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

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 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

Characteristics of subjects for determination of circulating omentin-1 levels.

<p>Data are mean ± SD or median (interquartile range). <i>P</i>-values for differences between variables were calculated using the students <i>t</i>-test in case of normally distributed data, or the Mann-Whitney U-test in case of non-Gaussian distributions data.</p>***<p>indicates <i>P</i><0.001;</p>**<p><i>P</i><0.01;</p>*<p><i>P</i><0.05;</p>#<p><i>P</i><0.10. 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>adapted from Rijzewijk et al. 2009 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0059697#pone.0059697-Rijzewijk1" target="_blank">[23]</a>.</p

Expression and secretion of omentin-1 in intrathoracal adipose tissue depots.

<p>Representative Western blot (<b>A</b>) and quantification (<b>B</b>) of omentin-1 expression in paired epicardial (EAT), pericardial (PAT), and subcutaneous (SAT) adipose tissue biopsies of patients with (DM2, n = 7) and without (ND, n = 6) type 2 diabetes. Equal loading was verified by probing the immunoblots with glyceraldehyde 3-phosphate dehydrogenase (GAPDH) antibody. (<b>C</b>) Quantification of omentin-1 levels in conditioned media generated from paired EAT, PAT and SAT explants from DM2- and ND-patients. Data are expressed as mean ± SEM (n = 6 patients per group). ***indicates <i>P</i><0.001; **<i>P</i><0.01, *<i>P</i><0.05 for differences between ND and DM2 (ANOVA followed by Bonferonni analysis for multiple comparisons); ^###indicates <i>P</i><0.001; ^##<i>P</i><0.01, and ^#<i>P</i><0.05 for differences between the various fat depots (paired <i>t</i>-test).</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