Objective: To test in humans the hypothesis that part of the association of adiponectin with insulin sensitivity is independent of lipid availability. Relationship between adiponectin, obesity and insulin resistance. Relação entre adiponectina, obesidade e resistência à insulina. Guilherme Ardenghi Balsan. Rev Assoc Med Bras (). Jan-Feb;61(1) doi: / Epub Jan 1. Relationship between adiponectin, obesity and.
T-cadherin binds to adiponectin, which is not a signaling receptor due to lack of intracellular signaling domains, to confer full cardioprotective potential to the latter. The autocrine effects are illustrated by their role in adipocyte differentiation.
Induction is greater than times that of adiponectin mRNA during the course of differentiation of adipose cells. Thus, adiponectin promotes adipocyte differentiation and increased insulin sensitivity. It has been shown that adiponectin administration leads to a rise in insulin-stimulated tyrosine phosphorylation of insulin receptors in muscle, both for rodents and humans.
According to Bacha et al. Additionally, insulin resistance may lead to endothelial dysfunction and changes in the insulin signaling pathway, specific or shared, in muscle tissue, adipose tissue and endothelial cells.
New genetic and nontraditional factors may be involved in these mechanisms. All these findings have added a new dimension to the association of obesity, insulin resistance and endothelial dysfunction, which may become a key target in the prevention of T2DM and cardiovascular diseases. As a result, there is inhibition of phosphofructokinase and hexokinase II, leading to increased intracellular concentration of glucose, as well as uptake.
However, other authors have different ideas and suggest that the inhibition of glucose transport or phosphorylation activity precedes the reduction in glycogen synthesis and glucose oxidation induced by free fatty acids. Phosphorylated IRS-1 of serine does not bind or activate phosphatidylinositol 3-kinase PI-3Kresulting in decreased transport of glucose and other manifestations of insulin resistance. Free fatty acids can also directly affect the expression, transcription or recruitment to the cell surface of the glucose transporter type 4 Glut In addition, free fatty acids reduce the hepatic clearance of insulin and increase the hepatic production of glucose, both enhancing the effects of insulin resistance.
People with T2DM have lower plasma adiponectin concentrations compared to non-diabetic individuals, regardless of BMI. In many studies, plasma adiponectin levels were lower in patients with coronary artery disease CAD than in controls matched for BMI and age. Hypoadiponectinemia, defined by the 25th percentile, was associated with an increase in 2 times in the prevalence of CAD in males, after accounting for other risk factors. While adiponectin levels are increased in patients with T1DM and terminal kidney disease, hypoadiponectinemia is an independent predictor of cardiovascular events in these patients.
Association Between Adiponectin and Insulin Resistance in Diabetic Urolithiasis.
Among male participants of a cohort, adiponectin was associated in type 2 diabetic patients with a decreased risk of CAD-related events myocardial infarction and coronary artery bypass graftingand that was partly due to the effects of adiponectin on HDL cholesterol levels. It is also suggested that lower levels of adiponectin are associated with defects in the catabolism of VLDL-apoB particles, which increases the effect of dyslipidemic insulin-resistance, mainly resulting in increased hepatic production of VLDL-ApoB.
These lipoproteins are closely connected to oxidation and they induce many adhesion molecules on endothelial cells, such as vascular cell adhesion molecule VCAM -1, intracellular adhesion molecule ICAM -1, and E-selectin Figure 1.
Mononuclear cells bind to endothelial cells via these adhesion molecules and migrate into the subendothelial space. This process is induced by several bio-reactive mediators, including monocyte chemotactic protein MCP-1which plays a prominent role. Since they are located on the vessel wall, the monocytes develop into macrophages, and while the LDL oxidizes, they differentiate into foam cells. This process is performed by acyl-coenzyme A [cholesterol acyltransferase-1 ACAT-1 ] in the macrophages, which catalyzes the formation of cholesterol esters.
As a secondary event, the synthesis of nitric oxide by the enzyme endothelial nitric oxide synthase eNOS is decreased Figure 1. Vascular cell adhesion molecules; ICAM Attractive monocyte chemo protein; NO: In addition, the production of nitric oxide from endothelial cells is stimulated by this adipokine. The main role of adiponectin in vascular physiology is to modulate the cross-link between endothelial cells, smooth muscle cells, leukocytes, and platelets, and protect against vascular injury and atherogenesis.
Atheroprotection is conferred by different actions of this protein, including anti-inflammatory effects, stimulation of nitric oxide production, mitigation of pro-atherogenic mediators and coronary plaque vulnerability modulation.
Adiponectin also down-regulates receptor expression. The anti-inflammatory properties of adiponectin are mediated in part by activation of Adipor1 e Adipor2 receptors in monocytes, macrophages and endothelial cells, and lessen the accumulation of inflammatory cells at sites of vascular injury.
These mediators activate signaling kinases and are also closely related to the production of endothelial reactive oxygen species ROS superoxide and H2O2which play a key role in the development of atherogenesis in the context of metabolic syndrome and diabetes mellitus. Decreased adiponectin levels and therefore its functionfor instance in the case of obesity and metabolic syndrome, make people more susceptible to atherosclerotic vascular disease.
The overall prevalence of diabetes in was million people worldwide, which is about 6. In addition, projections for show that the prevalence may reach million people, i. The burden of diabetes on the global economy has increased in the past decade, reachingmillion US dollars inand is expected to totalmillion dollars in Moreover, obesity also has an important genetic component that invariably exacerbates insulin resistance.
Thus, obesity and insulin resistance are usually present for many years before the appearance of other changes such as high blood pressure, dyslipidemia, T2DM and cardiovascular disease. Therefore, it is likely that there is genetic predisposition to develop the syndrome. A fragment of the C-terminal globular adiponectin is capable of reducing plasma glucose concentrations by increasing fatty acid oxidation in muscle Figure 2.
The Adipor1 receptor is predominantly found in skeletal muscle. Most studies have used globular adiponectin binding, which seems to have increased biological activity in skeletal muscle compared to the full-length form of the protein.
The in vivo physiological significance of the globular isoform remains unclear, since the vast majority of circulating adiponectin is in full-length form. AMPK phosphorylation in C2C12 myotubes can be prevented by ceramidase inactivation, again indicating a role for sphingolipid metabolism with adiponectin signaling in this tissue.
Adiponectin binding results in increased glucose uptake through GLUT4 translocation and non-oxidative glycolysis, while reducing the content of intramyocellular triacylglycerols and promoting oxidation of fatty acids. Furthermore, adiponectin has an effect on the number of mitochondria and types of oxidative fibers. The binding of globular adiponectin and full-length adiponectin is reduced in obese rats and in insulin-resistant rats, which may be due to a lower density of adiponectin receptors.
Myotubes in cultures from obese patients, with and without diabetes, reveal that impaired adiponectin stimulates the phosphorylation of AMPK and fatty acid oxidation, suggesting that adiponectin deficiency impairs the action of the receptor. These effects can be seen in in vitro samples of patients that are independent of other potentially confounding circulating hormonal factors e. The vast majority of studies focused on in vitro or in vivo studies were mostly performed with globular adiponectin.
Therefore, therapeutic strategies directed at bioavailability of adiponectin are likely to have a significant beneficial effect on atherogenesis.
For example, the effect of insulin and insulin resistance on the specific inflammatory response of fatty tissue is a growing area of research. However, the main limitation of the study is heterogeneity in terms of follow-up time months and baseline insulin sensitivity in patients with high blood pressure hypertension without glucose tolerance, with poor glycemic control in the included trials.
We found that, based on meta-regression analysis, the longer the follow-up therapy duration is or the more impaired the insulin sensitivity is, the more effective in the increase of adionectin levels telmisartan compared with other ARB therapy is.
Most trials included used a relatively small sample size less than patients.
Relationship between adiponectin, obesity and insulin resistance.
To confirm the results, a large randomized trial with telmisartan, including only patients with impaired glucose tolerance or diabetes, and with longer follow-up time minimum 12 months would be required. Recent studies show that the blockers of cannabinoid receptor type 1, in addition to improving cardiometabolic risk factors also regulate adiponectin levels in vivo.
Last, up-regulation of adiponectin receptors and the use of adiponectin receptor agonists may also prove to be of clinical value in the future. Lifestyle modifications and cardiovascular drugs such as fenofibrate, Angiotensin-converting enzyme ACE inhibitors, angiotensin II type 1 receptor blockers ARBsand thiazolidinediones TZDs increase plasma adiponectin levels, reduce insulin resistance, and improve endothelial function. These may be mechanisms to reduce cardiovascular disease.
These integrated mechanisms would help to explain the beneficial effects of combination therapy in recent clinical trials. Thus, there is no scientific justification to recommend a combination of lifestyle changes and multiple drugs, belonging to separate classes, to prevent atherosclerosis and coronary heart disease. In therapeutic interventions aimed at adiponectin, evidence suggests that the combination of inflammatory signaling pathways and insulin signaling pathways cause metabolic insulin resistance and endothelial dysfunction that synergistically predispose to cardiovascular disease in metabolic syndrome Figure 3.
Prospective studies are needed to examine the possibility of increasing adiponectin levels in the context of insulin sensitivity, to improve primary outcomes, including the incidence of diabetes mellitus and cardiovascular events. Despite the well-established role of proinflammatory cytokines, e.
Very recently published data suggest that adiponectin levels are increased in patients with chronic heart failure. In fact, adiponectin levels are positively correlated with the levels of brain natriuretic peptide and the severity of ventricular dysfunction estimated according to the New York Heart Association NYHA.
Cachexia appears to be a link, since reduction in body weight can regulate the synthesis of adiponectin. High levels of adiponectin may simply reflect the hyper-catabolic state in severe heart failure.
Therefore, it is necessary to clarify whether increased levels of adiponectin may be involved in the pathogenesis of heart failure or if they simply reflect the degree of cachexia in these patients. This increases the risk of developing insulin resistance and cardiovascular disease due to the molecule's regulatory role in the organism. Of the three soluble forms of adiponectin, the high molecular weight multimer seems to be the most important biological role.
At the cellular level, adiponectin increases the bioavailability of endothelial nitric oxide and has anti-inflammatory, anti-apoptotic and anti-atherogenic properties. Adiponectin is a key mediator of systemic insulin sensitivity and glucose homeostasis. These effects are achieved through a diverse range of important targets, including liver, pancreas, cardiac myocytes and immune system, and the adipose tissue itself.
The main metabolic effects of adiponectin are suppression of hepatic glucose production and modulation of suppressing inflammatory responses in other cell types, including macrophages. Moreover, through its action on sphingolipid pathways, it has potent anti-apoptotic action, which has been particularly documented in the case of beta cells and cardiac myocytes. First, our study was cross-sectional, which limited our ability to infer a causal relation between adiponectin concentrations and development of MS in T1DM.
Association Between Adiponectin and Insulin Resistance in Diabetic Urolithiasis.
Second, we measured insulin sensitivity using clinical parameters with eGDR and did not have access to direct, detailed measures of insulin resistance using euglycemic-hyperinsulinemic clamp test. Third, our analyses were based on a single measurement of total fasting adiponectin that may not reflect the relation over time.
Whether adiponectin is a marker of MS as well as all components of MS according to the IDF criteria in T1DM patients and whether higher adiponectin concentrations have a protective role in the development of the MS in T1DM need to be clarified in future follow-up studies.
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