Signaling pathways of β-cell death in type 2 diabetes mellitus: the role of innate immunity
https://doi.org/10.14341/DM10242
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disease, the development of which is mediated by both genetic disorders and various intracellular and extracellular molecular processes. One of the main pathogenetic mechanisms for the development of T2DM is a progressive decrease in the mass and functional reserve of β-cells, which largely determines the course of T2DM. The mechanisms of action of most sugar-lowering drugs are associated with increased secretion of insulin, so it is obvious that the effectiveness of the therapy will also largely depend on the functional state of β-cells. All this explains the great interest in studying the mechanisms of damage of β-cells in T2DM and factors that can accelerate this process, leading to their death and the development of a relative and then absolute insulin deficiency. The mechanisms of dysfunction β-cells in T2DM have not been studied much. This article provides an overview of the data of domestic and foreign literature of recent years on the molecular, intracellular features of various mechanisms of damage and death of β-cells in type 2 diabetes. The results of studies aimed at studying the possible factors and processes leading to their launch are presented.
About the Authors
Zilya. A. Kalmykovа
Endocrinology Research Centre
Russian Federation
Russian Federation
MD, PhD student
Irina V. Kononenko
Endocrinology Research Centre
Russian Federation
Russian Federation
MD, PhD, leading research associate
Olga M. Smirnova
Endocrinology Research Centre
Russian Federation
Russian Federation
MD, PhD, Professor, chief research associate
Marina Vladimirovna Shestakova
Endocrinology Research Centre
Russian Federation
Russian Federation
MD, PhD, Professor
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Supplementary files
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1. Fig. 1. Programmable cell death of β-cells in type 2 diabetes mellitus: FASL - FAS ligand; FAS - death receptor from the family of tumor necrosis factors (TNF); TRAIL - TNF-inducing ligand (tumor-necrosis-factor-related apoptosis-inducing ligand); TNF - tumor necrosis factor; DISC - death induction signaling complex; FADD - receptor-linked adapter protein (FAS receptor associated death domen); SR - free radicals; OS - oxidative stress; CHOP is a transcription factor involved in the regulation of apoptosis; Bax, Bak, Bad-family of proapoptotic proteins; Bcl - a family of anti-apoptogenic proteins; ER - endoplasmic reticulum; SER - ER stress; GRP94 - glucose-regulated protein, chaperone; ORP150 - oxygen-regulated protein, chaperone; BIP - immunoglobulin binding protein, chaperone (binding immunoglobulin protein); PERK, IRE1, ATF6 - “ER stress sensors” - transmembrane proteins having a regulatory domain immersed in the lumen of the ER; PERK - PKR-like kinase of the endoplasmic reticulum (pancreatic endoplasmic reticulum kinase); IRE1 - type 1 inositol-dependent enzyme; ATF6 - activating transcription factor 6; TXNIP - thioredoxin-interacting protein (thioredoxin-interacting protein); PAMPs - pathogen-associated molecular patterns (pathogen-associated molecular patterns); DAMPs - molecules released during tissue damage (damage-associated molecular-pattern molecules); P2X7 - purinergic receptor; NLRP3 - containing the NACHT, LRR and PYD domains protein 3 (NACHT, LRR and PYD domains-containing protein 3); ASC - adapter molecule of the NLRP3-inflammasome (apoptosis associated speck-like protein containing a CARD); IL-1β - interleukin 1 beta; IL-18 - interleukin 18; AMPK - AMP-activated protein kinase (AMP-activated protein kinase); mTOR — mammalian rapamycin target (mammalian Target Of Rapamycin); mTORC-1 - mTOR complex 1 (mTOR complex 1); Atg - a family of proteins associated with autophagy (autophagy-related protein); PI3K-1 - phosphatidylinositol-3-kinase-1 (phosphatidylinositol-3-kinase); LC3 - autophagy protein (light chain 3); CNG - end products of glycation. | |
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2. Fig. 2. The process of initiation of autophagy of β-cells in type 2 diabetes mellitus: CNG - end glycation products; OS - oxidative stress; ER - endoplasmic reticulum; SER - ER stress; AMPK - AMP-activated protein kinase (AMP-activated protein kinase); mTOR — mammalian rapamycin target (mammalian Target Of Rapamycin); mTORC-1 - mTOR complex 1 (mTOR complex 1); Atg - a family of proteins associated with autophagy (autophagy-related protein); ACT - protein kinase B; PDK1 - pyruvate dehydrogenase kinase, isoform 1 (phosphoinositide-dependent protein kinase-1); PI3K-1 - phosphatidylinositol-3-kinase-1 (phosphatidylinositol-3-kinase); LC - autophagy proteins (light chain); ULK - Unc-51-like kinase (Unc-51-Like Kinase); Beclin - autophagy cell system protein; FIP200 is a protein interacting with the FAK family of 200 kDa (FAK family-interacting protein of 200 kDa). | |
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3. Fig. 3. The structure of the NLRP3 inflammasomes: LRR is a domain containing a leucine-rich repeat domain; NAD - NBD-associated domain (NBD-associated domain); NACHT - protein, inhibiting neuronal apoptosis (neuronal apoptosis inhibitory protein); ASC is an adapter molecule containing CARD and PYD domains (apoptosis associated speck-like protein containing a CARD). | |
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Review
For citations:
Kalmykovа Z.A., Kononenko I.V., Smirnova O.M., Shestakova M.V. Signaling pathways of β-cell death in type 2 diabetes mellitus: the role of innate immunity. Diabetes mellitus. 2020;23(2):174-184. (In Russ.) https://doi.org/10.14341/DM10242
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