scholarly journals Muscle Insulin Resistance and the Inflamed Microvasculature: Fire from Within

2019 ◽  
Vol 20 (3) ◽  
pp. 562 ◽  
Author(s):  
Jia Liu ◽  
Zhenqi Liu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Action ◽  
Microvascular Perfusion ◽  
Glucose Disposal ◽  
Inflammatory Factors ◽  
Early Event ◽  
Low Grade ◽  
Obesity And Diabetes

Insulin is a vascular hormone and regulates vascular tone and reactivity. Muscle is a major insulin target that is responsible for the majority of insulin-stimulated glucose use. Evidence confirms that muscle microvasculature is an important insulin action site and critically regulates insulin delivery to muscle and action on myocytes, thereby affecting insulin-mediated glucose disposal. Insulin via activation of its signaling cascade in the endothelial cells increases muscle microvascular perfusion, which leads to an expansion of the endothelial exchange surface area. Insulin’s microvascular actions closely couple with its metabolic actions in muscle and blockade of insulin-mediated microvascular perfusion reduces insulin-stimulated muscle glucose disposal. Type 2 diabetes is associated with chronic low-grade inflammation, which engenders both metabolic and microvascular insulin resistance through endocrine, autocrine and paracrine actions of multiple pro-inflammatory factors. Here, we review the crucial role of muscle microvasculature in the regulation of insulin action in muscle and how inflammation in the muscle microvasculature affects insulin’s microvascular actions as well as metabolic actions. We propose that microvascular insulin resistance induced by inflammation is an early event in the development of metabolic insulin resistance and eventually type 2 diabetes and its related cardiovascular complications, and thus is a potential therapeutic target for the prevention or treatment of obesity and diabetes.

scholarly journals Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

2021 ◽  
Vol 22 (11) ◽  
pp. 5603
Author(s):  
Anna Litwiniuk ◽  
Wojciech Bik ◽  
Małgorzata Kalisz ◽  
Agnieszka Baranowska-Bik
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Alzheimer's Disease ◽  
Chronic Inflammation ◽  
Amyloid Β ◽  
Inflammatory Factors ◽  
Low Grade ◽  
Neurodegenerative Dementia

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid β (Aβ) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1β signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD.

scholarly journals Docking protein 1 and free fatty acids are associated with insulin resistance in patients with type 2 diabetes mellitus

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110482
Author(s):  
Xiaoqin Ha ◽  
Xiaoling Cai ◽  
Huizhe Cao ◽  
Jie Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Effective Means ◽  
Model Assessment ◽  
High Concentration ◽  
Obesity And Diabetes ◽  
Docking Protein

Objective Insulin resistance (IR) is a key defect in type 2 diabetes mellitus (T2DM); therefore, effective means of ameliorating IR are sought. Methods We performed a retrospective cohort study of 154 patients with T2DM and 39 with pre-diabetes (pre-DM). The effects of IR and a high concentration of FFA on gene expression were determined using microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) in patients with T2DM or pre-DM. Results Serum FFA concentration and homeostasis model assessment of IR (HOMA-IR) were significantly higher in patients with T2DM but no obesity and in those with pre-DM than in controls. HOMA-IR was significantly associated with T2DM. RT-qPCR showed that the expression of FBJ murine osteosarcoma viral oncogene homolog ( FOS) and AE binding protein 1 ( AEBP1) was much lower in the circulation of participants with obesity and diabetes. RT-qPCR showed that the expression of docking protein 1 ( DOK1) was significantly lower in the blood of participants with diabetes but no obesity and in those with pre-DM than in controls. Conclusions FFA and DOK1 are associated with IR in patients with T2DM but no obesity or pre-DM. The downregulation of DOK1 might inhibit lipid synthesis and induce lipolysis, inducing or worsening IR.

scholarly journals Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes

2012 ◽  
Vol 167 (4) ◽  
pp. 569-578 ◽  
Author(s):  
Francisco J Ortega ◽  
Mónica Sabater ◽  
José M Moreno-Navarrete ◽  
Neus Pueyo ◽  
Patricia Botas ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Weight Loss ◽  
Lipid Metabolism ◽  
Inflammatory Markers ◽  
Low Grade ◽  
Model Assessment ◽  
Glucose And Lipid Metabolism ◽  
Obese Subjects

ObjectiveIncreased circulating calprotectin has been reported in obese subjects but not in association with measures of insulin resistance and type 2 diabetes (T2D). The main aim of this study was to determine whether calprotectins in plasma and urine are associated with insulin resistance.DesignWe performed both cross-sectional and longitudinal (diet-induced weight loss) studies.MethodsCirculating calprotectin concentrations (ELISA), other inflammatory markers, homeostasis model assessment of insulin resistance (HOMA-IR), and parameters of glucose and lipid metabolism were evaluated in 298 subjects (185 with normal (NGT) and 62 with impaired (IGT) glucose tolerance and 51 T2D subjects). Calprotectin was also evaluated in urine samples from 71 participants (50 NGT and 21 subjects with IGT). Insulin sensitivity (SI, Minimal Model) was determined in a subset of 156 subjects, and the effects of weight loss were investigated in an independent cohort of obese subjects (n=19).ResultsCirculating calprotectin was significantly increased in IGT–T2D (independently of BMI) and positively associated with HOMA-IR, obesity measures, inflammatory markers, and parameters of glucose and lipid metabolism. Similar findings were reported for calprotectin concentrations in urine. In the subset of subjects, the association of calprotectin withSIwas independent of BMI and age. In fact,SItogether with C-reactive protein contributed to 27.4% of calprotectin variance after controlling for age and blood neutrophils count. Otherwise, weight loss led to decreased circulating calprotectin in parallel to fasting glucose and HOMA-IR.ConclusionThese findings suggest that circulating and urinary concentrations of calprotectin are linked to chronic low-grade inflammation and insulin resistance beyond obesity.

IL-6 as a Surrogate Biomarker: The IL-6 Clinical Value for the Diagnosis of Insulin Resistance and Type 2 Diabetes.

2021 ◽  
pp. 1-13
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Diagnostic Value ◽  
Low Grade ◽  
Clinical Value ◽  
Insulin Resistant ◽  
Tnf Α ◽  
Low Grade Inflammation

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus (T2D). It occurs as a result of lipid disorders and increased levels of circulating free fatty acids (FFAs). FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased levels fatty acid has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes. Among the biomarkers that are accompanying low grade inflammation include IL-1β, IL-6 and TNF-α. The current review point out the importance of measuring the inflammatory biomarkers especially focusing on the conductance and measurement for IL-6 as a screening laboratory test and its diagnostic value in clinical practice.

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.

scholarly journals Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism

2006 ◽  
Vol 92 (2) ◽  
pp. 386-395 ◽  
Author(s):  
Arya M. Sharma ◽  
Bart Staels
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Endocrine Function ◽  
Low Grade ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Abstract Context: Adipose tissue is a metabolically dynamic organ, serving as a buffer to control fatty acid flux and a regulator of endocrine function. In obese subjects, and those with type 2 diabetes or the metabolic syndrome, adipose tissue function is altered (i.e. adipocytes display morphological differences alongside aberrant endocrine and metabolic function and low-grade inflammation). Evidence Acquisition: Articles on the role of peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes were sourced using MEDLINE (1990–2006). Evidence Synthesis: Articles were assessed to provide a comprehensive overview of how PPARγ-activating ligands improve adipose tissue function, and how this links to improvements in insulin resistance and the progression to type 2 diabetes and atherosclerosis. Conclusions: PPARγ is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage. Furthermore, PPARγ activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFα, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply. The effects of PPARγ also extend to macrophages, where they suppress production of inflammatory mediators. As such, PPARγ activation appears to have a beneficial effect on the relationship between the macrophage and adipocyte that is distorted in obesity. Thus, PPARγ-activating ligands improve adipose tissue function and may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

scholarly journals Insulin resistance: Impact on therapeutic developments in diabetes

2019 ◽  
Vol 16 (2) ◽  
pp. 128-132 ◽  
Author(s):  
Clifford J Bailey
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Action ◽  
Glucose Lowering ◽  
Therapeutic Practice ◽  
Improve Insulin Action ◽  
Clinical Awareness

Insulin resistance has a broad pathogenic impact affecting metabolic, cardio-renal and other disease areas. Extensive studies to dissect the mechanisms of insulin resistance have provided valuable insights to shape current clinical awareness and advance therapeutic practice. However, the development of direct interventions against insulin resistance has been hindered by its complex and highly variable presentations, especially in type 2 diabetes. Among glucose-lowering agents, metformin and thiazolidinediones provide cellular actions that counter some effects of insulin resistance: reduced glucotoxicity and weight-lowering with antidiabetic therapies also improve insulin action, except that endogenously- or exogenously-created hyperinsulinaemia may partially compromise these benefits. Increasing awareness of the pervasiveness and damaging ramifications of insulin resistance heightens the need for more specifically targeted and more effective therapies.

scholarly journals Influence of metabolic disorders on phenotypic modulation of vascular endothelium in type 2 diabetes mellitus

2017 ◽  
Vol 70 (11-12) ◽  
pp. 437-443
Author(s):  
Romana Mijovic ◽  
Branislava Ilincic ◽  
Suncica Kojic-Damjanov ◽  
Biljana Vuckovic ◽  
Radmila Zeravica ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Adhesion Molecules ◽  
Vascular Endothelium ◽  
Low Grade ◽  
Phenotypic Modulation

Introduction. Endothelium is a dynamic, strategically positioned defensive regulator of vascular homeostasis. Physiology and Pathophysiology of Vascular Endothelium. Endothelial phenotypic modulation involves five basic characteristics: the expression of leukocyte adhesion molecules, the production of cytokines, change in the shape and the permeability of the endothelium, prothrombotic changes and upregulation of autoantigens. Obesity, Metabolic Inflammation and Vascular Endothelium One of the most important pathophysiological manifestations of adiposopathy may be the phenotypic conversion of vascular endothelium. Insulin Resistance and Vascular Endothelium. Under the conditions of insulin resistance and consequent hyperinsulinemia, there is imbalance between the production of endothelial vasoconstrictors and vasodilators, increased expression of adhesion molecules, and platelet hyperreactivity. Hyperglycemia and Vascular Endothelium. Hyperglycemia causes endothelial dysfunction by various mechanisms that involve activation of polyol pathway and production of sorbitol, increased formation of advanced glycation end products, activation of various isoforms of protein kinase C and activation of hexosamine pathway. Dyslipidemia and vascular endothelium. Dyslipidemia takes an important role in a cascade of pathophysiological processes that result in endothelial activation and chronic dysfunction. Conclusion. Hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, visceral obesity and low-grade inflammation are the main factors responsible for development of endothelial dysfunction in type 2 diabetes mellitus.

scholarly journals Estimated glucose disposal rate and risk of stroke and mortality in type 2 diabetes: a nationwide cohort study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Alexander Zabala ◽  
Vladimer Darsalia ◽  
Marcus Lind ◽  
Ann-Marie Svensson ◽  
Stefan Franzén ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cohort Study ◽  
Cox Regression ◽  
Glucose Disposal ◽  
Risk Of Death ◽  
Increased Risk ◽  
Estimated Glucose Disposal Rate ◽  
Glucose Disposal Rate

Abstract Background and aims Insulin resistance contributes to the development of type 2 diabetes (T2D) and is also a cardiovascular risk factor. The aim of this study was to investigate the potential association between insulin resistance measured by estimated glucose disposal rate (eGDR) and risk of stroke and mortality thereof in people with T2D. Materials and methods Nationwide population based observational cohort study that included all T2D patients from the Swedish national diabetes registry between 2004 and 2016 with full data on eGDR and categorised as following: < 4, 4–6, 6–8, and ≥ 8 mg/kg/min. We calculated crude incidence rates and 95% confidence intervals (CIs) and used multiple Cox regression to estimate hazard ratios (HRs) to assess the association between the risk of stroke and death, according to the eGDR categories in which the lowest category < 4 (i.e., highest grade of insulin resistance), served as a reference. The relative importance attributed of each factor in the eGDR formula was measured by the R2 (± SE) values calculating the explainable log-likelihoods in the Cox regression. Results A total of 104 697 T2D individuals, 44.5% women, mean age of 63 years, were included. During a median follow up-time of 5.6 years, 4201 strokes occurred (4.0%). After multivariate adjustment the HRs (95% CI) for stroke in patients with eGDR categories between 4–6, 6–8 and > 8 were: 0.77 (0.69–0.87), 0.68 (0.58–0.80) and 0.60 (0.48–0.76), compared to the reference < 4. Corresponding numbers for the risk of death were: 0.82 (0.70–0.94), 0.75 (0.64–0.88) and 0.68 (0.53–0.89). The attributed relative risk R2 (± SE) for each variable in the eGDR formula and stroke was for: hypertension (0.045 ± 0.0024), HbA1c (0.013 ± 0.0014), and waist (0.006 ± 0.0009), respectively. Conclusion A low eGDR (a measure of insulin resistance) is associated with an increased risk of stroke and death in individuals with T2D. The relative attributed risk was most important for hypertension.

The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control

2006 ◽  
Vol 42 ◽  
pp. 105-117 ◽  
Author(s):  
Bente Klarlund Pedersen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Chronic Diseases ◽  
The Body ◽  
Muscle Fibres ◽  
Low Grade ◽  
Regular Exercise ◽  
Anti Inflammatory

Chronic low-grade systemic inflammation is a feature of chronic diseases such as cardiovascular disease and type 2 diabetes. Regular exercise offers protection against all-cause mortality, primarily by protection against atherosclerosis and insulin resistance and there is evidence that physical training is effective as a treatment in patients with chronic heart diseases and type 2 diabetes. Regular exercise induces anti-inflammatory actions. During exercise, IL-6 (interleukin-6) is produced by muscle fibres. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra (interleukin-1 receptor antagonist) and IL-10 (interleukin-10) and inhibits the production of the pro-inflammatory cytokine TNF-a (tumour necrosis factor-a). In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. It is suggested that regular exercise induces suppression of TNF-a and thereby offers protection against TNF-a-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine, that is produced and released by contracting skeletal muscle fibres, exerting its effects in other organs of the body. Myokines may be involved in mediating the beneficial health effects against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.

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