Adiponectin plasma concentration, type 2 diabetes mellitus, cardiovascular diseases and features of metabolic syndrome

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1 Monika Żurawska-Kliś 1, Jacek Kasznicki 1, Marcin Kosmalski 1, Janusz Śmigielski 2, Józef Drzewoski 1 ORIGINAL 1 Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Poland 2 Department of Medical Informatics and Statistics, Medical University of Lodz, Poland Adiponectin plasma concentration, type 2 diabetes mellitus, cardiovascular diseases and features of metabolic syndrome Abstract Background. The aim of the study was to assess the relationship between adiponectin plasma concentration and anthropometric variables of obesity, type 2 diabetes mellitus (T2DM) as well as atherosclerotic-related cardiovascular diseases (CVD). Material and methods. 96 randomly selected subjects participated in the study, including 64 T2DM patients (aged ± ± 13.5 years; 34 women and 30 men; mean HbA 1c 7.9 ± ± 1.6%) and 32 without T2DM (aged ± years; 18 women and 14 men). Of 96 subjects, 37 diabetic patients and 19 non-diabetic subjects had documented CVD, defined as coronary heart disease, stroke or peripheral artery disease. Body mass index (BMI), waist circumference, waist to hip ratio (WHR) and blood pressure were determined. Plasma concentrations of adiponectin, glucose, insulin, total cholesterol and triglycerides were measured at fasting. Results. Circulating adiponectin level was significantly lower in T2DM patients than in non-diabetic subjects (7.26 ± ± 4.42 mg/ml vs ± 5.90 mg/ml; P < 0.001). Significant inverse correlations between adiponectin circulating level and WHR (r = 0.31; P < 0.05), total cholesterol (r = 0.26; P < 0.05), triglycerides (r = 0.35; P < 0.001) and HbA 1c (r = 0.25; P < 0.05) were found in T2DM patients. In subjects without diabetes the correlation was found only between adiponectin and triglycerides levels (r = 0.40; P < 0.05). Adiponectin plasma concentration did not differ depending on the presence or absence of CVD neither in diabetic nor in non-diabetic subjects. Conclusions. Adiponectin level in T2DM patients correlated negatively with WHR, total cholesterol, triglycerides and HbA 1c levels. No significant correlation between adiponectin level and atherosclerotic-related cardiovascular diseases was found both in T2DM patients and subjects without diabetes. Diabet Dośw Klin 2009; 9, 2: key words: adiponectin, obesity, type 2 diabetes mellitus, cardiovascular diseases Introduction Adiponectin is of particular interest in cardiometabolic diseases because of its close associations with insulin sensitivity and obesity. Plasma levels of adiponectin correlate inversely with glucose and insulin concentration, insulin resistance and HbA 1c [1, 2]. Several clinical studies have shown that adiponectin concentration is lower in obese and type 2 diabetic subjects [3 5]. Plasma concentrations of adiponectin are inversely associated with Address for correspondence: Józef Drzewoski, MD, PhD Klinika Chorób Wewnetrznych z Oddzialem Diabetologii i Farmakologii Klinicznej Uniwersytet Medyczny w Łodzi ul. Parzeczewska 35, Zgierz Tel (+48 42) , Fax (+48 42) jdrzew@poczta.onet.pl; jkasznicki@vp.pl Diabetologia Doświadczalna i Kliniczna 2009, 9, 2, Copyright 2009 Via Medica, ISSN markers of inflammation such as fibrinogen and C-reactive protein [6]. It was also reported that adiponectin attenuates leucocytes adhesion to endothelial cells via inhibition of adhesion molecules expression [7]. Adiponectin inhibits macrophage transformation to foam cells as well as their phagocytic activity [8, 9]. In addition, adiponectin diminishes oxidized low density lipoproteins accumulation in blood vessel wall and increases nitric oxide production in endothelial cells [10]. It is suggested that adiponectin via the above mentioned mechanisms may not only protect against atherosclerosis but also retard its progression [11, 12]. However, it is worth stressing that the results of some studies did not confirm significant link between adiponectin and cardiovascular disease [13 15]. The aim of our study was to assess the correlation of adiponectin plasma concentration and anthropometric variables of obesity, type 2 diabetes mellitus (T2DM) as well as atherosclerotic-related cardiovascular diseases (CVD) in T2DM subjects and in non-diabetic subjects. 81

2 Diabetologia Doświadczalna i Kliniczna 2009, Vol. 9, No. 2 Material and methods Patient selection The study population consisted of 96 randomly selected patients recruited from the Department of Internal Medicine, Diabetology and Clinical Pharmacology and from diabetic outpatient medical clinic between September 2003 and December Sixty four patients (aged ± 13.5 years; 34 women and 30 men; mean HbA 1c 7.9 ± 1.6%) were diagnosed with type 2 diabetes before the study entry. Thirty two subject (aged ± ± years; 18 women and 14 men) were diabetes free. Fasting serum glucose levels and 2 h after an oral glucose load were used to classify subjects according to the 1999 World Health Organization criteria into normal glucose metabolism. The patients were assigned into two subgroups: with or without cardiovascular disease (coronary artery disease, stroke and/or peripheral artery disease) confirmed by reviewing their medical records. All patients with type 2 diabetes were treated with diet, oral hypoglycemic agents (sulphonylureas and/or metformin), and/or insulin. The patients diagnosed with CVD were treated with appropriate medications, including angiotensin-converting enzyme inhibitors, beta- -blockers, calcium channel blockers, angiotensin receptor blockers, anti-platelet agents, lipid lowering agents and nitroglycerine. All participants received a complete physical examination including systolic and diastolic blood pressure, body weight, height, waist-to-hip ratio measurements, and evaluation of clinical signs of cardiovascular disease. Stature was measured to 0.5 cm on a stadiometer, and weight was measured to 0.1 kg on a balance scale. The waist circumference of each subject was measured at the level of umbilicus to the nearest millimeter with a fiberglass tape measure. Patients were not included if they suffered from any acute infections or chronic inflammatory processes, severe renal and liver dysfunction, autoimmune diseases or cancer. The study protocol was approved by the local ethics committee. Written informed consent was obtained from all patients before entering the study. Blood sampling Blood was sampled at fasting for the measurement of plasma glucose (FPG), plasma insulin, HbA 1c, total cholesterol, triglycerides and adiponectin concentration. ELISA (enzyme-linked immunosorbent assay) kits were used for the measurements of adiponectin and insulin plasma levels. Plasma glucose and lipids were assayed by routine automated laboratory methods. Total adiponectin was measured by Quantikine Human Adiponectin/Acrp30 Immunoassay, RáD Systems, UK (Catalog Number DRP300RaD) with an inter-assay coefficient of variation (CV) between 5.8% and 6.9%, and intra-assay CV of %. Insulin plasma levels were measured using INS-EASIA Assay, Biosource, Belgium (Catalog Number KAP1251) with an inter- and intra-assay CV between 4.5 and 9.5%, and 3.0 and 5.3%, respectively. Adiponectin and insulin concentrations were measured in plasma specimens that had been frozen at 20 o C and stored for no longer than 6 months. The following variables were also determined: body mass index BMI [(body weight)/(height) 2 ], waist circumference, waist to hip ratio WHR [(waist)/(hip)] and systolic and diastolic blood pressure. The insulin resistance index was calculated based on homeostasis model assessment (HOMA-IR) [16]. Statistical analysis Results are shown as means ± SD. Because of the skewness of the distributions U Mann-Withney s test was used to assess the differences between variables. Univariate associations of adiponectin with measures of adiposity, insulin, glucose, insulin resistance, lipids and blood pressure were determined using Spearman s rang correlation analysis. c 2 test was used to evaluate the relationships for non-continuous variables [17]. P values < 0.05 were considered statistically significant. Results The number of subjects in each group is given in Table 1, along with baseline demographic and descriptive characteristic. Type 2 diabetes mellitus patients exhibited significantly higher waist circumference, WHR and BMI compared with non-diabetic subjects. Fasting plasma glucose was also significantly higher in diabetic patients. There were no significant differences between those two groups in regard to the following variables: age, sex, systolic and diastolic blood pressure, fasting insulin level, total cholesterol and triglyceride concentrations, HOMA-IR. Significantly higher levels of total adiponectin were found in women compared to men (10.5 ± 6.21 mg/ml vs ± 5.04 mg/ml; P < 0.05; data not shown). Of the participants, 37 diabetic patients and 19 nondiabetics presented with CVD defined as coronary heart disease, stroke and/or peripheral artery disease (data not shown). In order to compare the relationship of adiponectin with diabetes mellitus and CVD we evaluated adiponectin plasma concentrations depending on the presence of diabetes mellitus, as well as CVD. The data are shown in Tables 2 and 3, and Figures 1 and

3 Monika Żurawska-Kliś et al., Adiponectin plasma concentration, type 2 diabetes mellitus Table 1. Characteristic of studied populations T2DM Non-T2DM P N Women/men 34/30 18/14 NS Age (years) ± ± NS Body mass index [kg/m 2 ] ± ± 4.95 < 0.05 Waist circumference [cm] ± ± 11.9 < Waist to hip ratio 0.95 ± ± 0.07 < 0.05 Systolic blood pressure [mm Hg] ± ± 13.2 NS Diastolic blood pressure [mm Hg] ± ± NS Fasting glucose [mmol/l] 7.8 ± ± 0.4 < Fasting insulin [miu/ml] 11.6 ± ± 9.64 NS HOMA-IR [U] 3.73 ± ± 2.13 NS Total cholesterol [mmol/l] 5.4 ± ± 0.9 NS Triglycerides [mmol/l] 1.9 ± ± 0.9 NS Data are shown as mean ± SD, T2DM type 2 diabetic subjects, non-t2dm non-diabetic subjects, N number of patients, NS not statistically significant Table 2. Adiponectin plasma concentration depending on the presence of type 2 diabetes mellitus Group of patients Adiponectin concentration [mg/ml] T2DM (+) (n = 64) 7.26 ± 4.42 T2DM ( ) (n = 32) ± 5.90 T2DM (+) diabetic subjects, T2DM ( ) non-diabetic subjects Table 3. Adiponectin plasma concentration depending on the presence of cardiovascular disease (CVD) Group of patients Adiponectin concentration [mg/ml] Figure 1. Adiponectin plasma concentration in diabetics [DM (+)] vs. non-diabetics [DM ( )] CVD (+) (n = 56) 9.81±5.43 CVD ( ) (n = 40) 8.88±6.33 CVD (+) patients with CVD, CVD ( ) patients without CVD As mentioned, there was a significant difference in adiponectin plasma level between type 2 diabetic patients and the subjects without diabetes (P < 0.001). On the contrary, adiponectin plasma levels did not differ according to presence or absence of CVD. The entire group of the patients enrolled in our study was also subdivided into four groups: 1. healthy subjects [T2DM( ),CVD( )]; 2. patients suffering from CVD only [T2DM( ), CVD(+)]; 3. type 2 diabetic subjects without CVD [T2DM(+), CVD( )]; 4. subjects suffering from both T2DM and CVD [T2DM(+),CVD(+)]. Figure 2. Adiponectin plasma concentration in subjects suffering from cardiovascular disease [CVD (+)] vs. subjects without cardiovascular disease [CVD ( )] 83

4 Diabetologia Doświadczalna i Kliniczna 2009, Vol. 9, No. 2 Table 4. Adiponectin plasma concentrations depending on the presence or absence of type 2 diabetes mellitus (T2DM) together with cardiovascular disease (CVD) Group of patients Adiponectin concentration [mg/ml] 1. T2DM ( ) CVD ( ) (n = 13) 14.5 ± T2DM ( ) CVD (+) (n = 19) ± T2DM (+) CVD ( ) (n = 27) 6.38 ± T2DM (+) CVD (+) (n = 37) 7.93 ± 4.85 We found significant differences of adiponectin plasma concentrations comparing the group of healthy subjects (group 1) with the group 3 (P < 0.001) and the group 4 (P < 0.01), as well as comparing the group 2 with the group 3 (P <0.001) and the group 4 (P < 0.001). The presence of CVD did not influence adiponectin plasma level neither in diabetic nor in non-diabetic subjects as there were no significant differences of adiponectin level between the group 1 and 2 as well as between the group 3 and 4. Spearman s rang correlation revealed significant inverse correlations between adiponectin plasma level and WHR (r = 0.31; P <0.05), total cholesterol (r = 0.26; P < 0.05), triglycerides (r = 0.35; P < 0.001) and HbA 1c (r = 0.25; P < 0.05) in T2DM patients. The only correlation in the control group was found between adiponectin and triglycerides (r = 0.40; P < 0.05). Discussion Figure 3. Distribution of adiponectin plasma concentration in subjects with and without diabetes depending on the presence of cardiovascular disease Figure 4. Distribution of adiponectin plasma concentration in subjects with and without cardiovascular disease depending on the presence of diabetes Adiponectin plasma concentrations in each group are shown in Table 4 and Figures 3 and 4. Adiponectin level has been reported to be significantly lower in diabetic compared to nondiabetic subjects [3]. The results of the present study and our previous work confirm these observations [5]. We also confirmed that serum adiponectin levels were significantly higher in diabetic women than in man, suggesting that at least some adiponectin concentration variability is sex related [18]. Interestingly, the difference between diabetic and non-diabetic subjects remains statistically significant regardless of the presence or absence of CVD. It was demonstrated between type 2 diabetic patients with CVD and non-diabetic patients (with and without CVD), as well as between type 2 diabetic patients without CVD and non-diabetic patients (with and without CVD). Adiponectin concentration in both groups of the patients did not differ according to the presence or absence of CVD. Moreover, we did not find statistically significant difference neither between type 2 diabetic patients with and without CVD, nor between non-diabetics with and without CVD. These data may suggest that the presence of CVD does not significantly influence adiponectin plasma concentration. On the contrary, Kumada et al. [19] reported significantly lower adiponectin concentrations in patients with coronary artery disease (CAD) compared to control subjects. Hotta et al. [20] found that plasma levels of adiponectin in diabetic individuals with CAD were lower than in diabetic patients without CAD. Observations made by Cavusoglu et al. [21] revealed that adiponectin plasma concentration was an independent predictor of myocardial infarction, cardiac mortality and all-cause mortality in a 2-year follow-up study. Pischon et al. [22] showed that high plasma adiponectin concentrations were associated with lower risk of MI in men. Otsuka et al. [23] found that non- 84

5 Monika Żurawska-Kliś et al., Adiponectin plasma concentration, type 2 diabetes mellitus -diabetic patients with CAD (n = 122) presented with lower adiponectin levels compared to those without CAD and multiple logistic regression analysis demonstrated that adiponectin independently correlated with the presence of CAD. However, it should be pointed out that we included in our study the patients not only with coronary heart disease but also with stroke and/or peripheral artery disease. Therefore, one can speculate that the patient population and inclusion criteria might have an impact on the results obtained in different centers. Shimada et al. [24] reported no predictive value of adiponectin for restenosis after elective coronary stenting. Similarly, Kuller et al. [14] did not show any relationship of adiponectin level with the risk of death from coronary heart disease. Nakamura et al. [15] noted significantly lower adiponectin plasma levels in patients with acute myocardial infarction and unstable angina pectoris but not with stable angina pectoris, compared to the control group. Zoccali et al. [25] observed that adiponectin levels were reduced in individuals with CVD, independently of obesity and diabetes. On the other hand, the data of Dunajska et al. [13] showed that men with coronary atherosclerosis had lower plasma adiponectin level than control subjects (16.2 ± 9.2 vs ± 6.7 mg/ml; P < 0.05). However, after including BMI and waist circumference as covariate data, the difference in adiponectin levels between men with CAD and control subjects lost statistical significance. Differences in the results between these studies may reflect underlying differences in the study populations. Serum concentration of total adiponectin is reduced in obese subjects. Several reports have suggested that reduction in plasma adiponectin level may be related to the elevation of insulin resistance [26]. However, data concerning the association between adiponectin and insulin resistance have been controversial. The inverse correlation was reported both in animals and humans [4]. On the other hand, observations made by other authors remain in contrast with these results [1]. Available data indicate also a negative relationship between plasma adiponectin level and fasting insulin level [3]. These observations were however not confirmed by other investigators [27, 28]. Similarly, the results of our study did not show any correlation between adiponectin plasma concentration, insulin and HOMA-IR. Some authors demonstrate the negative correlation between plasma adiponectin concentration and blood glucose level as well as HbA 1c [1, 2], however this was not confirmed by all authors [27, 29]. We partially confirmed the above relationships, as we have found a significant inverse correlation between adiponectin level and HbA 1c. Our results support the hypothesis that the relationship between adiponectin and insulin resistance may be more complex than initially thought. There are reports providing some indication that adiponectin levels can also be disassociated from insulin resistance. Abbasi et al. [30] pointed out that the relationship between adiponectin and insulin resistance is probably not one of direct cause and effect in all instances. They suggest that it is possible that in some situations their relationship may be mediated in part by insulin levels, by other hormones such as catecholamines or androgens, proinflammatory cytokines, medications, or possibly by changes in adiponectin clearance [30]. The data reveal the negative correlation between adiponectin plasma concentration and waist circumference, BMI and WHR, although some authors do not confirm these observations. The results concerning relationship of adiponectin level with blood pressure are also controversial [31]. In fact, we also noted the negative relationship between plasma adiponectin level and WHR, but not with waist circumference, BMI or blood pressure. Moreover, this correlation was revealed only in diabetic patients and was not shown in subjects without diabetes. The relationship between adiponectin and WHR in diabetic patients seems to be extremely relevant as this index estimates fat tissue distribution and is a measure of abdominal adiposity. Moreover, many authors suggest that WHR or waist circumference is much better and more precise measure of abdominal adiposity than BMI. This correlation seems to be relevant in the light of increasing prevalence of adiposity-related diseases. Recent clinical trials reveal negative relationship between adiponectin and total cholesterol and triglycerides [3, 4]. In our study, the significant correlation between adiponectin and total cholesterol was found only in type 2 diabetic patients. Relationship between adiponectin and triglycerides levels was demonstrated both in diabetics and subjects without diabetes. Limitations of the study The main limitation of our study is the relatively small sample size, which may have led to unstable estimates and a lack of power to detect significant associations. Another limitation of the present work is the fact that the actual adiponectin concentration depends on many endogenic and egzogenic factors, including age, gender, smoking and alcohol consumption [18, 32]. It has been recognized that some medications used by our patients could have potential impact on adiponectin plasma concentration. Numerous studies demonstrated that adiponectin levels are increased by various agents including thiazolidinediones. sulphonylureas, beta blockers, sartans and statins [33, 34]. It was also demonstrated that adiponectin levels correlate with renal function [35]. However, we would like to emphasize that it is very difficult, if not impossible, to recruit the patients not taking drugs that may influence adiponectin level. 85

6 Diabetologia Doświadczalna i Kliniczna 2009, Vol. 9, No. 2 Another limitation is the possibility of selection bias or ascertainment bias. Only subjects presenting with symptoms suggestive of CVD reported in their medical report were reported as having CVD. It is therefore possible that some CVD-affected patients buried among those classified as non-cvd. This may reduce the difference between the groups. The majority of studies concerning this issue were considering only coronary artery disease, and did not take into account the coexisting macrovascular abnormalities including stroke or peripheral artery disease. It seems also relevant that total adiponectin level and not high-molecular weight (HMW) adiponectin isoform was measured in our study. The result of some studies indicate that HMW adiponectin isoform appears to distinguish better the differences between certain groups of patients than assays for total adiponectin [36]. On the other hand, findings of Blüher et al. [37] did not support the superiority of HMW over total adiponectin in assessing metabolic variables such as insulin resistance or lipid profile. Adiponectin level correlates also with measures of obesity as well as glucose and lipids concentrations. Therefore, we suggest that adiponectin plasma level should be used as a potential marker of insulin-resistance related diseases, including type 2 diabetes mellitus and cardiovascular disorders, not solely but only when combined with other markers of cardiometabolic diseases such as measures of obesity, lipid and glucose concentrations, and others. Conclusions In summary, the results of the present study confirm that adiponectin plasma concentrations are significantly lower in type 2 diabetic subjects. In addition, its level correlates inversely with WHR, total cholesterol, triglycerides and HbA 1c. Our findings suggest that the link between adiponectin plasma concentration and type 2 diabetes mellitus is much stronger than between adiponectin level and cardiovascular diseases. However, to clarify the relationship of adiponectin with adiposity-related disorders further longitudinal and prospective studies are needed. This study was supported by grant number and from Medical University of Lodz, Poland. References 1. Heliovaara MK, Strandberg TE, Karonen SL, Ebeling P. Association of serum adiponectin concentration to lipid and glucose metabolism in healthy humans. Horm Metab Res 2006; 38: Mantzoros CS, Li T, Manson JE, Meigs JB, Hu FB. Circulating adiponectin levels are associated with better glycemic control, more favorable lipid profile, and reduced inflammation in women with type 2 diabetes. J Clin Endocrinol Metab 2005; 90: Esposito K, Pontillo A, Di Palo C. et al. Effect of weight loss and life style changes on vascular inflammatory markers in obese women: a randomized trial. 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