Role of Neuronal Guidance Cues in the Pathophysiology of Obesity: A Peripheral and Central Overview

2021 ◽  
Vol 27 ◽  
Author(s):  
Daniela Sayuri Inoue ◽  
Mohammad Fauzan Bin Maideen ◽  
Alberto Jiménez-Maldonado ◽  
Fábio Santos Lira
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Diseases ◽  
Low Grade ◽  
Obese Patients ◽  
Guidance Cues ◽  
Integrative View ◽  
New Treatments ◽  
Neuronal Guidance

: Obesity is associated with an exacerbated synthesis and secretion of several molecules, which culminates in chronic low-grade inflammation and insulin resistance. Such conditions affect molecular and physiological responses of several organs and, if not resolved, predispose to the obese patients to suffer other diseases such as Type 2 diabetes, atherosclerosis, cancer, neural injuries, and cognitive impairments. A microenvironment with an excess of pro-inflammatory cytokines released by different cells, including immune and adipose cells lead to suffer metabolic and non-metabolic diseases during obesity. In this context, the role of neuronal guidance cues named netrin, semaphorin and ephrin is novel. Specifically, the available literature indicates that besides to their classic role as molecules that guide to the axon with its target site, the neuronal guidance cues exhibit immunomodulatory functions from adipose tissue to the neural environment. In the current narrative review, we discuss the participation of the neuronal guidance cues on the physiology and pathophysiology of obesity. We also discuss the feedback loop of the obesity on the netrin, semaphorin and ephrin functions that impair the structure and function of the brain. The integrative view of the neuronal guidance cues can be relevant to design new treatments focused to attenuate metabolic and immune disorders that suffering obese patients, and lead to them to acquire worse diseases such as Type 2 diabetes, atherosclerosis, cancer, and neural injuries.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

2015 ◽  
Vol 172 (4) ◽  
pp. R167-R177 ◽  
Author(s):  
Kristine H Allin ◽  
Trine Nielsen ◽  
Oluf Pedersen
Keyword(s):  
Type 2 Diabetes ◽  
Gut Microbiota ◽  
Metabolic Diseases ◽  
Short Chain Fatty Acids ◽  
Intestinal Content ◽  
Low Grade ◽  
Bacterial Fermentation ◽  
Underlying Mechanisms

Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have demonstrated several underlying mechanisms including host signalling through bacterial lipopolysaccharides derived from the outer membranes of Gram-negative bacteria, bacterial fermentation of dietary fibres to short-chain fatty acids and bacterial modulation of bile acids. On top of this, an increased permeability of the intestinal epithelium may lead to increased absorption of macromolecules from the intestinal content resulting in systemic immune responses, low-grade inflammation and altered signalling pathways influencing lipid and glucose metabolism. While mechanistic studies on mice collectively support a causal role of the gut microbiota in metabolic diseases, the majority of studies in humans are correlative of nature and thus hinder causal inferences. Importantly, several factors known to influence the risk of type 2 diabetes, e.g. diet and age, have also been linked to alterations in the gut microbiota complicating the interpretation of correlative studies. However, based upon the available evidence, it is hypothesised that the gut microbiota may mediate or modulate the influence of lifestyle factors triggering development of type 2 diabetes. Thus, the aim of this review is to critically discuss the potential role of the gut microbiota in the pathophysiology and pathogenesis of type 2 diabetes.

scholarly journals THE ROLE OF AMPK AND MTOR IN THE DEVELOPMENT OF INSULIN RESISTANCE AND TYPE 2 DIABETES. THE MECHANISM OF METFORMIN ACTION (literature review)

2016 ◽  
Vol 57 (3) ◽  
pp. 77-90
Author(s):  
V. M. Pushkarev ◽  
L. K. Sokolova ◽  
V. V. Pushkarev ◽  
M. D. Tronko
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Literature Review ◽  
Metabolic Diseases ◽  
Mechanisms Of Action ◽  
Low Grade ◽  
Biochemical Mechanisms ◽  
Low Grade Inflammation

It was analyzed the cellular and molecular links between chronic low-grade inflammation and caused by inflammation insulin resistance and type 2 diabetes. Particular emphasis is placed on the participation of AMPK and mTORC1 in the development of metabolic diseases caused by obesity. A detailed analysis of the biochemical mechanisms of action of the main drug used in the treatment of insulin resistance and type 2 diabetes — metformin.

scholarly journals The role of selected mechanisms of innate immunity in the pathogenesis of diabetes

2021 ◽  
Vol 11 (9) ◽  
pp. 544-549
Author(s):  
Paulina Trojanowska ◽  
Magdalena Chrościńska-Krawczyk ◽  
Alina Trojanowska ◽  
Ewa Tywanek ◽  
Jakub Wronecki ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Metabolic Diseases ◽  
Inflammatory Diseases ◽  
The Body ◽  
Low Grade ◽  
Intracellular Space ◽  
Cytoplasmic Proteins

Understanding the important role of the non-specific immune response in protecting the body against the development of numerous diseases has become partially possible after the discovery of several classes of pattern recognition receptors (PRR), such as Toll-like or NOD-like receptors. A group of cytoplasmic proteins called the inflammasome, which detect PAMP and DAMP through the PRR receptors, is able to activate pro-inflammatory cytokines and trigger an acute inflammatory reaction both in the extracellular and intracellular space. Low-grade systemic and local inflammation contributes to the development and progression of various conditions, including autoimmune and metabolic diseases, such as diabetes, metabolic syndrome and atherosclerosis, which until recently were not even considered inflammatory diseases. This review will discuss the role of innate immunity in the development of type 1 and type 2 diabetes, focusing on the role of specific innate immunity receptors and insulin resistance involved in these diseases pathogenesis.

Role of Circulating Microparticles in Type 2 Diabetes Mellitus: Implications for Pathological Clotting

2021 ◽  
Author(s):  
Siphosethu Cassandra Maphumulo ◽  
Etheresia Pretorius
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Systemic Inflammation ◽  
Blood Cells ◽  
Low Grade ◽  
Chronic Hyperglycemia ◽  
Increased Risk

AbstractType 2 diabetes mellitus (T2DM) is a multifactorial chronic metabolic disease characterized by chronic hyperglycemia due to insulin resistance and a deficiency in insulin secretion. The global diabetes pandemic relates primarily to T2DM, which is the most prevalent form of diabetes, accounting for over 90% of all cases. Chronic low-grade inflammation, triggered by numerous risk factors, and the chronic activation of the immune system are prominent features of T2DM. Here we highlight the role of blood cells (platelets, and red and white blood cells) and vascular endothelial cells as drivers of systemic inflammation in T2DM. In addition, we discuss the role of microparticles (MPs) in systemic inflammation and hypercoagulation. Although once seen as inert by-products of cell activation or destruction, MPs are now considered to be a disseminated storage pool of bioactive effectors of thrombosis, inflammation, and vascular function. They have been identified to circulate at elevated levels in the bloodstream of individuals with increased risk of atherothrombosis or cardiovascular disease, two significant hallmark conditions of T2DM. There is also general evidence that MPs activate blood cells, express proinflammatory and coagulant effects, interact directly with cell receptors, and transfer biological material. MPs are considered major players in the pathogenesis of many systemic inflammatory diseases and may be potentially useful biomarkers of disease activity and may not only be of prognostic value but may act as novel therapeutic targets.

scholarly journals Physical Exercise as Therapy for Type 2 Diabetes Mellitus: From Mechanism to Orientation

2019 ◽  
Vol 74 (4) ◽  
pp. 313-321 ◽  
Author(s):  
Dan Yang ◽  
Yifan Yang ◽  
Yanlin Li ◽  
Rui Han
Keyword(s):  
Type 2 Diabetes ◽  
Exercise Therapy ◽  
Metabolic Diseases ◽  
Whole Body ◽  
Mechanism Study ◽  
Physiological Mechanisms ◽  
Glycolipid Metabolism ◽  
Randomized Controlled Studies

Background: Exercise therapy plays an important role in the prevention and treatment of type 2 diabetes (T2DM). The mechanism of exercise therapy in the improvement of glycolipid metabolism of T2DM is very complex and not completely clear. Summary: Exercise training improves the whole body metabolic health in patients with T2DM, leading to an increase in glycolipid uptake and utilization, improved insulin sensitivity, optimized body mass index, and modulated DNA methylation, etc. Recent findings support that some cytokines such as irisin, osteocalcin, and adiponectin are closely related to exercise and metabolic diseases. This study briefly reviews the physiological mechanisms of exercise therapy in diabetes and the potential role of these cytokines in exercise. Key Messages: More high-quality, targeted, randomized controlled studies are needed urgently, from mechanism study to treatment direction, to provide a more theoretical basis for exercise therapy and to explore new therapeutic targets for diabetes.

scholarly journals Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

2020 ◽  
Vol 295 (31) ◽  
pp. 10842-10856 ◽  
Author(s):  
Wen Liu ◽  
Ye Yin ◽  
Meijing Wang ◽  
Ting Fan ◽  
Yuyu Zhu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Low Grade ◽  
High Fat ◽  
Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

The role of single nucleotide polymorphisms in GIPR gene in the changes of secretion in hormones and adipokines in patients with obesity with type 2 diabetes

2018 ◽  
Vol 64 (2) ◽  
pp. 208-216 ◽  
Author(s):  
D.A. Skuratovskaia ◽  
M.A. Vulf ◽  
E.V. Kirienkova ◽  
N.I. Mironyuk ◽  
P.A. Zatolokin ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Receptor Gene ◽  
Obese Patients ◽  
Nucleotide Polymorphisms ◽  
Normal Expression ◽  
Before And After ◽  
Regulation Of Carbohydrate Metabolism ◽  
Plasma Leptin

The relationship between the rs2302382, rs8111428 and Glu354Gln (rs1800437) polymorphisms in GIPR (glucosedependent insulinotropic polypeptide receptor) gene and plasma levels of mediators involved in the regulation of carbohydrate metabolism in obese patients with type 2 diabetes (before and after a test breakfast) was investigated. The contribution of polymorphic variants of rs2302382, rs8111428 in GIPR gene in the predisposition to type 2 diabetes in individuals belonging to the Slavic population of Russia was found. Polymorphisms rs2302382 and rs8111428 in the GIPR gene were characterized by the nonequilibrium cohesion. The decrease in the level of expression of the GIPR gene in adipose tissue of the small intestine mesentery in the carriers of the CC genotype rs2302382 and AA rs8111428 was associated with the increase in the plasma leptin level, whereas during normal expression, the plasma content of insulin, and GIP (in persons with the genotype of the polymorphism rs2302382 and AG polymorphism rs8111428), resistin and ghrelin (in individuals with the genotype of the polymorphism rs2302382) increased. We propose the stimulating effect of GIP on the secretion of resistin, leptin and ghrelin, with an increase in insulin production in obese patients with type 2 diabetes.

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