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Rubtsov PM, Igudin EL, Tiulpakov AN. [Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs]. Mol Biol (Mosk). 2015;49(4):555-60doi: 10.7868/S002689841504014X.
Rubtsov, P. M., Igudin, E. L., & Tiulpakov, A. N. (2015). [Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs]. Molekuliarnaia biologiia, 49(4), 555-60. https://doi.org/10.7868/S002689841504014X
Rubtsov, P M, et al. "[Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs]." Molekuliarnaia biologiia vol. 49,4 (2015): 555-60. doi: https://doi.org/10.7868/S002689841504014X
Rubtsov PM, Igudin EL, Tiulpakov AN. [Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs]. Mol Biol (Mosk). 2015 Jul-Aug;49(4):555-60. doi: 10.7868/S002689841504014X. Russian. PMID: 26299854.
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Mol Biol (Mosk). 2015 Jul-Aug;49(4):555-60. doi: 10.7868/S002689841504014X.

[Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs].

Molekuliarnaia biologiia

[Article in Russian]
P M Rubtsov, E L Igudin, A N Tiulpakov

Affiliations

  1. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.
  2. Moscow Institute of Physics and Technology (State University), Dolgoprudnyi, Moscow Region, 141700 Russia.
  3. [email protected].
  4. Endocrinological Research Center, Ministry of Healthcare of the Russian Federation, Moscow, 117036 Russia.

PMID: 26299854 DOI: 10.7868/S002689841504014X

Abstract

The impairment of glucose homeostasis leads to hyperglycemia and type-2 diabetes mellitus. Glucokinase (GK), an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate in pancreatic ß-cells, liver hepatocytes, specific hypothalamic neurons, and intestine enterocytes, is a key regulator of glucose homeostasis. In hepatocytes, GK controls the glucose uptake and glycogen synthesis and inhibits the glucose synthesis via the gluconeogenesis pathway. Glucokinase regulatory protein (GKRP) synthesized in hepatocytes acts as an endogenous GK inhibitor. During fasting, GKRP binds GK, inactivates it, and transports it into the cell nucleus, thus isolating it from the hepatocyte carbohydrate metabolism. In the beginning of the 2000s, the research was mainly focused on the development and trials of the small molecule GK activators as potential antidiabetic glucose-lowering drugs. However, the use of such substances increased the risk of hypoglycemia, and clinical studies of most synthetic GK activators are currently discontinued. Allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents increasing the GK activity that can substitute GKA. In this review, we discuss the recent advances and the current state of art in the development of potential antidiabetic drugs targeted to GK as a key regulator of glucose homeostasis.

Keywords: MODY; allosteric regulators; antidiabetic drugs; glucokinase; glucokinase activators; glucokinase regulatory protein; type-2 diabetes mellitus

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