Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction

Background-Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes. Methods and Results-Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca2+ fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a. Conclusions-Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease

Cardioprotective Properties of Omentin-1 in Type 2 Diabetes: Evidence from Clinical and In Vitro Studies

Context: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. Methods: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. Results: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P,0.05). The improved diastolic function followin

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies

Contains fulltext : 118105.pdf (publisher's version ) (Open Access)CONTEXT: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. METHODS: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. RESULTS: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin. CONCLUSION: These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2

Correlations between plasma omentin-1 levels and anthropometric, plasma, hemodynamic parameters, and cardiac dimensions and function.

<p>Data are Pearson’s r. In case of non-Gaussian distributions, parameters were ln-transformed for correlation analysis. A, diastolic atrial contraction; BMI, body mass index; DM2, type 2 diabetes; E, early diastolic filling phase; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LV, left ventricular; MFAE, myocardial fatty acid esterification; MFAO, myocardial fatty acid oxidation; MFAU, myocardial fattu acid uptake; MMRGlu, myocardial metabolic glucose metabolism; M-value, whole body insulin sensitivity.</p>#<p><i>P</i><0.10;</p>*<p><i>P</i><0.05;</p>**<p><i>P</i><0.01;</p>***<p><i>P</i><0.001.</p

Effect of recombinant omentin on sarcomere shortening and calcium fluxes in primary adult rat cardiomyocytes.

<p>Primary rat cardiomyocytes were incubated with control medium or conditioned media from epicardial adipose tissue from patients with type 2 diabetes (EAT) for 30 min in the absence or presence of recombinant omentin before analysis of sarcomere shortening and cytosolic Ca²⁺-fluxes. Effect of exposure of cardiomyocytes to EAT and omentin on departure velocity of contraction (<b>A</b>), peak sarcomere shortening (<b>B</b>), return velocity of contraction (<b>C</b>), departure velocity of cytosolic [Ca²⁺] (<b>D</b>), peak fura-2 fluorescence (<b>E</b>) and departure velocity of cytosolic [Ca²⁺] (<b>F</b>). Data were collected during at least 4 independent experiments using cardiomyocyte preparations from different rats and conditioned media from different donors, and are expressed as mean ± standard error of the mean. Differences among the groups were evaluated using the Kruskal-Wallis method followed by a Dunns multiple comparison test. ***<i>P</i><0.001; **<i>P</i><0.01, versus control adipocyte medium (control), ^###<i>P</i><0.001; ^##<i>P</i><0.01 EAT versus EAT+omentin.</p

Plasma omentin-1 levels in men with uncomplicated type 2 diabetes.

<p>Plasma omentin-1 levels, fat distribution, insulin sensitivity and diastolic parameters were determined in healthy control men (n = 14) and men with uncomplicated type 2 diabetes (DM2) (n = 78). (<b>A</b>) Whisker plot (median, min-max) depicting plasma omentin-1 levels in controls and DM2-patients. Differences in circulating omentin-1 levels were analyzed using a Mann-Whitney U-test. **indicates <i>P</i><0.01. Regression analysis identified significant correlations between baseline omentin-1 plasma levels and E peak filling rate (<b>B</b>), early deceleration peak (<b>C</b>), M-value (<b>D</b>), visceral fat volume (<b>E</b>), and systolic blood pressure (<b>F</b>). A straight line indicates a regression line for all subjects. A dashed line indicates a regression line for healthy controls only.</p

Characteristics of patients from which adipose tissue biopsies were collected.

<p>Data are presented as mean ± SD. <i>P</i>-values for differences between anthropometric variables were calculated using the Mann-Whitney U-test in case of continuous data, and using Fisher’s exact test for medication use.</p>*<p><i>P</i><0.05. BMI, body mass index; DM2, type 2 diabetes; ND, non-DM2.</p

Plasma omentin-1 levels in men with uncomplicated type 2 diabetes before and after 24-week pioglitazone treatment versus 24-week metformin treatment.

<p>(<b>A</b>) Plasma omentin levels before (0) and after 24 weeks of treating males with uncomplicated type 2 diabetes with metformin or pioglitazone. <i>P</i>-values for treatment-effects were calculated using a Wilcoxon signed rank test. **indicates a <i>P</i><0.01. Pearson regression analysis showed that only in the pioglitazone group changes in omentin-1 levels positively correlated with changes in early peak filling rate (<b>B</b>), early deceleration peak (<b>C</b>), and early deceleration mean (<b>D</b>).</p

Effect of recombinant omentin on insulin action in primary adult rat cardiomyocytes.

<p>Western blot (<b>A</b>) and quantification (<b>B</b>) of recombinant omentin on insulin action. Lysates from primary adult rat cardiomyocytes exposed for 24 h to control adipocyte medium (control) or recombinant omentin in the absence or presence of conditioned media generated from epicardial adipose tissue from patients with type 2 diabetes (EAT) were analyzed for insulin-induced Akt-Ser473-phosphorylation. Data were collected during at least 6 independent experiments using cardiomyocyte preparations from different rats and conditioned media from different donors, and are expressed as mean ± standard error of the mean. Open bars, basal; filled bars, insulin stimulated cells. Differences among the groups were evaluated by ANOVA following Bonferroni analysis for multiple comparisons. *<i>P</i><0.001 effect of insulin (filled bars) versus basal (open bars); ^###<i>P</i><0.001 control versus EAT, ^##<i>P</i><0.01 EAT versus EAT+omentin.</p