Published online before print January 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.103077
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(Hypertension. 2008;51:534.)
© 2008 American Heart Association, Inc.
Original Articles Part 2 |
Hyperresistinemia Is Associated With Coexistence of Hypertension and Type 2 Diabetes
From the Departments of Molecular and Genetic Medicine (Y.T., H.O., M.Kurata, J.Y., M.O., W.N., H.M.) and Integrated Medicine and Infomatics (M.Kurokawa, T.O., J.H.), Ehime University Graduate School of Medicine, Ehime, Japan.
Correspondence to Yasunori Takata, Department of Molecular and Genetic Medicine, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan. E-mail ytakata{at}m.ehime-u.ac.jp
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Abstract |
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Numerous studies have demonstrated that high blood pressure substantially increases the risk of microvascular and macrovascular complications in patients with type 2 diabetes mellitus (T2DM). Currently, we found that serum resistin, an adipocyte- and monocyte-derived cytokine, was positively correlated with several components of the metabolic syndrome, including hypertension in T2DM. To investigate the association of resistin with an etiologic difference among subjects with hypertension with T2DM, hypertension without T2DM, and normotensive T2DM, we analyzed 210 subjects, including 91 with hypertension with T2DM, 55 with hypertension without T2DM, and 64 with normotensive T2DM. Serum resistin level was higher in subjects with hypertension with T2DM, followed by subjects with normotensive T2DM and hypertension without T2DM, irrespective of antihypertensive treatment status (20.9±17.6 and 14.0±8.9 versus 11.2±7.6 ng/mL, respectively; P<0.01). Simple regression analysis revealed that resistin positively correlated with blood pressure (systolic blood pressure: r=0.29, P<0.01; diastolic blood pressure: r=0.21, P<0.05) and intima-media thickness (r=0.27; P<0.05) in patients with T2DM but not in subjects with hypertension without T2DM. Multiple regression analysis, adjusted for age, gender, body mass index, fasting glucose, high-density lipoprotein cholesterol, white blood cell counts, and glomerular filtration rate, further revealed that resistin was an independent factor for high blood pressure in patients with T2DM (P<0.05). In vitro gene expression analysis in human coronary endothelial cells revealed that resistin induced fatty acid binding protein, a key molecule of insulin resistance, diabetes, and atherosclerosis. These results suggest that hyperresistinemia would contribute to the pathogenesis of hypertension in patients with T2DM, significantly linked to vascular complications and cardiovascular events.
Key Words: resistin • hypertension • type 2 diabetes • atherosclerosis
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Introduction |
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The frequency of diabetes mellitus is increasing rapidly worldwide. Numerous studies have shown that diabetes and hypertension (HT) are major risk factors for the development of cardiovascular and renal damage.1–3 More than 80% of patients with type 2 diabetes mellitus (T2DM) develop HT, and
20% of patients with HT develop diabetes.4 The coexistence of HT and T2DM renders a diabetic patient approximately twice as likely to experience cardiovascular events as a nondiabetic person.5 Moreover, numerous trials have demonstrated that lowering blood pressure in high-risk patients with diabetes can reduce deaths from strokes, overall mortality, and cardiovascular disease events, and can slow the progression of renal disease in patients with T2DM.5–7 Despite these observations, similarities or differences in the etiologies of HT in diabetic and normal glucose tolerance subjects remain to be elucidated. We currently demonstrated that serum resistin, a monocyte- and adipocyte-derived cytokine, was positively correlated with insulin resistance, T2DM, and the accumulation of metabolic syndrome (MetS) factors, including HT in the Japanese general population.8–11 Moreover, a growing volume of evidence demonstrates that a circulating resistin level and resistin gene single nucleotide polymorphisms are associated with the development of diabetes, HT, and atherosclerosis.10–19
To further investigate the association between hyperresistinemia and the coexistence of HT and T2DM, we investigated 210 subjects, including subjects with HT with T2DM (HTDM), HT without T2DM (HTNDM), and normotension with T2DM (NTDM). Furthermore, to examine candidate genes affected by resistin in human coronary artery endothelial cells (HCAECs), we performed in vitro gene expression studies.
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Methods |
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Subjects
A total of 210 Japanese subjects with T2DM and/or HT were recruited from the patient population of Ehime University Hospital for this study. The characteristics of the study groups are summarized in Table 1. HT was defined as a systolic blood pressure of
140 mm Hg and/or a diastolic blood pressure of 90 mm Hg on repeated measurements or receiving antihypertensive treatment, whereas T2DM was diagnosed based on the 1998 American Diabetes Association criteria.20 Subjects with type 1 diabetes, secondary HT, stroke, and myocardial infarction were excluded from this study. This study was approved by the ethics committee of the Ehime University Graduate School of Medicine, and all of the subjects were informed of the purpose of the study and gave their written consent before enrollment.
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Clinical and Biological Assessment
Blood pressure measurements and carotid ultrasonographic investigations were performed as described previously.21,22 Serum resistin was measured using a human resistin ELISA kit (LINCO Research, Inc), following the manufacturer’s recommended protocol. The linearity was maintained below 0.16 ng/mL. Interassay and intra-assay coefficient variations were 6.9% and 1.7% (low levels) and 7.2% and 8.1% (high levels), respectively.
The estimate of homeostasis model assessment of insulin resistance was calculated with the formula: fasting insulin (µU/mL)xfasting glucose (mg/dL)/405. The abbreviated Modification of Diet in Renal Disease equation was used for assessment of glomerular filtration rate (GFR) as follows: GFR (mL/min per 1.73 m2=0.881x186xserum–creatinine (mg/dL)–1.154xage (years)–0.203x (0.742 if female).
Cell Culture and Treatment
HCAECs (Cambrex) were cultured in EGM-2 complete medium (Cambrex) supplemented with 10% FBS.23 Quiescent HCAECs at passages 4 through 5 were incubated with vehicle or human recombinant resistin (Biovision) at 10, 50, and 100 ng/mL, respectively, for 24 hours.
Gene Expression Analysis
We performed a human atherosclerosis real-time PCR array (RT2 Profiler PCR Array, Super array)24 in 2 different sets of control versus resistin-treated samples, according to instructions provided by the manufacturer. Isolation of total RNA from HCAECs and quantitative real-time PCR were performed as described previously.25 We used the primers listed in the online supplement (available at http://hyper.ahajournals.org).
Statistical Analysis
All of the values are expressed as means±SDs. Statistically significant differences between groups were evaluated using one-way ANOVA with Scheffe posthoc tests, as appropriate. Associations between serum resistin and all of the other parameters were analyzed by simple regression followed by multiple regression analysis. For these regression analyses, categorical variables were used for gender (male=1, female=2). Analyses yielding P<0.05 were considered statistically significant.
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Results |
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Serum Resistin Appeared to Be Highest in HTDM, Followed by NTDM and HTNDM
To identify an etiologic difference of high blood pressure between in diabetic and nondiabetic subjects, known determinants of high blood pressure, MetS, and atherosclerosis were measured in 210 Japanese subjects (91 HTDM, 64 NTDM, and 55 HTNDM subjects) to identify differences among these populations. Only 4 subjects were treated by the thiazolidinedione pioglitazone. Characteristics of these 3 study groups are summarized in Table 1. Serum resistin was markedly elevated in HTDM versus NTDM and HTNDM subjects (20.9±17.6, 14.0±8.9, and 11.2±7.6, respectively). HTDM subjects also had significantly higher white blood cell (WBC) counts and carotid intima-media thicknesses than NTDM or HTNDM subjects. Both NTDM and HTDM subjects had lower uric acid and high-density lipoprotein cholesterol (HDL-C) levels than HTNDM subjects. Similar analyses were performed for subjects taking neither antihypertensive agents nor thiazolidinediones (87 subjects; 15 HTDM, 62 NTDM, and 10 HTNDM subjects). In these nontreated populations, HTDM subjects again had significantly higher serum resistin than NTDM and HTNDM subjects (28.6±24.6, 14.0±8.8, and 12.1±6.7, P<0.01, respectively by ANOVA; P<0.01, HTDM versus HTNDM or NTDM with Scheffe test). No gender differences were observed with any of these parameters, except diastolic blood pressure, which was significantly higher in male versus female HTNDM subjects (88.1±13.1 versus 82.0±14.9, respectively).
Serum Resistin Was Positively Correlated With Mean Blood Pressure in T2DM But Not in Nondiabetic HT
To identify determinants of high blood pressure in subjects with T2DM, simple regression analysis involving mean blood pressure as a dependent variable was performed. It revealed that serum resistin was positively correlated with mean blood pressure in subjects with diabetes (HTDM: r=0.21, P<0.05; diabetes mellitus total: r=0.28, P<0.01), but neither in HTNDM (Table 2) nor normal control subjects (data not shown).
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We, therefore, performed simple and multiple regression analysis to identify whether associations of serum resistin with factors related to HT and atherosclerosis differ between diabetes mellitus and HTNDM (Table 3 and 4
). Simple regression analyses (Table 3) revealed that serum resistin positively correlated with age (r=0.25; P<0.05), systolic and diastolic blood pressure (r=0.29 and r=0.21, respectively; P<0.05), WBC count (r=0.22; P<0.05), and intima-media thickness (r=0.27; P<0.05) and inversely correlated with HDL-C (r=–0.181; P<0.05) and GFR (r=–0.27; P<0.01) in subjects with T2DM. However, in nondiabetic subjects, serum resistin correlated only with triglyceride level (Table 3). Analyses for 91 subjects without antihypertensive agents showed that only the T2DM subjects, but not the HTNDM subjects, again demonstrated significant associations between serum resistin and systolic and diastolic blood pressure (r=0.22, P<0.05 and r=0.23, P<0.05, respectively). A multiple regression analysis, adjusted for age, female gender, body mass index, fasting glucose, HDL-C, WBC count, and GFR, revealed that resistin was an independent predictor of both systolic and diastolic blood pressure in diabetic subjects (P=0.01 and P<0.05, respectively; Table 4). Taken together, these results suggest that serum resistin is closely associated with blood pressure in T2DM subjects, but not in nondiabetic subjects, regardless of treatment status with antihypertensive medications.
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Resistin Increased Gene Expression of the Fatty Acid Binding Protein Family in HCAECs
To further clarify the etiology of high blood pressure in T2DM associated with hyperresistiremia, we performed in vitro gene expression studies using a real-time PCR array approach to examine candidate genes affected by resistin in HCAECs. There was a relatively good correlation between the coefficients of variation obtained for individual genes in both the control and resistin-treated groups. Gene expression analysis using PCR array revealed that treatment of resistin induced fatty acid binding protein (FABP), collagen type 3 
1, and CD44 in HCAECs (6.90-, 4.12-, and 1.89-fold, respectively). PCR array results were replicated by quantitative real-time PCR, which demonstrated that resistin treatment increased gene expression of the FABP family (heart, epidermal, and adipocyte FABPs), a key molecule of MetS, diabetes and atherosclerosis in HCAECs (Figure). We also checked monocyte chemoattractant protein-1 and endothelin-1 as possible positive controls of resistin effects.17 Resistin increased monocyte chemoattractant protein-1 mRNA as expected, whereas endothelin-1 mRNA was unchanged (data not shown).
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P<0.05 vs control). |
Discussion |
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Despite the evidence of the excess risk associated with the coexistence of HT and T2DM,1–7 very limited information exists on the etiology for this coexistence. In the present study, we demonstrate that serum resistin is significantly increased in HTDM compared with NTDM and HTNDM subjects, and the serum resistin level positively correlates with blood pressure in T2DM but not nondiabetic subjects, regardless of antihypertensive treatment status.
Consistent with our results, with a small number of essential HT subjects, Zhang et al26 have showed that serum resistin levels in essential HT with T2DM are significantly higher than those in essential HT with IGT and normal glucose tolerance. Furuhashi et al27 have reported that circulating resistin was not correlated with blood pressure among normal control subjects and subjects with nondiabetic essential HT. Similarly, we found that there was no significant difference in the serum resistin level between HTNDM and normal control subjects (male: 10.7±2.4; female: 11.2±1.4).
We have reported recently that the G/G genotype of the human resistin gene promoter single nucleotide polymorphism at –420C>G variant increases T2DM susceptibility by enhancing promoter activity, which, in turn, leads to an increased monocyte resistin mRNA and serum resistin level in the Japanese general population.10,11 Kunnari et al19 found the following: (1) an association between the resistin –420C>G promoter variant and diastolic BP in patients with T2DM but not in the control group; (2) The –420C>G variant was associated with the presence of cerebrovascular disease; and (3) the +157C>T variant was also associated with high blood pressure in patients with T2DM but not in control subjects. These observations suggest that a physiologically relevant interaction exists between hyperresistinemia and high blood pressure in T2DM but not in nondiabetic subjects.
Recently, Ellington et al28 have demonstrated a negative association of plasma resistin with GFR in hypertensive subjects. Consist with their report, we also showed that serum resistin was inversely associated with GFR in subjects with T2DM, whereas the association between serum resistin level and blood pressure still remained significant when adjusted for age, gender, body mass index, glucose, HDL-C, WBC count, and GFR (Table 4), indicating that resistin was an independent factor for high blood pressure in diabetic subjects.
We have reported recently that serum resistin concentration was higher in Japanese patients with T2DM compared with the subjects with normal glucose tolerance.10,11 Multiple regression analysis showed that serum resistin level was an independent factor of insulin resistance and the accumulation of MetS factors in the Japanese general population. However, body mass index level was not correlated with resistin.8 Because monocytes/macrophages are the main source of resistin expression in humans, adiposity itself may not simply correlate with serum resistin.29 In the present study, we demonstrated a correlation between WBC count and serum resistin level and that WBC count was markedly higher in HTDM versus NTDM and HTNDM subjects. These finding suggests the possibility of an influence of resistin derived from leukocytes on the pathogenesis of the coexistence of HT and T2DM, at least in part.
Recent studies have reported that resistin increases the expression of endothelin-1, adhesion molecules, monocyte chemoattractant protein-1, metalloproteinase, and other mediators that may lead to endothelial dysfunction and promote vasoconstriction17,23 and induces human aortic smooth muscle cell proliferation.30 Furthermore, the resistin-like molecule- has been shown to have vasoconstrictive properties.31 These results propose the influence of resistin on vasoconstriction.
In gene expression analysis, we found that resistin treatment induced HCAEC expression of the FABP family. Mounting evidence suggests that the FABP family plays important roles in the development of MetS and atherosclerosis.32–37 For example, a recent study demonstrated that partial genetic deletion of the heart FABP gene normalizes fasting glucose levels and improves insulin sensitivity in high-fat, diet-induced obese mice.32 Similarly, ablation of the adipocyte FABP gene was shown to provide protection against atherosclerosis, independent of its effects on glucose and lipid metabolism.33,34 Niizeki et al35 have also reported that elevated serum heart FABP levels are associated with HT and renal function in the general Japanese population. Lam and colleagues36,37 have demonstrated that serum adipocyte FABP levels are independently associated with carotid intima-media thickness and predict the development of the MetS independent of adiposity on 5-year follow-up. These results suggest an etiologic relationship between resistin and FABP gene family expression in the development of HT, MetS, and atherosclerosis. Further studies, however, including in vivo analyses, will be required to fully elucidate the relationship between resistin and the FABP family.
Perspectives
In summary, hyperresistinemia is associated with HT in patients with T2DM but not in nondiabetic subjects. Thus, therapies that decrease resistin levels may constitute a new strategy to improve the coexistence of HT and T2DM. Furthermore, hyperresistinemia and resistin gene variants may predict the future onset of HT and T2DM, significant risk factors for atherosclerosis and cardiovascular events. Further studies, including functional analyses and large population sample investigations, will be required to fully clarify the role of the resistin gene in T2DM and HT.
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Acknowledgments |
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We thank Christopher J. Lyon, Mitsuharu Murase, and Shiro Bandou for suggestions. We also thank Tomoko Hamasaki for technical assistance.
Sources of Funding
H.M. was supported by grants for scientific research from the Ministry of Education, Culture, Science, Sports and Technology of Japan and from Ehime University. H.O. was supported by Kurozumi Medical Foundation and Astellas Foundation for Research on Metabolic Disorders.
Disclosures
None.
Received October 12, 2007; first decision November 9, 2007; accepted December 6, 2007.
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