Published online before print September 6, 2007, doi: 10.1161/STROKEAHA.107.485540
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(Stroke. 2007;38:2844.)
© 2007 American Heart Association, Inc.
Research Letters |
Leptin:Adiponectin Ratio Is an Independent Predictor of Intima Media Thickness of the Common Carotid Artery
From the Centro SISA per lo Studio della Aterosclerosi (G.D.N., S.R., L.G., K.G., A.L.C.), Ospedale Bassini, Cinisello Balsamo, Milan, Italy; the Department of Pharmacological Sciences (G.D.N., A.L.C.), University of Milan, Italy; and the Institute of Endocrinology (E.D., P.M.), University of Milan, Italy.
Correspondence to Giuseppe Danilo Norata, Department of Pharmacological Sciences, Via Balzaretti 9, 20100 Milano, Italy. E-mail danilo.norata{at}unimi.it
Abstract
Background and Purpose— The evaluation of the leptin:adiponectin ratio (L:A) has been suggested as an atherosclerotic index in patients with type 2 diabetes and a useful parameter to assess insulin resistance in patients with and without diabetes.
Methods— We investigated, therefore, the relationship between L:A ratio and intima media thickness (IMT), an independent predictor of cardiovascular disease, in 110 healthy males.
Results— L:A ratio was significantly correlated to body mass index, waist, hip, waist-to-hip ratio, systolic blood pressure, IMT, high-density lipoprotein, apolipoprotein A-I, glucose, and the homeostasis model of insulin resistance–revised. No significant correlation was observed with age, diastolic blood pressure, low-density lipoprotein, triglycerides, apolipoprotein B, ApoB/ApoA-I ratio, insulin, alanine transaminase, 
-glutamyl-transferase, and resistin. In addition, when the relationship between IMT and adiponectin or leptin alone was analyzed, only leptin plasma levels significantly associated with IMT (r=0.301, P<0.01). In a multiple regression analysis including in the statistical model the risk factors known to affect IMT (age, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, triglycerides, total cholesterol, body mass index, glucose, and L:A ratio), we observed that only age, L:A, and glucose were independent predictors of IMT. As expected, obese subjects (body mass index >30 kg/m2) showed a significantly higher L:A ratio compared with nonobese subjects (1.20 versus 0.42, respectively, P<0.001); in addition, subjects with the metabolic syndrome showed a significantly higher L:A ratio level (0.79) compared with subjects without (0.52) (P<0.01).
Conclusions— We show here that the L:A ratio is a powerful independent predictor of IMT in healthy subjects and correlates with several anthropometric, metabolic, and clinical parameters better than each single adipokine.
Key Words: body mass index • IMT • leptin:adiponectin ratio • waist-to-hip ratio
Several clinical studies have shown that elevated leptin plasma levels predict acute cardiovascular events, restenosis after coronary angioplasty, and cerebral stroke independently of traditional risk factors.1 Leptin and adiponectin are mainly secreted by the adipose tissue. Their circulating concentrations are increased and reduced, respectively, in obese and/or diabetic subjects. Several experimental studies have shown that increased leptin may directly or indirectly (through promoting insulin resistance?) exert multiple action at the cardiovascular level,1 whereas reduction or lack of adiponectin, like in KO mice, results in accelerated atherosclerotic progression.2
More recently, the evaluation of the leptin:adiponectin ratio (L:A) has been suggested as an atherosclerotic index in patients with type 2 diabetes and a useful parameter to assess insulin resistance in patients with and without diabetes.3–5 We investigated, therefore, the relationship among L:A ratio, intima media thickness (IMT), and other cardiometabolic parameters in healthy males.
Materials and Methods
A total of 110 healthy males randomly selected from the general population (29 to 78 years old)6 were enrolled in this study. Subjects who presented with at least one of the following criteria—use of drugs for dyslipidemia or diabetes, presence of liver or kidney disease, and thyroid dysfunction—were excluded. The study was approved by the ethics committee of the Centre for the Study of Atherosclerosis (University of Milan, Italy) and the participating subjects signed an informed consent. Measurement of biochemical parameters and clinical outcome were performed with standard procedures and are described elsewhere.6,7 Briefly glucose, insulin and lipids were measured using the Cobas Mira Plus analyser (Horiba, ABX, France), ApoA-I and ApoB were measured following turbidimetric analysis and processing in the Cobas Mira Plus analyzer and resistin was measured using a commercially available sandwich enzyme-linked immunosorbent assay kit (MBL International Corp, Woburn, Mass). Ultrasound scanning and reading of carotid arteries were performed by a single expert sonographer using an 8-MHz transducer (Biosound 2000 II sa) with an axial and lateral resolution of 0.385 and 0.500 mm, respectively. The sonographer was blinded to the subject’s identity. B-mode evaluations are obtained from echographic images of the far wall in the first centimeter of common carotid arteries, proximal to the bulb dilation, in lateral projection. Five standardized points 5, 10, 20, 25, and 30 mm from the carotid bulb were measured in both arteries and averaged to calculate the mean IMT for each subject.8 Circulating concentrations of total leptin were measured using a commercial radioimmunoassay kit for human leptin (Linco Research Inc, St. Louis, Mo) and plasma adiponectin levels (all the isoforms) were measured using a commercial enzyme-linked immunosorbent assay kit (Assaypro, Wienfield, Mo). The presence of metabolic syndrome was defined according to the National Cholesterol Program, Adult Treatment Panel III (NCP-ATPIII) guidelines. Data were analyzed using the program SPSS 12.0 for Windows (Chicago, Ill). The relationship between L:A and other clinical and metabolic parameters was performed using Spearman’s rank correlation test. Multiple stepwise regression analysis was performed with IMT level as the dependent variable and by entering the independent variables with the highest partial correlation coefficient at each step with an F value probability for inclusion of 0.05 and 0.01 for removal. Group differences or correlations with P<0.05 were considered as statistically significant.
Results and Discussion
The characteristics of the subjects selected for this study are shown in Table 1. The age ranged between 29 and 78 years; hypertension was present in 23%, dyslipidemia in 35%, and diabetes in 4.6% of subjects.
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L:A ratio was significantly correlated to body mass index, waist, hip, waist-to-hip ratio, systolic blood pressure, IMT, high-density lipoprotein, apolipoprotein A-I, glucose, and the homeostasis model of insulin resistance–revised (Table 1). No significant correlation was observed with age, diastolic blood pressure, low-density lipoprotein, triglycerides, apolipoprotein B, ApoB/ApoA-I ratio, insulin, alanine transaminase, -glutamyl-transferase, and resistin (Table 1). In addition, when the relationship between IMT and adiponectin or leptin alone was analyzed, only leptin plasma levels were significantly associated with IMT (r=0.301, P<0.01).
We performed multiple regression analysis including in the statistical model the risk factors known to affect IMT (age, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, triglycerides, total cholesterol, body mass index, glucose, and L:A ratio); we observed that only age, L:A, and glucose were independent predictors of IMT (Table 2); the analysis of variance inflation factors excluded multicollinearity for these variables.
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As expected, obese subjects (body mass index >30 kg/m2; n=19; mean age 61±7 years) showed a significantly higher L:A ratio compared with nonobese subjects (1.20 versus 0.42, respectively, P<0.001); in addition, subjects with the metabolic syndrome (n=13, mean age 55±13 years) showed a significantly higher L:A ratio level (0.79) compared with subjects without (0.52; P<0.01).
Our data indicate, for the first time, that the L:A ratio, together with age and glucose, is an independent predictor of IMT in healthy subjects. Of note, when the predictive power on IMT levels of leptin and adiponectin per se was assessed by multiple regression analysis, none of the 2 adipokines appeared to be an independent predictor of IMT, whereas body mass index resulted in an independent predictor of IMT. It is reasonable that the obesity status could influence the levels of adipokines; however, our data suggest that the evaluation of L:A ratio could be a powerful predictor of IMT independent of body mass index not only in patients with diabetes,3 but also in healthy subjects.
According to our data, the L:A ratio is a powerful marker for predicting IMT thickness and, possibly, cardiovascular outcome. Furthermore, because the levels of the 2 adipokines are more sensitive to metabolic perturbations, the ratio could be of interest to monitor the severity of the metabolic syndrome, in agreement with Inoue et al, who suggested the use of the L:A ratio to assess insulin resistance in subjects without hyperglycemia5 and Satoh et al, who suggested the use of the L:A ratio as an atherogenic index in obese type 2 diabetes subjects.9
In conclusion, we show here that the L:A ratio is a powerful independent predictor of IMT in healthy subjects and correlates with several anthropometric, metabolic, and clinical parameters better than each single adipokine. Further studies are warranted to clarify whether modification of the L:A ratio after lifestyle and/or pharmacological treatment could result in beneficial effects in terms of cardiovascular outcome.
Acknowledgments
The excellent technical support of Ms Paola Assi and Giovanna Micciché is gratefully acknowledged.
Sources of Funding
This work was supported by grants from Università degli Studi di Milano (FIRST) and Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN).
Disclosures
None.
Received February 16, 2007; revision received March 28, 2007; accepted April 4, 2007.
References
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2. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006; 116: 1784–1792.[CrossRef][Medline] [Order article via Infotrieve]
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5. Inoue M, Yano M, Yamakado M, Maehata E, Suzuki S. Relationship between the adiponectin–leptin ratio and parameters of insulin resistance in subjects without hyperglycemia. Metabolism. 2006; 55: 1248–1254.[CrossRef][Medline] [Order article via Infotrieve]
6. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Catapano AL. Effects of fractalkine receptor variants on common carotid artery intima-media thickness. Stroke. 2006; 37: 1558–1561.
7. Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L, Catapano AL. Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol. 2007; 156: 279–284.
8. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, Maggi FM, Catapano AL. Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J Intern Med. 2005; 258: 21–27.[CrossRef][Medline] [Order article via Infotrieve]
9. Satoh N, Naruse M, Usui T, Tagami T, Suganami T, Yamada K, Kuzuya H, Shimatsu A, Ogawa Y. Leptin-to-adiponectin ratio as a potential atherogenic index in obese type 2 diabetic patients. Diabetes Care. 2004; 27: 2488–2490.
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