Promising pharmacological targets for the treatment of the diseases associated with the impaired insulin receptor signaling pathway

Abstract

ОБЗОРЫСахарный диабет (СД) занимает одно из первых мест в мире среди наиболее распространенных хро-нических заболеваний. В ряд социально значимых заболеваний СД ставят такие его особенности, как большая частота встречаемости, высокий риск ин-валидизации и смертности больных. В 2013 г., по данным Международной диабетической федерации, численность больных СД в мире составила 386 млн человек. Учитывая темпы распространения заболе-вания, согласно прогнозам экспертов ВОЗ, число пациентов с диагнозом СД достигнет к 2035 г. 592 млн человек в основном за счет больных СД 2-го типа (СД2) [1]. По данным Минздрава России, уро-вень инвалидизации по причине СД составляет 2,1 случая на 100 тыс. населения [2].СД представляет собой гетерогенную группу ме-таболических расстройств, которые характеризуют-ся общим симптомом -хронической гиперглике-мией, а также абсолютным или относительным де-фицитом продукции инсулина, либо его действия [3]. СД 1-го типа возникает из-за недостаточной продукции инсулина вследствие потери функцио- Diabetes mellitus (DM) is one of the most widespread chronic diseases in the world. In DM type 2, peripheral tissues demonstrate strong resistance to endogenous insulin (insulin resistance) which is caused by impaired ability of the hormone to stimulate glucose uptake in target cells (muscle, adipose or brain tissue, liver, etc.) and to reduce blood glucose level. Research data suggest that all mentioned reasons are most likely to be based on a disruption of signal transduction from insulin receptor (IR) into insulin-dependent intracellular signaling cascades. Contemporary DM treatment strategy is aimed at the maintenance of optimal blood glucose level by improving insulin production and increasing insulin sensitivity of tissue as well as prevention of macro-and microvascular complications and decrease of their intensity. At the same time, the search for new targets for creation of innovative anti-diabetic compounds can be considered a promising task due to the optimization of existing approaches and development of the novel ones taking into account results of the latest research into DM etiology and pathogenesis. A special position among possible targets is occupied by insulin receptor (IR) and IR-associated signaling pathways. Belonging to tyrosine kinase receptor family, IR has been actively studied during the last decades. This review considers in particular the IR structure and functioning of receptor-associated signaling pathways. The paper contains data on novel ligand-mimetics and IR sensitizers as well as other molecules, which affect different components of IR-associated signaling pathways, thus exerting significant antidiabetic effect. Action of these compounds is aimed at improvement of basic metabolic disorders resulting in hyperglycemia and is mainly carried out due to the following effects: activation and potentiation of insulin signaling, increase of insulin sensitivity of peripheral tissues; recovery of insulin secretion physiological mechanisms; reduction of glucose production in liver.