Address correspondence and reprint requests come Christos S. Mantzoros, MD, department of Endocrinology, Diabetes and Metabolism, department of internal Medicine, Beth Israel Deaconess clinical Center, Harvard clinical School, 99 Brookline Ave., RN 325A, Boston, MA 02215. E-mail: cmantzoratbidmc.harvard.edu
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Abstract

OBJECTIVE—Adiponectin and resistin, two recently uncovered adipocyte-secreted hormones, may attach obesity through insulin resistance and/or metabolic and also cardiovascular hazard factors. We performed a cross-sectional examine to investigate the combination of adiponectin and also resistin with inflammatory markers, hyperlipidemia, and also vascular reactivity and also an interventional research to investigate whether atorvastatin mediates its beneficial effects by altering adiponectin or resistin levels.

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RESEARCH DESIGN and METHODS—Associations amongst vascular reactivity, inflammation markers, resistin, and adiponectin were assessed cross-sectionally making use of fasting blood samples acquired from 77 topics who had diabetes or were at high danger to develop diabetes. The impact of atorvastatin top top adiponectin and resistin levels was investigated in a 12-week-long randomized, double-blind, placebo-controlled study.

RESULTS—In the cross-sectional study, we confirm prior optimistic correlations that adiponectin with HDL and an adverse correlations v BMI, triglycerides, C-reactive protein (CRP), and also plasma activator inhibitor (PAI)-1 and report a negative correlation with tissue plasminogen activator. The hopeful association through HDL and the an unfavorable association through PAI-1 remained far-reaching after adjusting for sex and also BMI. We also confirm prior result of a negative correlation the resistin with HDL and also report because that the an initial time a hopeful correlation with CRP. All of these associations remained significant after adjusting because that sex and BMI. No associations the adiponectin or resistin with any aspects that vascular reactivity to be detected. In the interventional study, atorvastatin reduced lipid and CRP levels, but adiponectin and also resistin to be not specifically altered.

CONCLUSIONS—We conclude that adiponectin is significantly associated with inflammatory markers, in part, through an basic association with obesity, conversely, resistin’s associations v inflammatory markers show up to be independent the BMI. Lipid profile and also inflammatory marker alters produced by atorvastatin can not be attributed to changes of one of two people adiponectin or resistin.


Obesity and insulin resistance are connected with cardiovascular threat factors, including transformed levels of inflammatory markers and endothelial dysfunction (1). Two recently figured out adipocyte-secreted hormones, adiponectin and resistin, are thought to connect obesity v insulin resistance and also cardiovascular danger (1–7). Adiponectin, a recently uncovered 244-amino acid, adipose-specific protein (2), is discovered in high concentration in the peripheral circulation (3), and also its circulating levels are lessened in excessive weight and form 2 diabetes (4). Adiponectin levels room inversely associated with main or in its entirety adiposity, as well as hyperlipidemia and also insulin resistance individually of BMI (5,6). Resistin levels have actually been report to be markedly elevated in obese mice and to be decreased by insulin sensitizers, such as rosiglitazone and also other thiazolidinediones, and by the management of antiresistin antiserum, which also leads to a far-reaching decrease in blood glucose (7). This initial findings in mice were challenged by succeeding observations, however, demonstrating enhanced or diminished resistin levels in obesity as well as variable responses to thiazolidinediones (8,9) and a null association in between circulating resistin and also insulin resistance in people (10,11). Interestingly, return resistin has actually structural similarity to proteins involved in inflammatory procedures (12), turn around resistin levels have actually never been studied in relation to inflammatory markers in humans. In contrast, adiponectin has actually been associated with markers of inflammation, such together C-reactive protein (CRP) and also tumor necrosis factor-α (TNF-α) (13,14), but associations through several various other inflammatory markers remain to be studied.

Thus, we have studied cross-sectionally whether adiponectin is inversely associated and also if resistin is positively linked with inflammatory markers, hyperlipidemia, and also vascular reactivity. We additionally studied, in the context of a 12-week-long, double-blind, randomized, placebo-controlled clinical trial, whether atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, which reduces full cholesterol, LDL (15), and triglycerides (16), increases HDL levels (17), and may mediate enhanced insulin sensitivity (18), affects these outcomes by changing adiponectin and/or resistin levels.


RESEARCH DESIGN and METHODS

The present study had 77 previously studied subjects (19) who had actually diabetes v no serious long-term complications (defined as macroalbuminuria, significant neuropathy, and/or peripheral vascular condition associated with foot ulceration or various other lower-extremity amputations) or were thought about at higher risk to develop type 2 diabetes 보다 the general populace (a hopeful family background and a normal 75-g oral glucose tolerance test, subjects with at least one first-degree relative with form 2 diabetes, or topics with impaired glucose tolerance), making use of previously explained criteria (20). The examine protocol was authorized by the institutional testimonial boards in ~ the Joslin Diabetes Center and the Beth Israel Deaconess medical Center. ~ being educated on the purpose and procedures of the study, all subjects signed an informed consent form. Subjects were evaluated at one initial screening visit, which associated a complete medical background and physical examination consisting of blood pressure, weight, height, waist-to-hip ratio, fundoscopy, and also evaluation because that clinical indications of neuropathy. Subjects were to exclude, if they had actually a known history of cardiovascular disease, punch or transient ischemic attack, untreated hypertension, liver disease, renal disease, severe dyslipidemia (triglycerides >600 mg/dl or cholesterol >350 mg/dl), or any type of other serious chronic an illness requiring active treatment. Females of child-bearing potential not making use of an effective type of nonhormonal birth control and also subjects taking lipid-lowering agents during the last 3 months, glucocorticoids, antineoplastic agents, psychosis agents, or bronchodilators ~ above a regular basis were likewise excluded.

Cross-sectional study

Blood samples were acquired after an overnight fast (∼10 h) and also a 24-h period totally free of alcohol or vigorous exercise. Topics were asked no to take your diabetes medicines (sulfonylureas or metformin) for 12 h before each visit. Those subjects using insulin were asked for to organize the rapid-acting insulin the morning of each visit. Blood samples were attracted from an antecubital vein with a 19-gauge needle without venous stasis, and the sera were stored at −70°C.

Interventional study

The result of atorvastatin on adiponectin and also resistin levels was investigated in a randomized, double-blind, placebo-controlled study. The 77 topics described above in the cross-sectional study were randomized in a double-blind way to receive either 20 mg that atorvastatin day-to-day or the corresponding placebo because that 12 weeks. The subjects were request to continue with their prior medications, diet plan, and also physical activity level in a consistent manner for the duration of the study. Topics were evaluated at baseline and reevaluated ~ a 12-week treatment duration at an departure visit through repeat laboratory evaluations. Vascular reactivity trial and error was likewise done in ~ baseline and also repeated at 12 weeks. To advice the combination of serum adiponectin levels, serum resistin levels, and also markers of vascular inflammation, fasting blood samples were acquired at baseline and at 12 weeks.

Hormone measurements

Blood samples were analyzed for HDL cholesterol, LDL cholesterol, complete cholesterol, triglycerides, endothelin-1 (ET1), CRP, tumor necrosis factor-α (TNF-α), intracellular adhesion molecule (ICAM), plasma activator inhibitor (PAI)-1, tissue plasminogen activator (tPA), adiponectin, and resistin. Plasma total cholesterol, HDL cholesterol, and also triglycerides to be measured using the Synchron CX analyzer (Beckman/Coulter) together previously described (21). LDL cholesterol was calculated from these results. Hormone concentrations were measured making use of commercially obtainable methods (10) as follows: adiponectin radioimmunoassay (Linco Research, St. Charles, MO) (sensitivity 2 μg/ml; intra-assay coefficient of sport 1.78–6.21%), human being resistin (BioVendor, Brno, Czech Republic) (0.2 ng/ml; 3.4–5.2%), dissolve ICAM (R & D Systems, Minneapolis, MN) (0.35 ng/ml; 3.3–4.8%), and also ET1 (R & D Systems) (1.0 pg/ml; 4.2–4.6%) were measured in plasma by the enzyme-linked immunosorbent assay method. TNF-α (Immulite DPC) (8.1 pg/ml; 2.6–3.6%) and CRP (Immulite DPC) (0.01 mg/dl; 4.2–6.4%) were measured through chemiluminescent immunoassay. PAI-1 (Diagnostica Stago, France) (1.0 ng/ml; 5.48–6.53%) and also tPA (Diagnostica Stago) (1.0 ng/ml; 4.49–4.54%) were additionally measured through the enzyme-linked immunosorbent assay method. To minimization variability, hormone levels to be measured in one assay for all subjects participating in the cross-sectional study and in one assay because that each topic in the interventional studies.

Vascular reactivity tests

The vascular reactivity that the forearm skin microcirculation to be evaluated by laser Doppler perfusion imaging measurements before and also after iontophoresis the acetylcholine chloride (, percent boost over baseline the endothelium-dependent vasodilation) and also sodium nitroprusside (, percent rise over baseline the endothelium-independent vasodilation) and as previously defined (22). To assess the endothelium-dependent reactivity in the macrocirculation, the flow-mediated brachial artery dilation to be measured by utilizing a high-resolution ultrasound with a 10.0-MHz linear array transducer and also an HDI Ultramark 9 system (Advanced modern technology Laboratories, Bothel, WA). Reactive hyperemia was developed by inflating a pneumatic tourniquet come 50 mmHg above the systolic push for 5 min distal come the brachial artery, and the flow at rest and reactive circulation were measured. All dimensions were in accordance with recently published indict (23). Endothelium-independent vasodilation in the macrocirculation (nitroglycerin-induced dilation ) was assessed by studying brachial artery diameter alters 5 min after ~ the administration of 400 μg the sublingual nitroglycerine (19). This test was performed 15 min after ~ the reactive hyperemia test and after obtaining a brand-new baseline reading.

Data analysis

Data to be summarized using conventional procedures. Any absent values due to insufficient sample or values outside the assay selection were excluded indigenous the evaluation of this specific variable only. In the cross-sectional study, we performed both Spearman’s and Pearson’s correlation analysis, and we report herein the Spearman’s correlation coefficients that are more conservative. Then us performed bivariate and multivariate regression analyses. We evaluated because that potential associations amongst serum adiponectin levels and also serum resistin level (dependent variables) and also BMI, metabolic markers (lipid profile), inflammation parameters (ICAM, ET1, TNF-α, CRP, PAI-1, tPA), and also vascular reactivity, every expressed as continuous variables. In the multivariate analysis models, we evaluated the same independent variables after managing for potential confounding by sex, sex and also BMI, and sex, BMI, and also HbA1c. Logarithmic revolution was supplied to normalize nonnormally dispersed dependent variables.

In the interventional study, we assessed the distinctions in adiponectin and resistin levels, lipid levels and inflammatory marker levels, and also BMI utilizing a combine t test because that parametrically distributed data and also the Wilcoxon matched-pair signed-rank test for nonparametrically distributed data to compare baseline data and also data in ~ the finish of the study. The t test was supplied to compare the baseline characteristics in between those receiving energetic treatments and those receiving placebo.

SPSS 8.0 software (SPSS, Chicago, IL) was used for statistical analysis. A P worth Table 1. Spearman correlations, consisting of all subjects, among adiponectin and also the metabolic markers, inflammatory markers, and also vascular reactivity, evidenced prior findings of the optimistic correlation through HDL (r = 0.42, P Table 2). We uncovered no correlation of adiponectin with vascular reactivity or glucose levels. Spearman correlations, including all subjects, among resistin and also the metabolic markers, inflammation markers, and vascular reactivity, shown prior findings of a negative correlation through HDL (r = −0.23, P Table 2). Resistin was not connected with any kind of other examine variable, including glucose.

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We climate performed bivariate regression analyses the adiponectin and of resistin v metabolic factors, inflammation markers, and vascular reactivity thought about as live independence variables (Tables 3 and also 4). We discovered a confident correlation the adiponectin through HDL and also a an adverse correlation of adiponectin v triglycerides, CRP, PAI-1, and tPA (Table 3). In addition, there was no association amongst adiponectin and also total cholesterol, LDL, ICAM, ET1, TNF-α, and also the vascular reactivity measurements (flow in ~ rest, flow-mediated brachial artery dilation, NID, ACH%, and NNP%). To readjust for potential confounders, us then perform multivariate regression analyses, adjusting because that successively presented covariates: sex, climate sex and also BMI, and finally sex, BMI, and also HbA1c. Through adjustment for sex, all of the optimistic and negative correlations discovered with the bivariate analyses remained significant. However, after ~ adjusting for both sex and also BMI, only the confident association through HDL and the negative association for PAI-1 remained significant (Table 3), indicating that adiponectin may mediate the effect of weight problems on triglycerides, CRP, and tPA. Finally, we discovered a positive correlation of resistin with CRP and also a an unfavorable correlation through HDL (Table 4), and these associations remained far-ranging after adjusting for sex, BMI, and also HbA1c, indicating the the effect of resistin is elevation of obesity and also glycemic control. We likewise ran these correlations of adiponectin and resistin v metabolic markers, inflammatory markers, and vascular reactivity, excluding the kind 1 diabetic subjects. We uncovered a comparable positive correlation the adiponectin v HDL (r = 0.40, P Table 5). CRP levels also decreased substantially in the atorvastatin group but did not readjust significantly in the placebo group. Serum adiponectin levels did not readjust significantly in either the placebo or active treatment group, and serum resistin levels decreased significantly yet to the same level in both groups (Table 5), indicating that atorvastatin has actually no particular effect ~ above these two hormones. Comparable results were acquired when diabetic and also nondiabetic subjects were thought about separately.