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Glucokinase activators — a promising class of antidiabetic drugs

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Abstract


Type 2 diabetes mellitus is an urgent problem of the modern healthcare. Despite a wide choice of oral hypoglycemic drugs, today there is a great need to create and introduce into clinical practice new, effective, and safe drugs for the treatment of diabetes. One of the promising targets for the creation of new antidiabetics is a glucokinase. It has an exceptionally high influence on glucose homeostasis, serving as a glucose “sensor” in pancreatic β-cells and controlling the rate of glycogen synthesis in the liver. In the present work, the molecular-genetic structure of the enzyme, as well as its interrelation with the organs and tissues of the organism, is presented. The modern ideas about activators of glucokinase as a promising class of antidiabetic drugs are outlined, their hypoglycemic and general antidiabetic effects proved in preclinical and clinical studies are considered. The most advanced activators of glucokinase, undergoing clinical trials, are indicated.


Alexander A. Spasov

Volgograd State Medical University

Author for correspondence.
Email: aspasov@mail.ru
ORCID iD: 0000-0002-7185-4826
SPIN-code: 8777-1303

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

MD, PhD, Professor

Vadim A. Kosolapov

Volgograd State Medical University

Email: vad-ak@mail.ru
ORCID iD: 0000-0002-6702-1207
SPIN-code: 3844-0149

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

MD, PhD, Professor

Denis A. Babkov

Volgograd State Medical University

Email: denis.a.babkov@gmail.com
ORCID iD: 0000-0002-9645-3324
SPIN-code: 6193-9704

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

PhD

Olga Yu. Mayka

Volgograd State Medical University

Email: 9889800088@mail.ru
ORCID iD: 0000-0003-3559-004X
SPIN-code: 6229-4052

Russian Federation, 1, Pavshikh Bortsov Sq., Volgograd, 400131

Аспирант каф. фармакологии ВолгГМУ

  • World Health Organisation [Internet]. World Health Day 2016: Beat diabetes [cited 2017 May 05]. Available from: http://www.who.int/campaigns/world-health-day/2016/en/
  • World Health Organisation [Internet]. Global health risks: Mortality and global health estimates [cited 2017 May 05]. Available from: www.who.int/gho/mortality_burden_disease/en/
  • Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442. doi: 10.1371/journal.pmed.0030442.
  • World Health Organization.Global status report on noncommunicable diseases2010. Geneva: World Health Organization; 2011.
  • Leighton B, Atkinson A, Coghlan MP. Small molecule glucokinase activators as novel anti-diabetic agents. Biochem Soc Trans. 2005;33(Pt 2):371-374. doi: 10.1042/BST0330371.
  • Deshpande AM, Bhuniya D, De S, et al. Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia. Eur J Med Chem. 2017;133:268-286. doi: 10.1016/j.ejmech.2017.03.042.
  • Paczal A, Balint B, Weber C, et al. Structure-activity relationship of azaindole-based glucokinase activators. J Med Chem. 2016;59(2):687-706. doi: 10.1021/acs.jmedchem.5b01594.
  • Min Q, Cai X, Sun W, et al. Identification of mangiferin as a potential glucokinase activator by structure-based virtual ligand screening. Sci Rep. 2017;7:44681. doi: 10.1038/srep44681.
  • Xu J, Lin S, Myers RW, et al. Discovery of orally active hepatoselective glucokinase activators for treatment of type II diabetes mellitus. Bioorg Med Chem Lett. 2017;27(9):2063-2068. doi: 10.1016/j.bmcl.2016.10.088.
  • Matschinsky FM, Porte D. Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics. F1000 Med Rep. 2010;2. doi: 10.3410/M2-43.
  • Kamata K, Mitsuya M, Nishimura T, et al. Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure. 2004;12(3):429-438. doi: 10.1016/j.str.2004.02.005.
  • Matschinsky FM, Zelent B, Doliba N, et al. Glucokinase activators for diabetes therapy: May 2010 status report. Diabetes Care. 2011;34(Suppl 2):S236-S243. doi: 10.2337/dc11-s236.
  • Reid S, Masters C. On the developmental properties and tissue interactions of hexokinase. Mech Ageing Dev. 1985;31(2):197-212. doi: 10.1016/s0047-6374(85)80030-0.
  • Coghlan M, Leighton B. Glucokinase activators in diabetes management. Expert Opin Investig Drugs. 2008;17(2):145-167. doi: 10.1517/13543784.17.2.145.
  • Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene. 2006;25(34):4683-4696. doi: 10.1038/sj.onc.1209595.
  • Schober E, Rami B, Grabert M, et al. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabet Med. 2009;26(5):466-473. doi: 10.1111/j.1464-5491.2009.02720.x.
  • Спасов А.А., Косолапов В.А., Бабков Д.А., Майка О.Ю. Влияние агониста рецептора GPR119 соединения MBX-2982 на активность глюкокиназы человека. // Бюллетень экспериментальной биологии и медицины. — 2017. — Т. 163. — № 5. — С. 657—660. [Spasov AA, Kosolapov VA, Babkov DA, Maika OY. Effect of GRP119 Receptor Agonist, Compound MBX-2982, on Activity of Human Glucokinase. Biull Eksp Biol Med. 2017;163(5):695-698. (In Russ.)]. doi: 10.1007/s10517-017-3881-0.
  • Rees MG, Gloyn AL. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour? Br J Pharmacol. 2013;168(2):335-338. doi: 10.1111/j.1476-5381.2012.02201.x.
  • Alexander B, Browse DJ, Reading SJ, Benjamin IS. A simple and accurate mathematical method for calculation of the EC50. J Pharmacol Toxicol Methods. 1999;41(2-3):55-58. doi: 10.1016/s1056-8719(98)00038-0.
  • Ishikawa M, Nonoshita K, Ogino Y, et al. Discovery of novel 2-(pyridine-2-yl)-1H-benzimidazole derivatives as potent glucokinase activators. Bioorg Med Chem Lett. 2009;19(15):4450-4454. doi: 10.1016/j.bmcl.2009.05.038.

Supplementary files

Supplementary Files Action
1. Fig. 1. Organs and tissues expressing HA, and their relationship to each other. View (141KB) Indexing metadata
2. Fig. 2. Conformational cycles of glucokinase. View (67KB) Indexing metadata
3. Fig. 3. Participation of glucokinase in the regulation of β-cell mass. View (105KB) Indexing metadata
4. Fig. 4. Structural model of glucokinase. The centers of binding of activators of glucokinase and glucose are noted. View (92KB) Indexing metadata
5. Fig. 5. Mechanism of action of activators of glucokinase on the liver and pancreas. View (112KB) Indexing metadata

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Copyright (c) 2018 Spasov A.A., Kosolapov V.A., Babkov D.A., Mayka O.Y.

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