scholarly journals Pathophysiological Implication of Fetuin-A Glycoprotein in the Development of Metabolic Disorders: A Concise Review

2019 ◽  
Vol 8 (12) ◽  
pp. 2033 ◽  
Author(s):  
Lynda Bourebaba ◽  
Krzysztof Marycz
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Metabolic Disorders ◽  
Glucose Transporter ◽  
Liver Disorder ◽  
Inflammatory Factors ◽  
Human Beings ◽  
Fetuin A ◽  
Nonalcoholic Fatty Liver ◽  
Metabolism Regulation

Alpha 2-Heremans-Schmid glycoprotein, also known as fetuin-A (Fet-A), is a multifunctional plasma glycoprotein that has been identified in both animal and human beings. The protein is a hepatokine predominantly synthesized in the liver, which is considered as an important component of diverse normal and pathological processes, including bone metabolism regulation, vascular calcification, insulin resistance, and protease activity control. Epidemiological studies have already consistently demonstrated significant elevated circulating Fet-A in the course of obesity and related complications, such as type 2 diabetes mellitus, metabolic syndrome, and nonalcoholic fatty liver disorder (NAFLD). Moreover, Fet-A has been strongly correlated with many parameters related to metabolic homeostasis dysregulation, such as insulin sensitivity, glucose tolerance, circulating lipid levels (non-esterified free fatty acids and triglycerides), and circulating levels of both pro- and anti-inflammatory factors (C-reactive protein, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6). Metabolic-interfering effects of Fet-A have thus been shown to highly exacerbate insulin resistance (IR) through blocking insulin-stimulated glucose transporter 4 (GLUT-4) translocation and protein kinase B (Akt) activation. Furthermore, the protein appeared to interfere with downstream phosphorylation events in insulin receptor and insulin receptor substrate signaling. The emerging importance of Fet-A for both diagnosis and therapeutics has therefore come to the attention of researchers and the pharmaceutical industry, in the prospect of developing new therapeutic strategies and diagnosis methods for metabolic disorders.

scholarly journals Adipocyte, Immune Cells, and miRNA Crosstalk: A Novel Regulator of Metabolic Dysfunction and Obesity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1004
Author(s):  
Sonia Kiran ◽  
Vijay Kumar ◽  
Santosh Kumar ◽  
Robert L Price ◽  
Udai P. Singh
Keyword(s):  
Insulin Resistance ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Metabolic Diseases ◽  
Liver Disorder ◽  
Low Grade ◽  
Peripheral Tissues ◽  
Nonalcoholic Fatty Liver ◽  
Cytokines And Chemokines

Obesity is characterized as a complex and multifactorial excess accretion of adipose tissue (AT) accompanied with alterations in the immune response that affects virtually all age and socioeconomic groups around the globe. The abnormal accumulation of AT leads to several metabolic diseases, including nonalcoholic fatty liver disorder (NAFLD), low-grade inflammation, type 2 diabetes mellitus (T2DM), cardiovascular disorders (CVDs), and cancer. AT is an endocrine organ composed of adipocytes and immune cells, including B-Cells, T-cells and macrophages. These immune cells secrete various cytokines and chemokines and crosstalk with adipokines to maintain metabolic homeostasis and low-grade chronic inflammation. A novel form of adipokines, microRNA (miRs), is expressed in many developing peripheral tissues, including ATs, T-cells, and macrophages, and modulates the immune response. miRs are essential for insulin resistance, maintaining the tumor microenvironment, and obesity-associated inflammation (OAI). The abnormal regulation of AT, T-cells, and macrophage miRs may change the function of different organs including the pancreas, heart, liver, and skeletal muscle. Since obesity and inflammation are closely associated, the dysregulated expression of miRs in inflammatory adipocytes, T-cells, and macrophages suggest the importance of miRs in OAI. Therefore, in this review article, we have elaborated the role of miRs as epigenetic regulators affecting adipocyte differentiation, immune response, AT browning, adipogenesis, lipid metabolism, insulin resistance (IR), glucose homeostasis, obesity, and metabolic disorders. Further, we will discuss a set of altered miRs as novel biomarkers for metabolic disease progression and therapeutic targets for obesity.

scholarly journals The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance

2019 ◽  
Vol 40 (5) ◽  
pp. 1367-1393 ◽  
Author(s):  
Matthew J Watt ◽  
Paula M Miotto ◽  
William De Nardo ◽  
Magdalene K Montgomery
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Liver Disorder ◽  
The Body ◽  
Limited Information ◽  
Peripheral Tissues ◽  
Nonalcoholic Fatty Liver ◽  
Induce Insulin Resistance ◽  
Glucose And Lipid Metabolism ◽  
Physiological Processes

AbstractThe liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry “omics” approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of “hepatokine” biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.

scholarly journals Wu-Mei-Wan Reduces Insulin Resistance via Inhibition of NLRP3 Inflammasome Activation in HepG2 Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Xueping Yang ◽  
Lingli Li ◽  
Ke Fang ◽  
Ruolan Dong ◽  
Jingbin Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Nlrp3 Inflammasome ◽  
Hepg2 Cells ◽  
Glucose Transporter ◽  
Interleukin 1 ◽  
Serine Phosphorylation ◽  
Inflammasome Activation ◽  
Glucose Consumption Rate

Wu-Mei-Wan (WMW) is a Chinese herbal formula used to treat type 2 diabetes. In this study, we aimed to explore the effects and mechanisms of WMW on insulin resistance in HepG2 cells. HepG2 cells were pretreated with palmitate (0.25 mM) to impair the insulin signaling pathway. Then, they were treated with different doses of WMW-containing medicated serum and stimulated with 100 nM insulin. Results showed that palmitate could reduce the glucose consumption rate in HepG2 cells and impair insulin signaling related to phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), thereby regulating the downstream signaling pathways. However, medicated serum of WMW restored impaired insulin signaling, upregulated the expression of phospho-IR (pIR), phosphatidylinositol 3-kinase p85 subunit, phosphoprotein kinase B, and glucose transporter 4, and decreased IRS serine phosphorylation. In addition, it decreased the expression of interleukin-1β and tumor necrosis factor-α, which are the key proinflammatory cytokines involved in insulin resistance; besides, it reduced the expression of NLRP3 inflammasome. These results suggested that WMW could alleviate palmitate-induced insulin resistance in HepG2 cells via inhibition of NLRP3 inflammasome and reduction of proinflammatory cytokine production.

scholarly journals INSULIN AND INSULIN RECEPTOR GENE POLYMORPHISMS AND SUSCEPTIBILITY TO NONALCOHOLIC FATTY LIVER DISEASE

2020 ◽  
Vol 57 (2) ◽  
pp. 203-208
Author(s):  
Hossein NOBAKHT ◽  
Touraj MAHMOUDI ◽  
Mohammad SABZIKARIAN ◽  
Seidamir Pasha TABAEIAN ◽  
Gholamreza REZAMAND ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Liver Disease ◽  
Fatty Liver ◽  
Insulin Receptor ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Gene Polymorphisms ◽  
Nonalcoholic Fatty Liver ◽  
Glutamyl Transferase

ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is an increasing global health concern defined by excessive hepatic fat content in the absence of excessive alcohol consumption. OBJECTIVE: Given the pivotal role of insulin resistance in NAFLD, we hypothesized that insulin (INS) and insulin receptor (INSR) gene polymorphisms may be associated with NAFLD risk. METHODS: A total of 312 subjects, including 153 cases with biopsy-proven NAFLD and 159 controls were enrolled in this case-control study. Four polymorphisms in INS (rs3842752, rs689) and INSR (rs1052371, rs1799817) genes were genotyped using PCR-RFLP method. RESULTS: The cases with NAFLD were older and had higher BMI, systolic blood pressure, diastolic blood pressure, as well as higher serum levels of aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl transferase than the controls (P<0.001). The “TT” genotype of INSR rs1799817 compared with “CC” genotype occurred more frequently in the controls than the cases with NAFLD and the difference remained significant after adjustment for confounding factors (P=0.018; OR=0.10, 95%CI=0.02-0.76). However, no significant difference was found for INS rs3842752, INS rs689, and INSR rs1052371 gene polymorphisms between the cases with NAFLD and the controls either before or after adjustment for the confounders. CONCLUSION: These findings corroborate the hypothesis that genetic polymorphisms related to insulin resistance play a role in NAFLD susceptibility. Specifically, the INSR rs1799817 “TT” genotype had a protective effect for NAFLD. However, our results remain to be validated in other studies.

scholarly journals Inhibitory effect of hyperglycemia on insulin-induced Akt/protein kinase B activation in skeletal muscle

2001 ◽  
Vol 280 (5) ◽  
pp. E816-E824 ◽  
Author(s):  
Akira Oku ◽  
Masao Nawano ◽  
Kiichiro Ueta ◽  
Takuya Fujita ◽  
Itsuro Umebayashi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Soleus Muscle ◽  
Insulin Signaling ◽  
Skeletal Muscles ◽  
Glucose Transporter ◽  
Protein Kinase B ◽  
Diabetic Rats

To determine the molecular mechanism underlying hyperglycemia-induced insulin resistance in skeletal muscles, postreceptor insulin-signaling events were assessed in skeletal muscles of neonatally streptozotocin-treated diabetic rats. In isolated soleus muscle of the diabetic rats, insulin-stimulated 2-deoxyglucose uptake, glucose oxidation, and lactate release were all significantly decreased compared with normal rats. Similarly, insulin-induced phosphorylation and activation of Akt/protein kinase B (PKB) and GLUT-4 translocation were severely impaired. However, the upstream signal, including phosphorylation of the insulin receptor (IR) and insulin receptor substrate (IRS)-1 and -2 and activity of phosphatidylinositol (PI) 3-kinase associated with IRS-1/2, was enhanced. The amelioration of hyperglycemia by T-1095, a Na+-glucose transporter inhibitor, normalized the reduced insulin sensitivity in the soleus muscle and the impaired insulin-stimulated Akt/PKB phosphorylation and activity. In addition, the enhanced PI 3-kinase activation and phosphorylation of IR and IRS-1 and -2 were reduced to normal levels. These results suggest that sustained hyperglycemia impairs the insulin-signaling steps between PI 3-kinase and Akt/PKB, and that impaired Akt/PKB activity underlies hyperglycemia-induced insulin resistance in skeletal muscle.

scholarly journals Latent Inflammation and Insulin Resistance in Adipose Tissue

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
I. S. Stafeev ◽  
A. V. Vorotnikov ◽  
E. I. Ratner ◽  
M. Y. Menshikov ◽  
Ye. V. Parfyonova
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Diseases ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Modern Society ◽  
Signaling Proteins ◽  
Inflammatory Signaling ◽  
Nonalcoholic Fatty Liver ◽  
Pi3 Kinase Pathway

Obesity is a growing problem in modern society and medicine. It closely associates with metabolic disorders such as type 2 diabetes mellitus (T2DM) and hepatic and cardiovascular diseases such as nonalcoholic fatty liver disease, atherosclerosis, myocarditis, and hypertension. Obesity is often associated with latent inflammation; however, the link between inflammation, obesity, T2DM, and cardiovascular diseases is still poorly understood. Insulin resistance is the earliest feature of metabolic disorders. It mostly develops as a result of dysregulated insulin signaling in insulin-sensitive cells, as compared to inactivating mutations in insulin receptor or signaling proteins that occur relatively rare. Here, we argue that inflammatory signaling provides a link between latent inflammation, obesity, insulin resistance, and metabolic disorders. We further hypothesize that insulin-activated PI3-kinase pathway and inflammatory signaling mediated by several IκB kinases may constitute negative feedback leading to insulin resistance at least in the fat tissue. Finally, we discuss perspectives for anti-inflammatory therapies in treating the metabolic diseases.

scholarly journals Endoplasmic Reticulum Stress Induces the Expression of Fetuin-A to Develop Insulin Resistance

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 2974-2984 ◽  
Author(s):  
Horng-Yih Ou ◽  
Hung-Tsung Wu ◽  
Hao-Chang Hung ◽  
Yi-Ching Yang ◽  
Jin-Shang Wu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
High Glucose ◽  
Normal Glucose Tolerance ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Fetuin A ◽  
Nonalcoholic Fatty Liver ◽  
Diagnosed Diabetes

Fetuin-A is a biomarker reported to be important in many metabolic disorders, including obesity, diabetes, and hepatic steatosis. Although it is well known that fetuin-A is increased in diabetes and nonalcoholic fatty liver disease (NAFLD), the levels of fetuin-A in diabetic patients with NAFLD are unknown. Furthermore, the regulation of fetuin-A expression is still obscure. In this study, a total of 180 age- and sex-matched subjects with normal glucose tolerance, NAFLD, newly diagnosed diabetes (NDD), and NDD with NAFLD were recruited. We found that the levels of fetuin-A were significantly increased in NDD with NAFLD as compared with NDD or NAFLD subjects. We further used HepG2 cells to investigate the regulation of fetuin-A. Treatment with endoplasmic reticulum (ER) stress activator, thapsigargin, increased the expression of fetuin-A mRNA and protein in a time- and dose-dependent manner. Pretreatment with ER stress inhibitor, 4-phenylbutyrate, reversed high glucose or palmitate-induced fetuin-A expression. Moreover, treatment with 4-phenylbutyrate in both streptozotocin-induced and high-fat diet-induced diabetic mice not only decreased hepatic fetuin-A levels but also improved hyperglycemia. Taken together, we found that fetuin-A levels were increased in diabetes patients with NAFLD. Moreover, ER stress induced by high glucose and palmitate increased the expression of fetuin-A and further contributed to the development of insulin resistance.

scholarly journals Avian and Mammalian Facilitative Glucose Transporters

2017 ◽  
Author(s):  
Mary Shannon Byers ◽  
Christianna Howard ◽  
Xiaofei Wang
Keyword(s):  
Insulin Resistance ◽  
Cell Membrane ◽  
Glucose Transport ◽  
Metabolic Disorders ◽  
Glucose Transporter ◽  
Glucose Transporters ◽  
Transporter Proteins ◽  
Somatic Tissues ◽  
Glucose Transporter Proteins

The GLUT members belong to a family of glucose transporter proteins that facilitate glucose transport across the cell membrane. The mammalian GLUT family consists of thirteen members (GLUTs 1-12 and HMIT). Humans have a recently duplicated GLUT member, GLUT14. Avians express the majority of GLUT members. The arrangement of multiple GLUTs across all somatic tissues signifies the important role of glucose across all organisms. Defects in glucose transport have been linked to metabolic disorders, insulin resistance and diabetes. Despite the essential importance of these transporters, our knowledge regarding GLUT members in avians is fragmented. It has been clear that there are no chicken orthologs of mammalian GLUT4 and GLUT7. Our examination of GLUT members in the chicken revealed that some chicken GLUT members do not have corresponding orthologs in mammals. We review the information regarding GLUT orthologs and their function and expression in mammals and birds, with emphasis on chickens and humans.

Nonalcoholic steatohepatitis

2010 ◽  
pp. 2480-2482
Author(s):  
Stephen F. Stewart ◽  
Chris P. Day
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Liver Disease ◽  
Nonalcoholic Steatohepatitis ◽  
Fatty Liver Disease ◽  
Liver Disorder ◽  
Nonalcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Developed World ◽  
Nonalcoholic Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the developed world, affecting 20 to 30% of Western adults. Nonalcoholic liver disease occurs with a range of severity from simple steatosis through nonalcoholic steatohepatitis (NASH) to fatty fibrosis—and, ultimately, cirrhosis. The condition is a manifestation of the metabolic syndrome, strongly associated with obesity, insulin resistance, and dyslipidaemia; dietary and genetic factors appear to determine susceptibility to the disease and its progression....

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