Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

Khunti K, Ceriello A, Cos X, De Block C. Achievement of guideline targets for blood pressure, lipid, and glycaemic control in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract. 2018;137:137–48.

Article  PubMed  Google Scholar 

Matschinsky 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.

Article  PubMed  PubMed Central  Google Scholar 

Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM, et al. Characterization of glucokinase regulatory protein-deficient mice. J Biol Chem. 2000;275(11):7826–31.

Article  CAS  PubMed  Google Scholar 

Velho G, Froguel P, Clement K, Pueyo ME, Rakotoambinina B, Zouali H, et al. Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young. Lancet. 1992;340(8817):444–8.

Article  CAS  PubMed  Google Scholar 

Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998;338(4):226–30.

Article  CAS  PubMed  Google Scholar 

Zečević K, Volčanšek Š, Katsiki N, Rizzo M, Milardović TM, Stoian AP, et al. Maturity-onset diabetes of the young (MODY)—in search of ideal diagnostic criteria and precise treatment. Progress Cardiovasc Dis. 2024. https://doi.org/10.1016/j.pcad.2024.03.004.

Article  Google Scholar 

Chow E, Wang K, Lim CKP, Tsoi STF, Fan B, Poon E, et al. Dorzagliatin, a dual-acting glucokinase activator, increases insulin secretion and glucose sensitivity in glucokinase maturity-onset diabetes of the young and recent-onset type 2 diabetes. Diabetes. 2023;72(2):299–308.

Article  CAS  PubMed  Google Scholar 

Meininger GE, Scott R, Alba M, Shentu Y, Luo E, Amin H, et al. Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes. Diabetes Care. 2011;34(12):2560–6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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(10):923–30.

Article  CAS  PubMed  Google Scholar 

Katz L, Manamley N, Snyder WJ, Dodds M, Agafonova N, Sierra-Johnson J, et al. AMG 151 (ARRY-403), a novel glucokinase activator, decreases fasting and postprandial glycaemia in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(2):191–5.

Article  CAS  PubMed  Google Scholar 

Vella A, Freeman JLR, Dunn I, Keller K, Buse JB, Valcarce C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aau3441.

Article  PubMed  Google Scholar 

Zhu D, Gan S, Liu Y, Ma J, Dong X, Song W, et al. 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(8):627–36.

Article  CAS  PubMed  Google Scholar 

Futamura M, Hosaka H, Kadotani A, Shimazaki H, Sasaki K, Ohyama S, et al. An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. J Biol Chem. 2006;281(49):37668–74.

Article  CAS  PubMed  Google Scholar 

Hale C, Lloyd DJ, Pellacani A, Veniant MM. Molecular targeting of the GK-GKRP pathway in diabetes. Expert Opin Ther Targets. 2015;19(1):129–39.

Article  CAS  PubMed  Google Scholar 

Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963;1(7285):785–9.

Article  CAS  PubMed  Google Scholar 

Toulis KA, Nirantharakumar K, Pourzitaki C, Barnett AH, Tahrani AA. Glucokinase activators for type 2 diabetes: challenges and future developments. Drugs. 2020;80(5):467–75.

Article  CAS  PubMed  Google Scholar 

Lloyd DJ, St Jean DJ Jr, Kurzeja RJ, Wahl RC, Michelsen K, Cupples R, et al. Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors. Nature. 2013;504(7480):437–40.

Article  CAS  PubMed  Google Scholar 

Filipski KJ, Pfefferkorn JA. A patent review of glucokinase activators and disruptors of the glucokinase–glucokinase regulatory protein interaction: 2011–2014. Expert Opin Ther Pat. 2014;24(8):875–91.

Article  CAS  PubMed  Google Scholar 

Brouwers M, Jacobs C, Bast A, Stehouwer CDA, Schaper NC. Modulation of glucokinase regulatory protein: a double-edged sword? Trends Mol Med. 2015;21(10):583–94.

Article  CAS  PubMed  Google Scholar 

Raimondo A, Rees MG, Gloyn AL. Glucokinase regulatory protein: complexity at the crossroads of triglyceride and glucose metabolism. Curr Opin Lipidol. 2015;26(2):88–95.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Galiero R, Caturano A, Vetrano E, Cesaro A, Rinaldi L, Salvatore T, et al. Pathophysiological mechanisms and clinical evidence of relationship between Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease. Rev Cardiovasc Med. 2021;22(3):755–68.

Article  PubMed  Google Scholar 

Softic S, Cohen DE, Kahn CR. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci. 2016;61(5):1282–93.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhu D, Li X, Ma J, Zeng J, Gan S, Dong X, et al. Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med. 2022;28(5):965–73.

Article  CAS  PubMed  Google Scholar 

Yang W, Zhu D, Gan S, Dong X, Su J, Li W, et al. 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(5):974–81.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Klein KR, Freeman JLR, Dunn I, Dvergsten C, Kirkman MS, Buse JB, et al. 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(4):960–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wang K, Shi M, Huang C, Fan B, Luk AOY, Kong APS, et al. Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis. Cardiovasc Diabetol. 2022;21(1):192.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan J, et al. The trans-ancestral genomic architecture of glycemic traits. Nat Genet. 2021;53(6):840–60.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis. PLoS Med. 2020;17(3): e1003062.

Article  PubMed  PubMed Central  Google Scholar 

Ghodsian N, Abner E, Emdin CA, Gobeil É, Taba N, Haas ME, et al. Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease. Cell Rep Med. 2021;2(11): 100437.

Article  CAS

Comments (0)

No login
gif