonists and safety in the preconception period. Curr. Opin. Endocrinol. Diabetes Obes. 2023, 30, 273–279.
[12]	Drucker, D.J.; Nauck, M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006, 368, 1696–1705.
[13]	Zaccardi, F.; Webb, D.R.; Htike, Z.Z.; Youssef, D.; Khunti, K.; Davies, M.J. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes. Metab. 2016, 18, 783–794.
[14]	Association, A.D. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetes: 2020. Diabetes Care. 2020, 43, S98–S110.
[15]	Doyle-Delgado, K.; Chamberlain, J.J.; Shubrook, J.H.; Skolnik, N.; Trujillo, J. Pharmacologic approaches to glycemic treatment of type 2 diabetes: synopsis of the 2020 American diabetes association’s standards of medical care in diabetes clinical guideline. Ann. Intern. Med. 2020, 173, 813–821.
[16]	Corathers, S.D.; Peavie, S.; Salehi, M. Complications of diabetes therapy. Endocrinol. Metab. Clin. N Am. 2013, 42, 947–970.
[17]	Atlas, D. International diabetes federation. In IDF Diabetes Atlas, 7th ed.; International Diabetes Federation: Brussels, Belgium, 2015, 33.
[18]	DeFronzo, R.A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009, 58, 773–795.
[19]	Wajchenberg, B.L. β-cell failure in diabetes and preservation by clinical treatment. Endocr. Rev. 2007, 28, 187–218.
[20]	Retnakaran, R.; Pu, J.J.; Emery, A.; Harris, S.B.; Reichert, S.M.; Gerstein, H.C.; McInnes, N.; Kramer, C.K.; Zinman, B. Determinants of sustained stabilization of β-cell function following short-term insulin therapy in type 2 diabetes. Nat. Commun. 2023, 14, 4514.
[21]	Wang, J.; Zhao, Z.N.; Xu, W.F. The first marketed glucokinase activator glucose-lowering drug-Dorzagliatin. Chin. Pharm. J. 2024, 59, 651–656.
[22]	Zhao, Z.N.; Shi, C.; Hu, X. Expert consensus on the pharmacy of glucokinase agonist dorzagliatin. Chin. J. Hosp. Pharm. 2024, 44, 245–250.
[23]	Girard, J.; Ferré, P.; Foufelle, F. Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Annu. Rev. Nutr. 1997, 17, 325–352.
[24]	Matschinsky, F.M. Regulation of pancreatic β-cell glucokinase. Diabetes. 2002, 51, S394–S404.
[25]	Deepa Maheshvare, M.; Raha, S.; König, M.; Pal, D. A pathway model of glucose-stimulated insulin secretion in the pancreatic β-cell. Front. Endocrinol. 2023, 14, 1185656.
[26]	Le Marchand, S.J.; Piston, D.W. Glucose suppression of glucagon secretion. J. Biol. Chem. 2010, 285, 14389–14398.
[27]	Campbell, J.E.; Newgard, C.B. Mechanisms controlling pancreatic islet cell function in insulin secretion. Nat. Rev. Mol. Cell Biol. 2021, 22, 142–158.
[28]	Theodorakis, M.J.; Carlson, O.; Michopoulos, S.; Doyle, M.E.; Juhaszova, M.; Petraki, K.; Egan, J.M. Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am. J. Physiol. Endocrinol. Metab. 2006, 290, E550–E559.
[29]	Matschinsky, F.M.; Wilson, D.F. 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.
[30]	Dunn-Meynell, A.A.; Routh, V.H.; Kang, L.; Gaspers, L.; Levin, B.E. Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes. 2002, 51, 2056–2065.
[31]	Han, H.S.; Kang, G.; Kim, J.S.; Choi, B.H.; Koo, S.H. Regulation of glucose metabolism from a liver-centric perspective. Exp. Mol. Med. 2016, 48, e218.
[32]	Nakamura, 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.
[33]	Liu, J.W.; Fu, H.; Kang, F.Y.; Ning, G.; Ni, Q.C.; Wang, W.Q.; Wang, Q.D. β-Cell glucokinase expression was increased in type 2 diabetes subjects with better glycemic control. J. Diabetes. 2023, 15, 409–418.
[34]	Willms, B.; Ben-Ami, P.; Söling, H. Hepatic enzyme activities of glycolysis and gluconeogenesis in diabetes of man and laboratory animals. Horm. Metab. Res. 1970, 2, 135–141.
[35]	Caro, J.; Triester, S.; Patel, V.; Tapscott, E.; Frazier, N.; Dohm, G. Liver glucokinase: decreased activity in patients with type II diabetes. Horm. Metab. Res. 1995, 27, 19–22.
[36]	Agius, L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem. J. 2008, 414, 1–18.
[37]	Van Schaftingen, E.; da-Cunha, M.V.; Niculescu, L. The regulatory protein of glucokinase. Biochem. Soc. Trans. 1997, 25, 136–140.
[38]	Shin, J.S.; Torres, T.P.; Catlin, R.L.; Donahue, E.P.; Shiota, M. A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 292, R1381–R1390.
[39]	Payne, V.A.; Arden, C.; Lange, A.J.; Agius, L. Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zucker fa/fa rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007, 293, R618–R625.
[40]	Hussain, K. Mutations in pancreatic ß-cell Glucokinase as a cause of hyperinsulinaemic hypoglycaemia and neonatal diabetes mellitus. Rev. Endocr. Metab. Disord. 2010, 11, 179–183.
[41]	Chakera, A.J.; Steele, A.M.; Gloyn, A.L.; Shepherd, M.H.; Shields, B.; Ellard, S.; Hattersley, A.T. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care. 2015, 38, 1383–1392.
[42]	Osbak, K.K.; Colclough, K.; Saint-Martin, C.; Beer, N.L.; Bellanné-Chantelot, C.; Ellard, S.; Gloyn, A.L. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum. Mutat. 2009, 30, 1512–1526.
[43]	Antal, Z. Maturity-onset diabetes of the young (MODY): genetic causes, clinical characteristics, considerations for testing, and treatment options. Endocrines. 2021, 2, 485–501.
[44]	Ellard, S.; Thomas, K.; Edghill, E.L.; Owens, M.; Ambye, L.; Cropper, J.; Little, J.; Strachan, M.; Stride, A.; Ersoy, B.; Eiberg, H.; Pedersen, O.; Shepherd, M.H.; Hansen, T.; Harries, L.W.; Hattersley, A.T. Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young. Diabetologia. 2007, 50, 2313–2317.
[45]	Sagen, J.V.; Bjørkhaug, L.; Molnes, J.; Raeder, H.; Grevle, L.; Søvik, O.; Molven, A.; Njølstad, P.R. Diagnostic screening of MODY2/GCKmutations in the Norwegian MODY registry. Pediatr. Diabetes. 2008, 9, 442–449.
[46]	Stanik, J.; Dusatkova, P.; Cinek, O.; Valentinova, L.; Huckova, M.; Skopkova, M.; Dusatkova, L.; Stanikova, D.; Pura, M.; Klimes, I.; Lebl, J.; Gasperikova, D.; Pruhova, S. De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia. 2014, 57, 480–484.
[47]	Agius, L. Targeting hepatic glucokinase in type 2 diabetes. Diabetes. 2009, 58, 18–20.
[48]	Scheen, A.J. New hope for glucokinase activators in type 2 diabetes? Lancet Diabetes Endocrinol. 2018, 6, 591–593.
[49]	Li, C.H.; Zhang, Y.; Chen, L.; Li, X.Y. Glucokinase and glucokinase activator. Life Metab. 2023, 2, load031.
[50]	Matschinsky, F.M. GKAs for diabetes therapy: why no clinically useful drug after two decades of trying? Trends Pharmacol. Sci. 2013, 34, 90–99.
[51]	Nakamura, A.; Terauchi, Y. Present status of clinical deployment of glucokinase activators. J. Diabetes Investig. 2015, 6, 124–132.
[52]	Scheen, A.J. Investigational insulin secretagogues for type 2 diabetes. Expert Opin. Investig. Drugs. 2016, 25, 405–422.
[53]	Zhu, D.L.; Gan, S.L.; Liu, Y.; Ma, J.H.; Dong, X.L.; Song, W.H.; Zeng, J.E.; Wang, G.X.; Zhao, W.J.; Zhang, Q.; Li, Y.K.; Fang, H.; Lv, X.F.; Shi, Y.Q.; Tian, H.M.; Ji, L.N.; Gao, X.; Zhang, L.H.; Bao, Y.Q.; Lei, M.X.; Li, L.; Zeng, L.Y.; Li, X.Y.; Hou, X.H.; Zhao, Y.; Hu, T.X.; Ge, X.Y.; Zhao, G.Y.; Li, Y.G.; Zhang, Y.; Chen, L. Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Diabetes Endocrinol. 2018, 6, 627–636.
[54]	Vella, A.; Freeman, J.L.R.; Dunn, I.; Keller, K.; Buse, J.B.; Valcarce, C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci. Transl. Med. 2019, 11, eaau3441.
[55]	Sheng, L.; Xu, H.R.; Chen, W.L.; Yuan, F.; Yang, M.J.; Li, H.; Li, X.-N.; Choi, J.; Zhao, G.Y.; Hu, T.H.; Li, Y.G.; Zhang, Y.; Chen, L. 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, 1619.
[56]	Grimsby, J.; Sarabu, R.; Corbett, W.L.; Haynes, N.E.; Bizzarro, F.T.; Coffey, J.W.; Guertin, K.R.; Hilliard, D.W.; Kester, R.F.; Mahaney, P.E.; Marcus, L.; Qi, L.D.; Spence, C.L.; Tengi, J.; Magnuson, M.A.; Chu, C.A.; Dvorozniak, M.T.; Matschinsky, F.M.; Grippo, J.F. Allosteric activators of glucokinase: potential role in diabetes therapy. Science. 2003, 301, 370–373.
[57]	Li, C. R&D strategies for type 2 diabetes: elucidate the underlying pathology and improve the impaired organ functions. Prog. Pharm. Sci. 2016, 40, 161–167.
[58]	Pfefferkorn, J.A.; Guzman-Perez, A.; Oates, P.J.; Litchfield, J.; Aspnes, G.; Basak, A.; Benbow, J.; Berliner, M.A.; Bian, J.W.; Choi, C.; Freeman-Cook, K.; Corbett, J.W.; Didiuk, M.; Dunetz, J.R.; Filipski, K.J.; Hungerford, W.M.; Jones, C.S.; Karki, K.; Ling, A.; Li, J.-C.; Patel, L.; Perreault, C.; Risley, H.; Saenz, J.; Song, W.; Tu, M.H.; Aiello, R.; Atkinson, K.; Barucci, N.; Beebe, D.; Bourassa, P.; Bourbounais, F.; Brodeur, A.M.; Burbey, R.; Chen, J.; D’Aquila, T.; Derksen, D.R.; Haddish-Berhane, N.; Huang, C.; Landro, J.; Lee Lapworth, A.; MacDougall, M.; Perregaux, D.; Pettersen, J.; Robertson, A.; Tan, B.J.; Treadway, J.L.; Liu, S.P.; Qiu, X.Y.; Knafels, J.; Ammirati, M.; Song, X.; DaSilva-Jardine, P.; Liras, S.; Sweet, L.; Rolph, T.P. Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical candidate for the treatment of type 2 diabetes mellitus. MedChemComm. 2011, 2, 828.
[59]	Liu, S.P.; Ammirati, M.J.; Song, X.; Knafels, J.D.; Zhang, J.; Greasley, S.E.; Pfefferkorn, J.A.; Qiu, X.Y. Insights into mechanism of glucokinase activation. J. Biol. Chem. 2012, 287, 13598–13610.
[60]	Bonadonna, R.C.; Heise, T.; Arbet-Engels, C.; Kapitza, C.; Avogaro, A.; Grimsby, J.; Zhi, J.; Grippo, J.F.; Balena, R. Piragliatin (RO4389620), a novel glucokinase activator, lowers plasma glucose both in the postabsorptive state and after a glucose challenge in patients with type 2 diabetes mellitus: a mechanistic study. J. Clin. Endocrinol. Metab. 2010, 95, 5028–5036.
[61]	Sarabu, R.; Bizzarro, F.T.; Corbett, W.L.; Dvorozniak, M.T.; Geng, W.P.; Grippo, J.F.; Haynes, N.E.; Hutchings, S.; Garofalo, L.; Guertin, K.R.; Hilliard, D.W.; Kabat, M.; Kester, R.F.; Ka, W.; Liang, Z.M.; Mahaney, P.E.; Marcus, L.; Matschinsky, F.M.; Moore, D.; Racha, J.; Radinov, R.; Ren, Y.; Qi, L.D.; Pignatello, M.; Spence, C.L.; Steele, T.; Tengi, J.; Grimsby, J. Discovery of piragliatin: first glucokinase activator studied in type 2 diabetic patients. J. Med. Chem. 2012, 55, 7021–7036.
[62]	Zhi, J.G.; Zhai, S.P. Effects of piragliatin, a glucokinase activator, on fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 2016, 56, 231–238.
[63]	Georgy, A.; Zhai, S.P.; Liang, Z.M.; Boldrin, M.; Zhi, J.G. Lack of potential pharmacokinetic and pharmacodynamic interactions between piragliatin, a glucokinase activator, and simvastatin in patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 2016, 56, 675–682.
[64]	Hale, C.; Lloyd, D.J.; Pellacani, A.; Véniant, M.M. Molecular targeting of the GK-GKRP pathway in diabetes. Expert Opin. Ther. Targets. 2015, 19, 129–139.
[65]	Raimondo, A.; Rees, M.G.; Gloyn, A.L. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Curr. Opin. Lipidol. 2015, 26, 88–95.
[66]	Egan, A.; Vella, A. TTP399: an investigational liver-selective glucokinase (GK) activator as a potential treatment for type 2 diabetes. Expert Opin. Investig. Drugs. 2019, 28, 741–747.
[67]	Vella, A.; Freeman, J.L.R.; Dunn, I.; Keller, K.; Buse, J.B.; Valcarce, C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci. Transl. Med. 2019, 11, eaau3441.
[68]	Buse, J.B.; Valcarce, C.; Freeman, J.L.; Dunn, I.; Dvergsten, C.; Sue Kirkman, M.; Kass, A.; Diner, J.; Bergamo, K.A. Simplici-T1: first clinical trial to test activation of glucokinase as an adjunctive treatment for type 1 diabetes. Diabetes. 2018, 67, 126–1LB.
[69]	Klein, K.R.; Freeman, J.L.R.; Dunn, I. The SimpliciT1 study: a randomized, double-blind, placebo-controlled phase 1b/2 adaptive study of TTP399, a hepatoselective glucokinase activator, for adjunctive treatment of type 1 diabetes. Diabetes Care. 2021, 44, 960–968.
[70]	Klein, K.R.; Boeder, S.C.; Freeman, J.L.R. Impact of the hepatoselective glucokinase activator TTP399 on ketoacidosis during insulin withdrawal in people with type 1 diabetes. Diabetes Obes. Metab. 2022, 24, 1439–1447.
[71]	Syed, Y.Y. Dorzagliatin: first approval. Drugs. 2022, 82, 1745–1750.
[72]	Committee of Expert Consensus on Clinical Application of Dorzagliatin. Expert consensus on clinical application of Dorzagliatin. Chin. J. Diabetes Mellitus. 2023, 15, 703–706.
[73]	Zhao, Z.N.; Shi, C.; Hu, X.; Jin, P. Expert consensus on the pharmacy of glucokinase agonist dorzagliatin. Chin. J. Hosp. Pharm. 2024, 44, 245–250.
[74]	Zhu, D.L.; Li, X.Y.; Ma, J.H.; Zeng, J.E.; Gan, S.L.; Dong, X.L.; Yang, J.; Lin, X.H.; Cai, H.Q.; Song, W.H.; Li, X.F.; Zhang, K.Q.; Zhang, Q.; Lu, Y.B.; Bu, R.F.; Shao, H.G.; Wang, G.X.; Yuan, G.Y.; Ran, X.W.; Liao, L.; Zhao, W.J.; Li, P.; Sun, L.; Shi, L.X.; Jiang, Z.S.; Xue, Y.M.; Jiang, H.W.; Li, Q.M.; Li, Z.B.; Fu, M.X.; Liang, Z.R.; Guo, L.; Liu, M.; Xu, C.; Li, W.H.; Yu, X.F.; Qin, G.J.; Yang, Z.; Su, B.L.; Zeng, L.Y.; Geng, H.F.; Shi, Y.Q.; Zhao, Y.; Zhang, Y.; Yang, W.Y.; Chen, L. Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 2022, 28, 965–973.
[75]	Yang, W.; Zhu, D.; Gan, S. Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 2022, 28, 974–981.
[76]	Zhu, D.L.; Gan, S.L.; Liu, Y.; Ma, J.H.; Dong, X.L.; Song, W.H.; Zeng, J.E.; Wang, G.X.; Zhao, W.J.; Zhang, Q.; Li, Y.K.; Fang, H.; Lv, X.F.; Shi, Y.Q.; Tian, H.M.; Ji, L.N.; Gao, X.; Zhang, L.H.; Bao, Y.Q.; Lei, M.X.; Li, L.; Zeng, L.Y.; Li, X.Y.; Hou, X.H.; Zhao, Y.; Hu, T.X.; Ge, X.Y.; Zhao, G.Y.; Li, Y.G.; Zhang, Y.; Chen, L. Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Diabetes Endocrinol. 2018, 6, 627–636.
[77]	Zhu, X.X.; Zhu, D.L.; Li, X.Y.; Li, Y.L.; Jin, X.W.; Hu, T.X.; Zhao, Y.; Li, Y.G.; Zhao, G.Y.; Ren, S.; Zhang, Y.; Ding, Y.H.; Chen, L. Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic β-cell function in patients with type 2 diabetes: a 28-day treatment study using biomarker-guided patient selection. Diabetes Obes. Metab. 2018, 20, 2113–2120.
[78]	Zeng, J.E.; Gan, S.L.; Mi, N.R.; Liu, Y.F.; Su, X.F.; Zhang, W.L.; Zhang, J.; Yu, F.; Dong, X.L.; Han, M.M.; Luo, J.F.; Zhang, Y.; Chen, L.; Ma, J.H. Diabetes remission in drug-naïve patients with type 2 diabetes after dorzagliatin treatment: a prospective cohort study. Diabetes Obes. Metab. 2023, 25, 2878–2887.
[79]	Chen, L.; Zhang, J.Y.; Sun, Y.; Zhao, Y.; Liu, X.; Fang, Z.Y.; Feng, L.G.; He, B.; Zou, Q.F.; Tracey, G.J. A phase I open-label clinical trial to study drug-drug interactions of Dorzagliatin and Sitagliptin in patients with type 2 diabetes and obesity. Nat. Commun. 2023, 14, 1405.
[80]	Miao, J.; Fu, P.; Ren, S.; Hu, C.; Wang, Y.; Jiao, C.F.; Li, P.; zhao, Y.; Tang, C.; Qian, Y.L.; Yang, R.; Dong, Y.L.; Rong, J.; Wang, Y.H.; Jin, X.W.; Sun, Y.; Chen, L. Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual-acting glucokinase activator. Clin. Transl. Sci. 2022, 15, 548–557.
[81]	Wang, K.; Feng, L.G.; Zhang, J.Y.; Zou, Q.F.; Xu, F.Y.; Sun, Z.Y.; Tang, F.X.; Chen, L. Population pharmacokinetic analysis of dorzagliatin in healthy subjects and patients with type 2 diabetes mellitus. Clin. Pharmacokinet. 2023, 62, 1413–1425.
[82]	Meininger, G.E.; Scott, R.; Alba, M.; Yue, S.T.; Luo, E.; Amin, H.; Davies, M.J.; Kaufman, K.D.; Goldstein, B.J. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care. 2011, 34, 2560–2566.
[83]	Ericsson, H.; Sjöberg, F.; Heijer, M.; Dorani, H.; Johansson, P.; Wollbratt, M.; Norjavaara, E. The glucokinase activator AZD6370 decreases fasting and postprandial glucose in type 2 diabetes mellitus patients with effects influenced by dosing regimen and food. Diabetes Res. Clin. Pract. 2012, 98, 436–444.
[84]	Ramanathan, V.; Vachharajani, N.; Patel, R.; Barbhiya, R. GKM-001, a liver-directed/pancreas-sparing glucokinase modulator (GKM), lowers fasting and post-prandial glucose without hypoglycemia in type 2 diabetic (T2D) patients. Diabetes. 2012, 61, A76.
[85]	Bunkholt Elstrand, M.; Dong, H.P.; Ødegaard, E.; Holth, A.; Elloul, S.; Reich, R.; Tropé, C.G.; Davidson, B. Mammalian target of rapamycin is a biomarker of poor survival in metastatic serous ovarian carcinoma. Hum. Pathol. 2010, 41, 794–804.
[86]	Bertelsen, B.I.; Steine, S.J.; Sandvei, R.; Molven, A.; Laerum, O.D. Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: Frequent PIK3CA amplification and AKT phosphorylation. Int. J. Cancer. 2006, 118, 1877–1883.
[87]	Itamochi, H.; Kigawa, J. Clinical trials and future potential of targeted therapy for ovarian cancer. Int. J. Clin. Oncol. 2012, 17, 430–440.
[88]	Tirmenstein, M.; Horvath, J.; Graziano, M.; Mangipudy, R.; Dorr, T.; Colman, K.; Zinker, B.; Kirby, M.; Cheng, P.T.W.; Patrone, L.; Kozlosky, J.; Reilly, T.P.; Wang, V.; Janovitz, E. Utilization of the zucker diabetic fatty (ZDF) rat model for investigating hypoglycemia-related toxicities. Toxicol. Pathol. 2015, 43, 825–837.
[89]	Amin, N.B.; Aggarwal, N.; Pall, D.; Paragh, G.; Denney, W.S.; Le, V.; Riggs, M.; Calle, R.A. Two dose-ranging studies with PF-04937319, a systemic partial activator of glucokinase, as add-on therapy to metformin in adults with type 2 diabetes. Diabetes Obes. Metab. 2015, 17, 751–759.
[90]	Denney, W.S.; Denham, D.S.; Riggs, M.R.; Amin, N.B. Glycemic effect and safety of a systemic, partial glucokinase activator, PF-04937319, in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomized, crossover, active-controlled study. Clin. Pharmacol. Drug Dev. 2016, 5, 517–527.
[91]	Kamimura, H.; Ito, S.; Chijiwa, H.; Okuzono, T.; Ishiguro, T.; Yamamoto, Y.; Nishinoaki, S.; Ninomiya, S.I.; Mitsui, M.; Kalgutkar, A.S.; Yamazaki, H.; Suemizu, H. Simulation of human plasma concentration–time profiles of the partial glucokinase activator PF-04937319 and its disproportionate N-demethylated metabolite using humanized chimeric mice and semi-physiological pharmacokinetic modeling. Xenobiotica. 2017, 47, 382–393.
[92]	Hale, C.; Lloyd, D.J.; Pellacani, A.; Véniant, M.M. Molecular targeting of the GK-GKRP pathway in diabetes. Expert Opin. Ther. Targets. 2015, 19, 129–139.
[93]	Kiyosue, A.; Hayashi, N.; Komori, H.; Leonsson-Zachrisson, M.; Johnsson, E. Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 2013, 15, 923–930.
[94]	Grimsby, J.; Sarabu, R.; Corbett, W.L.; Haynes, N.E.; Bizzarro, F.T.; Coffey, J.W.; Guertin, K.R.; Hilliard, D.W.; Kester, R.F.; Mahaney, P.E.; Marcus, L.; Qi, L.D.; Spence, C.L.; Tengi, J.; Magnuson, M.A.; Chu, C.A.; Dvorozniak, M.T.; Matschinsky, F.M.; Grippo, J.F. Allosteric activators of glucokinase: potential role in diabetes therapy. Science. 2003, 301, 370–373.
[95]	Georgy, A.; Zhai, S.P.; Liang, Z.M.; Boldrin, M.; Zhi, J.G. Lack of potential pharmacokinetic and pharmacodynamic interactions between piragliatin, a glucokinase activator, and simvastatin in patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 2016, 56, 675–682.
[96]	Katz, L.; Manamley, N.; Snyder, W.J.; Dodds, M.; Agafonova, N.; Sierra-Johnson, J.; Cruz, M.; Kaur, P.; Mudaliar, S.; Raskin, P.; Kewalramani, R.; Pellacani, A. AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. Diabetes Obes. Metab. 2016, 18, 191–195.
[97]	McVean, M.; Aicher, T.D.; Boyd, S.A. In combination therapy of ARRY-403 with metformin, sitagliptin or pioglitazone results in additive glucose lowering in female ZDF rats. Keystone Symposium: Type 2 Diabetes and Insulin Resistance. Banff, AB, Canada. 2009, 20–25.
[98]	Chung, J.; Alvarez-Nunez, F.; Chow, V.; Daurio, D.; Davis, J.; Dodds, M.; Emery, M.; Litwiler, K.; Paccaly, A.; Peng, J.; Rock, B.; Wienkers, L.; Yang, C.; Yu, Z.G.; Wahlstrom, J. Utilizing physiologically based pharmacokinetic modeling to inform formulation and clinical development for a compound with pH-dependent solubility. J. Pharm. Sci. 2015, 104, 1522–1532.
[99]	Aicher, T.D.; Anderson, D.; Boyd, S.A. ARRY-403, a novel glucokinase activator with potent glucose-dependent antihyperglycemic activity in animal models of type 2 diabetes mellitus. Keystone Symposium: Type 2 Diabetes and Insulin Resistance. Banff, AB, Canada. 2009.
[100]	Tsumura, Y.; Tsushima, Y.; Tamura, A.; Hasebe, M.; Kanou, M.; Kato, H.; Kobayashi, T. TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models. PLoS One. 2017, 12, e0172252.