title: [Glucokinase and glucokinase regulatory proteins as molecular targets for novel antidiabetic drugs].
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.
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.|Moscow Institute of Physics and Technology (State University), Dolgoprudnyi, Moscow Region, 141700 Russia.|rubtsov@eimb.ru.
authors: P M
authors: PM
authors: Rubtsov
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia.|Moscow Institute of Physics and Technology (State University), Dolgoprudnyi, Moscow Region, 141700 Russia.
authors: E L
authors: EL
authors: Igudin
authors: Endocrinological Research Center, Ministry of Healthcare of the Russian Federation, Moscow, 117036 Russia.
authors: A N
authors: AN
authors: Tiulpakov
keywords: MODY; allosteric regulators; antidiabetic drugs; glucokinase; glucokinase activators; glucokinase regulatory protein; type-2 diabetes mellitus