Abstract
Meteorin-like (Metrnl) is a newly discovered adipokine with favorable effect on insulin sensitivity. Previous studies have reported lower levels of Metrnl in obese patients. However, there is conflicting data regarding its circulating levels in type 2 diabetes mellitus (T2DM) and there is no data in patients with coronary artery disease (CAD). The aim of the present study was to evaluate the Metrnl serum level in patients with T2DM and CAD, and also to evaluate the serum levels of Metrnl with serum levels of adiponectin, IL-6 and TNF-α in patients. This study was conducted on 66 patients with CAD, 63 T2DM patients and 41 controls. The serum levels of Metrnl, adiponectin, IL-6 and TNF-α were measured using ELISA techniques. The serum levels of Metrnl were found to be lower in CAD (75.18 ± 28.48 pg/mL) and T2DM patients (73.89 ± 33.60 pg/mL) compared to the control group (95.33 ± 32.56 pg/mL) (p < 0.005 and p<0.003, respectively). Additionally, adiponectin decreased in CAD and T2DM patients as compared to the control group, while IL-6 and TNF-α were higher in CAD and T2DM patients. Metrnl showed independent association with the risk of CAD and T2DM presence. Furthermore, Metrnl illustrated a negative correlation with IL-6 and TNF-α in both CAD patients and also with BMI, insulin resistance, IL-6 and TNF-α in T2DM patients. Metrnl showed an association with CAD and T2DM presence and with components of their pathogenesis such as inflammation and insulin resistance. These results suggested a possible interaction between Metrnl and the pathogenesis of CAD and T2DM, however more studies are needed to prove this concept.
Introduction
The adipose tissue is an endocrine organ that secretes adipokines such as adiponectin, leptin, visfatin, resistin, vaspin, etc [1]. Adipokines play important roles in whole body glucose and lipid metabolism as well as in inflammation [1]. Additionally, obesity has a close relationship with cardiometabolic diseases such as type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) [2]. CAD is a leading cause of death worldwide, and atherosclerosis is the main underlying mechanism of CAD [3]. Atherosclerosis is a progressive inflammatory disease and results to the accumulation of lipids in the arterial cell wall [3–6]. T2DM is a chronic metabolic disease and insulin resistance and β-cell dysfunction are the main underlying mechanisms [7,8]. It has been reported that obesity is associated with chronic inflammation and dysregulation of adipokine secretion and could be a possible link between obesity and increased risk of T2DM and CAD [9].
Meteorin-like (Metrnl), also known as subfatin and cometin, is a newly discovered adipokine that is secreted by white adipose tissue and skeletal muscle [10–13]. It has been found that Metrnl increases during acute exposure to cold and induces thermogenesis associated genes in beige/brown adipose tissue [13]. Furthermore, Metrnl increases anti-inflammatory cytokines by promoting IL-4 expression [13]. Furthermore, several lines of evidence have shown the favorable effects of Metrnl on insulin sensitivity [12,14]. Metrnl increases insulin induced AKT phosphorylation, hence, it has been found that Metrnl deficiency leads to adipocyte insulin resistance. However, there are conflicting data regarding the circulating levels of Metrnl in T2DM [15,16]. In addition, there are no data regarding the circulating levels of Metrnl in patients with CAD. Moreover, it has been documented that T2DM and CAD patients suffer from increased expression of pro-inflammatory cytokines [17]. Therefore, the present study aimed to evaluate the serum levels of Metrnl in patients with T2DM and CAD, and its association with cardiometabolic variables and inflammatory cytokines.
Materials and methods
Subjects
This cross sectional study was conducted on 66 patients with CAD, 63 patients with T2DM and 41 healthy controls. The participants were recruited from Tehran Heart Center (Tehran, Iran) from April to December, 2017. CAD was diagnosed by a cardiologist according to the angiography results. Patients with > 70% stenosis in at least one coronary artery were diagnosed as CAD [18]. Furthermore, T2DM was diagnosed based on the criteria of the American Diabetes Association (ADA) [19]. Subjects without T2DM and CAD were included in the control group. Furthermore, patients with unstable angina, positive results of non-invasive test of heart function and any history of cardiovascular disease, including cerebrovascular, coronary artery and peripheral artery diseases and acute coronary syndrome were excluded from the healthy control and T2DM groups. The exclusion criteria for all participants were as follow: history and evidence of stroke, myocardial infarction, cancer, kidney disease, chronic inflammation, autoimmune diseases and the use of thiazolidinedione family drugs. The study was performed in accordance with the Declaration of Helsinki and approved by the ethical committee of AJA University of Medical Sciences. Written consent was obtained from all participants.
Anthropometrics and biochemical measurements
A standard formula (weight (kg) / height (m2)) was used for the calculation of body mass index (BMI). Furthermore, a standard sphygmomanometer was used to measure the systolic blood pressure (SBP) and diastolic blood pressure (DBP) after 15 min of rest. After overnight fasting, venous blood was collected from all participants. Fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine (Cr) were measured using commercially available kits (Pars Azmoon, Iran). Also, the ELISA technique was used for measuring fasting insulin level (Monobind, USA). The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated using the following equation: [FBG (mg/dL)] × [fasting blood insulin (μU/mL)] / 405 [20].
Measuring cytokines and adipokines
Serum levels of IL-6, TNF-α and Metrnl were measured using commercial ELISA kits (R & D System, USA). Furthermore, the intra- and inter-assay coefficients of variation (CV) of IL-6 and TNF-α were 6.4 and 9.1, and 5.4 and 7.2, respectively. The intra and inter-assay CV for Metrnl measurement were 6.2 and 7.1, respectively. Also, the serum level of adiponectin was assessed by the ELISA technique (Adipogen, South Korea), with intra- and inter-assay CV of 3.4 and 4.3%, respectively.
Statistical analysis
Categorical data are shown in frequency and percentage and tested by the Chi-square test. Continuous variables are given with mean and standard deviation (SD). The normality of continuous data was tested using the Kolmogorov-Smirnov test. Furthermore, normal distributed data was analyzed by one-way ANOVA with the Bonferroni post hoc test. Non-normal distributed data were evaluated by the Kruskal Wallis test supplemented by the Bonferroni test. In addition, the Spearman correlation test was used to evaluate the correlation between Metrnl as well as anthropometric and metabolic profiles. Non-normal distributed data were logarithmically transformed before correlation analysis. Analysis of covariance (ANCOVA) was carried out to remove the possible effects of covariates on the serum levels of Metrnl. Moreover, the association of Metrnl with the risk of T2DM and CAD presence were tested by multinomial logistic regression. All analyses were performed by SPSS version 16 (SPSS, USA) and a p value < 0.05 was considered as a significant threshold.
Results
Anthropometrics and biochemical measurements
Table 1 presents the anthropometric results, metabolic profiles and medications administered. There were no significant differences in terms of age (p = 0.152), sex (p = 0.095) and BMI (p = 0.280) between the studied groups. However, SBP was higher in the CAD group compared to the control. Also, the results showed significantly increased FBG and HOMA-IR in the T2DM group compared to the control and CAD groups. Furthermore, insulin was higher in the T2DM group compared to the control and CAD groups, and CAD compared to the control group. Moreover, TG was higher and HDL-C was lower in the T2DM group compared to the control group, while TC and LDL-C showed no significant differences between both groups.
Table 1. Anthropometric, metabolic and medications use of the studied population.
| Variables | Control | CAD | T2DM | P Value | |
|---|---|---|---|---|---|
| Age (year) | 56.4 ± 7.5 | 59.4 ± 7.9 | 58.6 ± 7.8 | 0.154 | |
| Sex (male) [n (%)] | 29 (70.7) | 54 (81.8) | 41 (65.1) | 0.095 | |
| BMI (kg/m2) | 26.0 ± 3.5 | 27.2 ± 4.1 | 26.3 ± 4.3 | 0.280 | |
| SBP (mmHg) | 124.9 ± 13.1 | 137.2 ± 17.4a** | 136.1 ± 20.0b** | 0.001 | |
| DBP (mmHg) | 77.4 ± 9.9 | 86.0 ± 13.3a** | 83.7 ± 14.7 | 0.005 | |
| FBG (mg/dL) | 95.8 ± 12.7 | 95.4 ± 11.7 | 160.3 ± 24.6b**,c** | < 0.001 | |
| Insulin (uU/ml) | 4.0 ± 2.1 | 6.5 ± 4.7a** | 10.4 ± 4.3 b**,c** | < 0.001 | |
| HOMA-IR | 0.95 ± 0.56 | 1.52 ± 1.10 | 4.19 ± 1.98 b**,c** | < 0.001 | |
| TG (mg/dL) | 126.6 ± 53.1 | 136.2 ± 49.5 | 154.7 ± 49.0 b* | 0.015 | |
| TC (mg/dL) | 175.1 ± 40.6 | 172.9 ± 45.0 | 185.2 ± 43.8 | 0.246 | |
| LDL-C (mg/dL) | 106.2 ± 33.4 | 104.6 ± 34.5 | 112.1 ± 36.9 | 0.462 | |
| HDL-C (mg/dL) | 46.2 ± 6.4 | 43.3 ± 11.2 | 41.8 ± 4.9b* | 0.029 | |
| Creatinine (mg/dL) | 1.14 ± 0.14 | 1.15 ± 0.19 | 1.16 ± 0.15 | 0.774 | |
| AST (U/L) | 18.3 ± 5.5 | 19.8 ± 6.8 | 19.3 ± 6.4 | 0.516 | |
| ALT (U/L) | 18.7 ± 7.7 | 21.6 ± 8.7 | 19.0 ± 7.9 | 0.111 | |
| Smoker [n (%)] | 10 (24.4) | 27 (40.9) | 24 (38.1) | 0.201 | |
| Medication [n (%)] | Insulin +OHA# | 0 (0) | 0 (0) | 28 (44.4) | < 0.001 |
| Statins | 0 (0) | 49 (74.2) | 31 (49.2) | < 0.001 | |
Continuous data are given in mean ± SD and categorical data are shown in frequency and percentage.
# OHA, oral hypoglycemic agents
* P value < 0.05
** P value < 0.01
a. Comparison between controls and CAD
b. Comparison between controls and T2DM
c. Comparison between CAD and T2DM
Serum levels of cytokines and adipokines
The serum levels of IL-6 were significantly elevated in the CAD (8.31 ± 3.56 pg/mL) and T2DM (8.96 ± 3.33 pg/mL) groups compared to the control group (5.37 ± 1.8 pg/mL) (p < 0.001 for both). Likewise, the serum levels of TNF-α were found to be higher in CAD (27.6 ± 6.3 pg/mL) and T2DM (27.7 ± 8.0 pg/mL) patients compared to the control (22.3 ± 7.4 pg/mL) (p = 0.001 for both). While adiponectin was significantly lower in the CAD (8.4 ± 3.2 μg/mL) and T2DM (9.6 ± 2.6 μg/mL) groups compared to the control (11.2 ± 3.4 μg/mL) (p < 0.001 and p = 0.033, respectively) (Table 2).
Table 2. Serum levels of adipokine and inflammatory cytokines.
| Variables | Control | CAD | T2DM | P Value |
|---|---|---|---|---|
| IL-6 (pg/mL) | 5.37 ± 1.8 | 8.31 ± 3.56a** | 8.96 ± 3.33b** | < 0.001 |
| TNF-α (pg/mL) | 22.3 ± 7.4 | 27.6 ± 6.3a** | 27.7 ± 8.0b** | < 0.001 |
| Adiponectin (μg/mL) | 11.2 ± 3.4 | 8.4 ± 3.2a** | 9.6 ± 2.6b* | < 0.001 |
| Metrnl (pg/mL) | 95.33 ± 32.56 | 75.18 ± 28.48a** | 73.89 ± 33.60bb** | < 0.001 |
* P Value < 0.05
** P Value < 0.01
a. Comparison between controls and CAD
b. Comparison between controls and T2DM
The serum levels of Metrnl were found to be lower in CAD (75.18 ± 28.48 pg/mL) and T2DM patients (73.89 ± 33.60 pg/mL) compared to the control (95.33 ± 32.56 pg/mL) (p < 0.005, p < 0.003, respectively) (Table 2). Statistical analysis using ANCOVA test demonstrated that decreased serum levels of Metrnl in CAD (p = 0.046) and T2DM (p = 0.004) patients were independent from the covariates (age, sex, BMI and medications). Moreover, Metrnl showed no significant difference in males compared to females.
Association of Metrnl with CAD and T2DM
Multinomial logistic regression revealed that decreased serum levels of Metrnl were associated with increased risks of CAD (OR [CI] = 0.982 [0.970–0.994]) and T2DM (OR [CI] = 0.981 [0.968–0.993]) incidence. Also, after adjusting for age, sex and BMI, the association with CAD and T2DM remained significant (Table 3). ROC curve analysis showed that a cut of the value of Metrnl = 74.86 pg/mL, had a relatively good sensitivity (68.3%) and specificity (66.7%) for discriminating CAD from the control (area under curve (CI): 0.684 (0.584–0.785), p = 0.001, Fig 1A). Also, discriminating T2DM from the control with a cut off value of Metrnl = 73.51 pg/mL had a relatively good sensitivity (68.3%) and specificity (63.5%) (area under curve (CI): 0.709 (0.612–0.807), p < 0.001, Fig 1B).
Table 3. Odds ratios of CAD and T2DM presence according to Metrnl serum levels.
| Model | Group | Odds ratio (CI) | P Value |
|---|---|---|---|
| Crude models | CAD | 0.982 (0.970–0.994) | 0.004 |
| T2DM | 0.981 (0.968–0.993) | 0.002 | |
| Adjusted models* | CAD | 0.980 (0.967–0.993) | 0.004 |
| T2DM | 0.981 (0.968–0.994) | 0.004 |
*Adjustment carried out for age, sex and BMI.
Fig 1. ROC curve for discriminating diseases status from control.
a) ROC curve for discriminating CAD from control. b) ROC curve for discriminating T2DM from control.
Correlation of Metrnl with anthropometric and biochemical parameters
Correlation analysis was performed in the control group and the results revealed that Metrnl significantly correlated with BMI (r = -0.318, p = 0.043) and HOMA-IR (r = -0.329, p = 0.036, Table 4).
Table 4. Spearman correlation of Metrnl with anthropometric and metabolic profiles.
| Control | CAD | T2DM | |
|---|---|---|---|
| Age | -0.129 | 0.225 | 0.121 |
| BMI | -0.318* | -0.146 | -0.354** |
| SBP | -0.168 | 0.035 | 0.039 |
| DBP | -0.077 | 0.034 | 0.075 |
| FBG | -0.266 | -0.192 | -0.420** |
| Insulin | -0.308 | -0.106 | -0.228 |
| HOMA-IR | -0.329* | -0.140 | -0.338** |
| TG | -0.180 | -0.111 | -0.023 |
| TC | -0.090 | -0.013 | -0.051 |
| LDL-C | -0.070 | 0.087 | -0.070 |
| HDL-C | 0.135 | -0.227 | -0.199 |
| Adiponectin | -0.091 | 0.258* | 0.174 |
| TNF-α | -0.306 | -0.294* | -0.335** |
| IL-6 | -0.260 | -0.319** | -0.296* |
| Creatinine | -0.222 | -0.110 | -0.055 |
| AST | -0.203 | -0.048 | 0.029 |
| ALT | -0.132 | 0.032 | -0.095 |
* P Value < 0.05
** P Value < 0.01
In addition, there was a positive correlation between Metrnl and adiponectin (r = 0.258, p = 0.036), in the correlation analysis of patients with CAD. Furthermore, Metrnl revealed a negative correlation with IL-6 (r = -0.319, p = 0.009) and TNF-α (r = -0.294,p = 0.017) (Table 4).
Metrnl demonstrated a negative correlation with BMI (r = -0.354, p = 0.004), FBG (r = -0.420, p = 0.001), HOMA-IR (r = -0.338, p = 0.007), TNF-α (r = -0.296) and IL-6 (r = -0.296, p = 0.018) in patients with T2DM (Table 4).
In addition, all significant correlations were adjusted for age and sex. All correlations remained significant after adjustment, except the correlation between Metrnl and HOMA-IR in the controls and correlation between Metrnl and adiponectin in CAD patients (S1 Table).
Discussion
The relationship between adipose tissue and cardiometabolic disease is a matter of ongoing research [21]. Adipokines as secretory factors from the adipose tissue are considered as potential candidates for the relation of the adipose tissue with whole body glucose and lipids metabolism[1,9]. Studies have shown the perturbation of circulatory adipokines in the context of cardiometabolic diseases such as T2DM, metabolic syndrome, CAD and nonalcoholic fatty liver disease [22–26]. Metrnl is a newly discovered adipokine with favorable effects on insulin resistance [10,11,14]. In the present study, the serum levels of Metrnl decreased in T2DM and CAD patients compared to the controls. In contrast with the present study, Chung et al., showed that the circulating levels of Metrnl were increased in patients with T2DM[15]. This contradiction might be as a result of medication or ethnic differences. Furthermore, in Chung et al.'s study, there is no data on medications whereas the serum levels of lipids (TC, LDL-C and TG) significantly reduced in patients with diabetes. This result suggested intensive lipid lowering therapies in patients with diabetes in Chung et al.’s study. It has been shown that PPAR-γ downregulation attenuates improving insulin sensitivity by Metrnl; therefore, medication that interferes with PPAR-γ signaling might affect the circulating levels of Metrnl. Our study population was free from PPAR-γ antagonists. In addition, Chung et al., selected the study population from the Korean sarcopenic obesity study that included patients with sarcopenia [27], and it has been shown that Metrnl is secreted by skeletal muscle in humans and mice [13]. Therefore, sarcopenia could be a confounding factor in Chung et al.’s study that affects the circulating levels of Metrnl. In line with the present study, Lee et al. demonstrated lower levels of Metrnl in newly diagnosed T2DM patients [16]. In the present study, the results revealed that the serum levels of Metrnl decreased in T2DM and CAD patients independent of age, sex, BMI and medications. Furthermore, our results showed that the decreased serum levels of Metrnl had independent association with increased risk of T2DM and CAD. The exact mechanism for linking Metrnl to the pathogenesis of CAD and T2DM is yet to be clarified. However, experimental studies have reported several favorable actions of Metrnl, such as adipose tissue browning [13], inhabitation of inflammation [13,14], improving insulin sensitivity and improving adipocyte functions[14,23]. It has been shown that a deficiency of Metrnl in adipocytes promotes insulin resistance [14] whereas the upregulation of Metrnl in adipocytes improves insulin sensitivity [14]. Moreover, Metrnl promotes insulin induced AKT phosphorylation [14], and it has been shown that the favorable effects of Metrnl on insulin sensitivity are mediated by PPAR-γ[14]. In the present study, Metrnl was found to be correlated with insulin resistance and the parameter of glucose and insulin metabolism in T2DM patients. Also, Metrnl showed a negative correlation with HOMA-IR in the control, but this correlation disappeared after adjusting for age and sex. Previous studies have shown a negative correlation of Metrnl with the parameter of insulin resistance in the population with and without T2DM and obese patients [16,28], but our results showed that the relation of Metrnl with insulin resistance is significant in the context of T2DM. This result is further in vivo evidence for the relationship between Metrnl and insulin resistance.
Furthermore, Metrnl inhibits TNF-α expression in high fat diet induced inflammation [14]. Metrnl also increased anti-inflammatory cytokines in mice [13]. In the present study, Metrnl had negative correlations with IL-6 and TNF-α in CAD and T2DM patients. These results suggest the possible role played by Metrnl in inflammatory milieu in the context of CAD and T2DM. Based on the fact that both T2DM and CAD are pro-inflammatory based diseases and the serum levels of IL-6 and TNF-α are elevated in the diseases[17], thus it appears that inflammation plays key roles in either the induction or stimulation of the disorders. As a result of the anti-inflammatory effects of Metrnl, via downregulation of IL-6 and TNF-α, it may be hypothesized that Metrnl not only plays crucial roles in the regulation of insulin pathways, it also improves CAD and T2DM pathogenesis via the down-regulation of inflammation. However, according to the fact that cytokines play important roles in network manners, thus, it appears that more investigations by evaluation of other inflammatory and anti-inflammatory cytokines elucidate the roles of Metrnl on the immune system.
White adipose tissue is the main secretion organ for Metrnl [10]. Previous studies showed that Metrnl increased in obese mice [13,14], whereas in the present study a negative correlation was found between BMI and Metrnl in the controls and T2DM patients. This contradiction might result from differences in human and animal studies. In line with our results, a study has shown lower levels of Metrnl in obese subjects and increased levels of Metrnl after bariatric surgery [28].
The results of the present study showed independent association of Metrnl with CAD and T2DM presence, and negative correlation with insulin resistance and inflammation. These results suggest a possible role for Metrnl in the pathogenic mechanisms of CAD and T2DM, which could be a possible explanation for the association of Metrnl with CAD and T2DM. However, the cross sectional design of the present study limited us to conclude that there is a casual relationship between Metrnl and diseases.
Supporting information
(DOCX)
Acknowledgments
We are thankful to Tehran heart center and Aja University of Medical Science, Tehran, Iran.
Data Availability
All relevant data are within the paper and its Supporting Information files.
Funding Statement
The authors received no specific funding for this work.
References
- 1.Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11: 85–97. 10.1038/nri2921 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Nakamura K, Fuster JJ, Walsh K (2014) Adipokines: A link between obesity and cardiovascular disease. Journal of Cardiology 63: 250–259. 10.1016/j.jjcc.2013.11.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A (2016) Epidemiology of coronary heart disease and acute coronary syndrome. Ann Transl Med 4 10.3978/j.issn.2305-5839.2015.12.66 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Libby P, Ridker PM, Hansson GK (2009) Inflammation in Atherosclerosis: From Pathophysiology to Practice. J Am Coll Cardiol 54: 2129–2138. 10.1016/j.jacc.2009.09.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Falk E (2006) Pathogenesis of Atherosclerosis. Journal of the American College of Cardiology 47: C7–C12. 10.1016/j.jacc.2005.09.068 [DOI] [PubMed] [Google Scholar]
- 6.Mahmoudi M, Aslani S, Fadaei R, Jamshidi AR (2017) New insights to the mechanisms underlying atherosclerosis in rheumatoid arthritis. Int J Rheum Dis 20: 287–297. 10.1111/1756-185X.12999 [DOI] [PubMed] [Google Scholar]
- 7.Khodabandehloo H, Gorgani-Firuzjaee S, Panahi G, Meshkani R (2016) Molecular and cellular mechanisms linking inflammation to insulin resistance and beta-cell dysfunction. Transl Res 167: 228–256. 10.1016/j.trsl.2015.08.011 [DOI] [PubMed] [Google Scholar]
- 8.Samuel VT, Shulman GI (2016) The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest 126: 12–22. 10.1172/JCI77812 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Freitas Lima LC, Braga VA, do Socorro de Franca Silva M, Cruz JC, Sousa Santos SH, de Oliveira Monteiro MM, et al. (2015) Adipokines, diabetes and atherosclerosis: an inflammatory association. Front Physiol 6: 304 10.3389/fphys.2015.00304 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Li ZY, Zheng SL, Wang P, Xu TY, Guan YF, Zhang YJ, et al. (2014) Subfatin is a novel adipokine and unlike Meteorin in adipose and brain expression. CNS Neurosci Ther 20: 344–354. 10.1111/cns.12219 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Jorgensen JR, Fransson A, Fjord-Larsen L, Thompson LH, Houchins JP, Andrade N, et al. (2012) Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Exp Neurol 233: 172–181. 10.1016/j.expneurol.2011.09.027 [DOI] [PubMed] [Google Scholar]
- 12.Zheng S, Li Z, Song J, Liu J, Miao C (2016) Metrnl: a secreted protein with new emerging functions. Acta Pharmacol Sin 37: 571–579. 10.1038/aps.2016.9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, et al. (2014) Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157: 1279–1291. 10.1016/j.cell.2014.03.065 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Li ZY, Song J, Zheng SL, Fan MB, Guan YF, Qu Y, et al. (2015) Adipocyte Metrnl Antagonizes Insulin Resistance Through PPARgamma Signaling. Diabetes 64: 4011–4022. 10.2337/db15-0274 [DOI] [PubMed] [Google Scholar]
- 15.Chung HS, Hwang SY, Choi JH, Lee HJ, Kim NH, Yoo HJ, et al. (2018) Implications of circulating Meteorin-like (Metrnl) level in human subjects with type 2 diabetes. Diabetes Res Clin Pract 136: 100–107. 10.1016/j.diabres.2017.11.031 [DOI] [PubMed] [Google Scholar]
- 16.Lee JH, Kang YE, Kim JM, Choung S, Joung KH, Kim HJ, et al. Serum Meteorin-like protein levels decreased in patients newly diagnosed with type 2 diabetes. Diabetes Research and Clinical Practice 135: 7–10. 10.1016/j.diabres.2017.10.005 [DOI] [PubMed] [Google Scholar]
- 17.Sepehri Z, Masoumi M, Ebrahimi N, Kiani Z, Nasiri AA, Kohan F, et al. (2016) Atorvastatin, Losartan and Captopril Lead to Upregulation of TGF-beta, and Downregulation of IL-6 in Coronary Artery Disease and Hypertension. PLoS One 11: e0168312 10.1371/journal.pone.0168312 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, et al. (1999) ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol 33: 1756–1824. [DOI] [PubMed] [Google Scholar]
- 19.(2017) 2. Classification and Diagnosis of Diabetes. Diabetes Care 40: S11–S24. 10.2337/dc17-S005 [DOI] [PubMed] [Google Scholar]
- 20.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: 412–419. [DOI] [PubMed] [Google Scholar]
- 21.Tateya S, Kim F, Tamori Y (2013) Recent Advances in Obesity-Induced Inflammation and Insulin Resistance. Front Endocrinol (Lausanne) 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Emamgholipour S, Moradi N, Beigy M, Shabani P, Fadaei R, Poustchi H, et al. (2015) The association of circulating levels of complement-C1q TNF-related protein 5 (CTRP5) with nonalcoholic fatty liver disease and type 2 diabetes: a case-control study. Diabetol Metab Syndr 7: 108 10.1186/s13098-015-0099-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Fadaei R, Moradi N, Baratchian M, Aghajani H, Malek M, Fazaeli AA, et al. (2016) Association of C1q/TNF-Related Protein-3 (CTRP3) and CTRP13 Serum Levels with Coronary Artery Disease in Subjects with and without Type 2 Diabetes Mellitus. PLoS One 11: e0168773 10.1371/journal.pone.0168773 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Moradi N, Fadaei R, Emamgholipour S, Kazemian E, Panahi G, Vahedi S, et al. (2018) Association of circulating CTRP9 with soluble adhesion molecules and inflammatory markers in patients with type 2 diabetes mellitus and coronary artery disease. 13: e0192159 10.1371/journal.pone.0192159 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Shanaki M, Fadaei R, Moradi N, Emamgholipour S, Poustchi H (2016) The Circulating CTRP13 in Type 2 Diabetes and Non-Alcoholic Fatty Liver Patients. PLoS One 11: e0168082 10.1371/journal.pone.0168082 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Shanaki M, Moradi N, Emamgholipour S, Fadaei R, Poustchi H (2017) Lower circulating irisin is associated with nonalcoholic fatty liver disease and type 2 diabetes. Diabetes Metab Syndr 11 Suppl 1: S467–s472. [DOI] [PubMed] [Google Scholar]
- 27.Kim TN, Yang SJ, Yoo HJ, Lim KI, Kang HJ, Song W, et al. (2009) Prevalence of sarcopenia and sarcopenic obesity in Korean adults: the Korean sarcopenic obesity study. Int J Obes (Lond) 33: 885–892. [DOI] [PubMed] [Google Scholar]
- 28.Pellitero S, Piquer-Garcia I, Ferrer-Curriu G, Puig R, Martinez E, Moreno P, et al. (2017) Opposite changes in meteorin-like and oncostatin m levels are associated with metabolic improvements after bariatric surgery. 10.1038/ijo.2017.268 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
(DOCX)
Data Availability Statement
All relevant data are within the paper and its Supporting Information files.