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Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Kadoglou N.P.E.,Surgery Academy | Tsanikidis H.,General Hospital of Katerini | Kapelouzou A.,Surgery Academy | And 5 more authors.
Metabolism: Clinical and Experimental | Year: 2010

Visfatin, ghrelin, and apelin are the most recently identified adipocytokines; but their response to insulin-sensitizing agents is poorly clarified. We aimed to assess the differential effects of either rosiglitazone or metformin monotherapy on the aforementioned adipocytokines in patients with type 2 diabetes mellitus (T2DM). One hundred T2DM patients (30 men, 70 women), with poor glycemic control (glycosylated hemoglobin >6.5%) while taking 850 mg of metformin daily, were enrolled. All participants were randomized to receive either adjunctive therapy with rosiglitazone (8 mg/d, n = 50) or the maximum dose (2550 mg/d) of metformin (MET group, n = 50). Anthropometric parameters, glycemic and lipid profile, high-sensitivity CRP (hs-CRP), insulin resistance (homeostasis model assessment of insulin resistance index [HOMA-IR]), visfatin, ghrelin, and apelin were assessed at baseline and after 14 weeks of therapy. Both rosiglitazone and metformin led to similar, significant improvement in glycemic profile and apelin levels, whereas lipid parameters, fat mass, and visfatin remained almost unaffected (P > .05). Insulin resistance was significantly attenuated in both groups, but to a lesser degree in the MET group (P = .045). Rosiglitazone-treated patients experienced a significant decrease in hs-CRP and systolic blood pressure compared with baseline values and those of the MET group (P < .05). Besides, rosiglitazone treatment considerably increased plasma ghrelin (3.74 ± 1.52 ng/mL) in comparison with either baseline (P = .034) or metformin monotherapy values (-2.23 ± 1.87 ng/mL, P = .008). On the other hand, the MET group, rather than the rosiglitazone group, had decreased body mass index (-0.79 ± 0.47 vs 0.56 kg/m2, P = .009). The aforementioned changes in apelin and ghrelin were independently associated with HOMA-IR changes. Both rosiglitazone and metformin favorably changed glycemic indexes and apelin levels. The addition of rosiglitazone seemed to confer greater benefits in ghrelin, hs-CRP, systolic blood pressure, and HOMA-IR regulation than metformin monotherapy. Although these results reflect improvement in cardiovascular risk profile, the overall clinical importance of insulin sensitizers must be further assessed. © 2010 Elsevier Inc. All rights reserved.


Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Kadoglou N.P.E.,Surgery Academy | Kapelouzou A.,Surgery Academy | Tsanikidis H.,General Hospital of Katerini | And 3 more authors.
Experimental and Clinical Endocrinology and Diabetes | Year: 2011

Objective: Vaspin, adiponectin and interleukin-6 (IL-6) constitute novel adipose-tissue derivatives, known as adipokines, which mediate insulin resistance. The aim of the present study was to evaluate the effects of metformin and rosiglitazone on serum levels of those novel adipokines in drug-naïve patients with type 2 diabetes mellitus (T2DM). Methods: 140 patients with T2DM, already treated with diet, but without adequate glycemic control (HbA1c>7%), were randomly assigned to: RSG+MET group, (n=70): Combination therapy with fixed dose of 4 mg rosiglitazone plus 500 mg metformin. MET group, (n=70): Half-maximum dose of metformin monotherapy (1 700 mg/day). Before and after 6-month treatment, body-mass index (BMI), blood pressure (BP), fat-mass, fasting plasma glucose (FPG), HbA1c, insulin resistance indexes (HOMA-IR, insulin), lipids, high-sensitivity CRP (hsCRP), vaspin, adiponectin, and interleukin-6 (IL-6) were measured. Results: Glucose regulation and insulin resistance were equivalently improved from baseline within both groups (p<0.05). There was a considerable amelioration of hsCRP, WBC, adiponectin, IL-6, systolic and diastolic BP with rosiglitazone/metformin combined treatment as compared to baseline (p<0.05) and MET group (p<0.05). In contrast, metformin monotherapy significantly reduced BMI (p<0.001), total-cholesterol (p=0.012) and LDL (p=0.020) levels compared to RSG+MET group. Importantly, serum vaspin concentration was equivalently decreased from baseline in both RSG+MET (0.96±0.75 ng/ml, p<0.001) and MET (0.92±0.57 ng/ml, p=0.001) group. The aforementioned vaspin changes correlated with changes in WHR, HbA1c, FPG, HOMA-IR, insulin, IL-6 (only in the RSG+MET group) and fat-mass. In standard multiple regression analysis, FPG, HbA1c, HOMA-IR and insulin remained independent determinants of serum vaspin levels changes (R2=0.836, p=0.004). Conclusions: Both rosiglitazone/metformin combination therapy and metformin monotherapy decreased serum vaspin levels through glucose and insulin sensitivity regulation, while they exerted differential effects on adiponectin, IL-6 and other cardiovascular risk factors in drug-naïve patients with T2DM. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York.


Kadoglou N.P.E.,National and Kapodistrian University of Athens | Sailer N.,Hippokratio General Hospital of Thessaloniki | Fotiadis G.,Hippokratio General Hospital of Thessaloniki | Kapelouzou A.,Surgery Academy | Liapis C.D.,National and Kapodistrian University of Athens
Experimental and Clinical Endocrinology and Diabetes | Year: 2014

Aim: Novel members of matrix metalloproteinases (MMPs), MMP-7 and MMP-8, have emerged as predictors of cardiovascular events. Our study aimed to evaluate serum MMP-7 and MMP-8 concentrations in patients with type 2 diabetes mellitus (T2DM) and the effects of atorvastatin on them. Methods: We enrolled 85 statin-free subjects with concomitant T2DM and hypercholesterolemia, but without overt micro-/macro-vascular complications (diabetic group - DG). 42 age- and gender-matched healthy subjects without chronic diseases or therapy served as healthy group (HG). All diabetic patients received fix dose of atorvastatin (20 mg/day). Clinical and anthropometrical parameters, lipids, fasting plasma glucose (FPG), serum MMP-7, MMP-8, their inhibitor (TIMP-1), IL-18, hsCRP and insulin resistance (HOMA-IR) were assayed at baseline in all participants and after 3 months in the DG. Results: At baseline, DG showed higher levels of BMI, systolic blood pressure, insulin resistance and FPG compared to HG (p<0.05). Similarly, DG appeared with elevated concentrations of MMP-7 (4.28±1.01 ng/ml vs 2.63±1.11 ng/ml, p<0.001), MMP-8 (73.07±21.96 ng/ml vs. 21.27±10.49 ng/ml, p<0.001) and inflammatory markers (WBC, hsCRP, IL-18, p<0.010). Importantly, atorvastatin treatment improved lipid profile, significantly reduced the concentrations of MMP-7, MMP-8 and inflammatory markers (p<0.01). Moreover, there was considerable suppression of both MMP-7/TIMP-1 and MMP-8/TIMP-1 ratios (p<0.01). In standard multiple regression analysis, the atorvastatin-induced reduction in MMP-7 was independently associated with LDL and IL-18 downregulation (R2=0.648, p=0.017). Similarly, IL-18 changes emerged as an independent determinant of MMP-8 alterations (R2=0.678, p=0.007). Conclusions: Hypercholesterolemic patients with T2DM showed elevated MMP-7 and MMP-8 serum concentrations. Atorvastatin reduced the latter concentrations and their ratio with TIMP-1. Those effects seemed mediated by the atorvastatin-induced suppression of inflammatory mediators. ClinicalTrials.gov Identifier: NCT00636766 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York.


Kadoglou N.P.E.,Aristotle University of Thessaloniki | Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Vrabas I.S.,Aristotle University of Thessaloniki | Kapelouzou A.,Surgery Academy | And 4 more authors.
Regulatory Peptides | Year: 2011

Aim: Vaspin and visfatin have emerged as novel adipokines, involved in atherosclerosis progression. The aim of the present study was to investigate the effects of atorvastatin and lifestyle modification on the above adipokines in hypercholesterolemic patients. Methods: One hundred four statin-free subjects with moderate cardiovascular risk (Framingham risk score of 10-20%) were randomly assigned to receive either atorvastatin 20. mg per day (AT group, n=52) or lifestyle modification (LM, group, n=52). For comparison, age and gender-matched blood donors, without any chronic cardiovascular or metabolic disease served as healthy controls (HC group, n=40). Clinical and anthropometrical parameters, lipids, fasting glucose, serum vaspin, visfatin and insulin levels were obtained at the beginning and after 12. weeks. Results: At the end of the study, intra-group and inter-group comparison revealed that atorvastatin administration considerably ameliorated most lipid parameters and downregulated hsCRP levels (p=0.002, p=0.041, respectively). Moreover, we observed a significant increase of vaspin concentrations after 12-week atorvastatin treatment (from 1.37 ± 0.6. ng/ml to 2.13 ± 0.61. ng/ml), as compared to baseline (p=0.007) and LM group (p=0.030). In standard multiple regression analysis, the atorvastatin-induced decrease of vaspin was independently associated with hsCRP reduction (p=0.015). On the other hand, within and between groups comparison revealed a non-significant (p>0.05) reduction of visfatin serum levels. In our study, lifestyle modification had totally modest influence on clinical and biochemical variables (p>0.05). Conclusion: In hypercholesterolemic patients with moderate estimated cardiovascular risk, atorvastatin administration reduced hsCRP and increased serum vaspin levels compared to lifestyle modification. The relation of those pleiotropic, non-lipid-lowering effects of statins with their clinical outcomes remains to be proved. © 2011 Elsevier B.V.


Kadoglou N.P.E.,National and Kapodistrian University of Athens | Fotiadis G.,Hippokratio General Hospital of Thessaloniki | Lambadiari V.,National and Kapodistrian University of Athens | Maratou E.,National and Kapodistrian University of Athens | And 2 more authors.
Peptides | Year: 2014

This study evaluated serum levels of novel adipokines in acute ischemic stroke (AIS) and their association with prognosis. We enrolled 168 patients with AIS and 58 stroke-free age- and sex-matched individuals (controls). Clinical parameters, carotid ultrasound, metabolic profile, vaspin, apelin, visfatin, and ghrelin were assayed. Stroke-patients were sampled at hospital admission and were prospectively followed-up (median 16 months) for the cardiovascular endpoint (cardiovascular death/stroke/myocardial infarction). At admission, stroke-patients appeared with higher levels of systolic blood pressure, hsCRP and worse metabolic profile (p < 0.05), (p > 0.05). Compared to controls, AIS group had significantly higher serum concentrations of visfatin (22.92 ± 9.72 ng/ml vs 16.56 ± 7.82 ng/ml, p = 0.006) and lower of vaspin (0.94 ± 0.43 ng/ml vs 1.84 ± 0.82 ng/ml, p = 0.019) and ghrelin (3.47 ± 1.44 ng/ml vs 5.93 ± 2.78 ng/ml, p < 0.001), while apelin did not differ between groups. Similar differences in adipokines were found between stroke subgroups with and without significant ipsilateral carotid stenosis (>50%) (p < 0.05). In stepwise logistic regression analysis adjusted for diabetes, hypertension, dyslipidemia and age, visfatin (p = 0.026) and ghrelin (p = 0.012) proved to be independent predictors of AIS. During follow-up, 27 patients achieved cardiovascular endpoint. In addition to coronary artery disease and NIHSS score, visfatin serum levels was associated with cardiovascular endpoint (HR: 1.255, 95% CI: 1.025-1.576). Our results suggested the association of AIS with higher visfatin and lower vaspin and ghrelin serum levels. Visfatin levels can be a predictor of cardiovascular mortality and morbidity in AIS. © 2014 Elsevier Inc.


Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Kadoglou N.P.E.,National and Kapodistrian University of Athens | Sailer N.,Hippokratio General Hospital of Thessaloniki | Moumtzouoglou A.,Hippokratio General Hospital of Thessaloniki | And 3 more authors.
Journal of Vascular Surgery | Year: 2010

Objective: Atherosclerotic plaque stabilization is a promising strategy to prevent cerebrovascular events in patients with carotid atherosclerosis. Vascular calcification inhibitors, known osteopontin (OPN) and osteoprotegerin (OPG), have emerged as novel cardiovascular biomarkers. This open-label, prospective study aimed to examine whether aggressive lipid-lowering therapy with atorvastatin is more effective than moderate lipid-lowering in increasing carotid plaque echogenicity, assessed by Gray-Scale Median (GSM) score and suppressing serum OPN and OPG levels in patients with moderate carotid stenosis. Methods: One hundred forty patients (64 males, 76 females), aged 50 to 75 years, with carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET]: 30%-60% for symptomatic and 30%-70% for asymptomatic), but without indications for surgical intervention, were enrolled. Patients with coronary heart disease, renal failure, hypothyroidism, osteoporosis, and ongoing use of statins were excluded. Patients were randomly assigned to: Group A (N = 70): Moderate lipid-lowering therapy with low-dose of atorvastatin (10 mg-20 mg) to target LDL-C <100 mg/dL. Group B (N = 70): Aggressive lipid-lowering therapy with high-dose of atorvastatin (80 mg) to target LDL-C <70 mg/dL. Blood pressure, lipid and glycemic indexes, hsCRP, serum OPN, and OPG were measured at baseline and after 12 months as well as the GSM score. Independent samples t test, paired samples t test, Pearson correlation, and multiple regression analysis were used (P < .05). Results: There were no significant differences between groups at baseline. Three patients in group A experienced either cerebrovascular or cardiac ischemic attacks, while two patients in group B underwent coronary angioplasty during follow-up. Group B showed a more pronounced improvement in total cholesterol and LDL-cholesterol compared with group A (P < .05). Moreover, atorvastatin treatment suppressed serum hsCRP, OPN, and OPG levels from baseline in both groups (P < .001). Notably, aggressive treatment decreased OPN (P = .012) and OPG (P = .025) levels to a greater degree compared with moderate treatment. Similarly, GSM score was remarkably increased in both groups, but that augmentation was greater in group B (from 66.39 ± 23.66 to 100.4 ± 25.31) than in group A (from 64.4 ± 23.62 to 85.39 ± 20.21) (P = .024). No change in the degree of carotid stenosis was noted in both treatment arms. Importantly, the aforementioned reduction in OPN (r = -0.517, P = .024) and OPG (r = -0.312, P = .008) levels was inversely associated with GSM score changes in univariate and standard multiple regression analysis (R2 = 0.411, P = .021). Conclusions: Among patients with moderate carotid stenosis, an aggressive atorvastatin regimen enhanced carotid plaque echogenicity and reduced serum OPN and OPG levels to a greater extent than respective moderate atorvastatin therapy. Most importantly, those atorvastatin-induced effects were associated with OPN and OPG suppression in a dose-dependent manner. © 2010 Society for Vascular Surgery.


Kadoglou N.P.E.,Aristotle University of Thessaloniki | Fotiadis G.,Hippokratio General Hospital of Thessaloniki | Kapelouzou A.,Surgery Academy | Kostakis A.,Surgery Academy | And 2 more authors.
Diabetic Medicine | Year: 2013

Objective: Adipokines, visfatin, apelin, vaspin and ghrelin have emerged as novel cardiovascular risk factors. We aimed to evaluate the effects of different exercise modalities on the aforementioned novel adipokines and carotid intima-media thickness in patients with Type 2 diabetes mellitus. Methods: One hundred patients with Type 2 diabetes were equivalently (n = 25) randomized into four groups: (1) a control group with patients encouraged to perform self-controlled exercise; (2) a supervised aerobic exercise group (exercise four times/week, 60 min/session, 60-75% of maximum heart rate); (3) a resistance training group (60-80% baseline maximum load achieved in one repetition); and (4) a combined aerobic exercise plus resistance training group, as in groups 2 and 3. All participants had HbA1c levels ≥ 48 mmol/mol (≥ 6.5%), without overt diabetic vascular complications. Blood samples, clinical characteristics, peak oxygen uptake and carotid intima-media thickness measurements were obtained at baseline and at the end of the study, after 6 months. Results: At baseline, there were non-significant differences between groups. All active groups significantly ameliorated glycaemic profile, insulin sensitivity and triglycerides levels compared with the control group (P < 0.05). Aerobic training further improved lipids, systolic blood pressure and exercise capacity compared with the resistance training and the control groups (P < 0.05). Moreover, high-sensitivity C-reactive protein and visfatin decreased, while vaspin and apelin circulating levels increased within the aerobic exercise group and the aerobic exercise plus resistance training group, and compared with the other groups (P < 0.05). Within- and between-group comparisons showed negligible alterations in ghrelin serum levels and body weight after all exercise modalities. Finally, aerobic training attenuated the carotid intima-media thickness progression (0.017 ± 0.006 mm) compared with the control subjects (0.129 ± 0.042 mm, P < 0.001). That effect was independently associated with visfatin and amelioration of peak oxygen uptake. Conclusions: In subjects with Type 2 diabetes, all exercise training modalities improved metabolic profile. Importantly, aerobic training predominantly ameliorated adipokines concentrations and carotid intima-media thickness progression. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.


Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Sailer N.,Hippokratio General Hospital of Thessaloniki | Moumtzouoglou A.,Hippokratio General Hospital of Thessaloniki | Kapelouzou A.,Surgery Academy | And 3 more authors.
European Journal of Clinical Investigation | Year: 2012

Background In patients with carotid stenosis, we prospectively investigated the association of novel adipokines, apelin and visfatin, with gray-scale median (GSM) score, a valid index of carotid plaque vulnerability. We also assessed the impact of atorvastatin therapy on the above biochemical and imaging markers. Materials and methods Seventy-four overweight [body-mass index (BMI)>25kg/m2, fat-mass>30%], statin-free patients, with carotid stenosis, but without indications for intervention were enrolled. Thirty-eight age-, sex- and BMI-matched healthy subjects served as healthy controls (HC). All patients received gradual titrated (10-80mg) atorvastatin therapy to target LDL-C<100mg/dL. GSM score, blood pressure (BP), fat-mass, lipid profile, and serum high-sensitivity C-reactive protein (hsCRP), apelin and visfatin levels were obtained at baseline and after 24months. Results At baseline, patients with carotid atherosclerosis had worse lipid profile, lower apelin and higher systolic BP, hsCRP, visfatin levels compared with HC (P<0·05). Notably, decreased apelin (P<0·001) and GSM score (P=0·010), while increased visfatin (P=0·019) and hsCRP (P=0·039) levels were found in symptomatic rather than asymptomatic patients. At baseline, GSM score correlated with fat-mass, BMI, LDL-C, visfatin and apelin (P<0·05). Apelin, visfatin and fat-mass remained independent determinants of baseline GSM score (R2=0·391, P=0·007). In parallel, we found that apelin increment and LDL-C reduction were independently associated with the atorvastatin-induced GSM increase (R2=0·411, P=0·011). Conclusion Increased fat-mass, low apelin and high visfatin serum levels seem to correlate with carotid plaque vulnerability in patients with carotid stenosis. The atorvastatin-induced modification of apelin and LDL-C may beneficially affect carotid plaque stability. © 2012 Stichting European Society for Clinical Investigation Journal Foundation.


Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Sailer N.,Hippokratio General Hospital of Thessaloniki | Kapelouzou A.,Surgery Academy | Lampropoulos S.,Mpodosakio General Hospital of Ptolemaida | And 3 more authors.
Acta Diabetologica | Year: 2012

To investigate the influence of atrovastatin treatment on carotid intima-media thickness (CIMT) and serumlevels of novel adipokines, like apelin, visfatin (nampt), and ghrelin, in patientswith type 2 diabetes mellitus (T2DM). 87 statin-free patients (50males) withT2DM, aged 55-70, but without carotid atherosclerotic plaqueswere initially enrolled. CIMT was assayed in all participants by ultrasound. Patients were then treated with atorvastatin (10-80 mg) to target LDL\100 mg/dl. Anthropometric parameters, blood pressure, glycemic and lipid profile, high-sensitivity CRP (hsCRP), insulin resistance (HOMA-IR), apelin, visfatin and ghrelin were measured at baseline and after 12 months. Atorvastatin treatment significantly improved lipid profile across with increased apelin (from 0.307 ± 0.130 pg/ml to 1.537 ± 0.427 pg/ml; P<0.001) and suppressed visfatin (from 21.54 ± 10.14 ng/ml to 15.13 ± 7.61 ng/ml; P = 0.002) serumlevels in our diabetic patients. Standardmultiple regression analysis showed that the atorvastatin-induced increment in apelin was independently associated with changes in total cholesterol (b =-0.510, P = 0.030) and LDL-cholesterol (β =-0.590, P<0.001) (R2 = 0.449, P = 0.014), while the reduction of visfatin concentration was independently associated with the change in hsCRP (b = 0.589, P<0.001; R2 = 0.256, P = 0.006), after adjustment for age, sex and BMI. CIMT and ghrelin did not alter significantly after 12 months of atorvastatin treatment (NS).Among participants, high-dose (80 mg) rather than lowdose (10 mg) of atorvastatin treatment yielded greater (P<0.05) changes in apelin, visfatin and CIMT levels despite the final equivalent levels of LDL. Atorvastatin administration increased apelin and decreased visfatin serum levels significantly, without change of CIMT, in patients with T2DM. However, high-dose of atorvastatin exerted more favourable impact on adipokines and CIMT than low-dose. Our results implicate another important link between adiposity and atherosclerosis. © 2011 Springer-Verlag.


Kadoglou N.P.E.,Aristotle University of Thessaloniki | Kadoglou N.P.E.,Hippokratio General Hospital of Thessaloniki | Fotiadis G.,Hippokratio General Hospital of Thessaloniki | Athanasiadou Z.,Hippokratio General Hospital of Thessaloniki | And 3 more authors.
Endocrine | Year: 2012

The purpose of this study was to investigate the effects of resistance training (RT) on novel cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM). We enrolled 52 overweight/obese, type 2 diabetic patients, with inadequate glycemic control (HbA1c > 6.5 %), but without overt diabetic vascular complications. Participants were randomly assigned into two equivalent groups (n = 26): (1) Resistance exercise group: subjects underwent a supervised RT program (3-times/week, 60 min/session, 2-3 sets of 8 machine-weight exercises, 60-80 % of one-repetition maximum). (2) Control group (CG): at study entrance, they received a structured exercise counseling to increase daily physical activity. Clinical parameters, cardiorespiratory capacity, glycemic and lipid profile, apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), Lipoprotein(a) [Lp(a)], insulin resistance (HOMA-IR), high-sensitivity CRP (hsCRP), fibrinogen were measured before and after 3 months. RT significantly reduced glycemic indexes, insulin resistance and systolic blood pressure, compared to CG (p < 0.05). Moreover, exercise-treated patients conferred a remarkable downregulation in ApoB levels (from 135.92 ± 30.97 mg/dL to 85.9 ± 26.46 mg/dL, p < 0.001) as compared to CG (from 126.33 ± 36.59 mg/dL to 116.23 ± 27.52 mg/dL, p = 0.872) (p < 0.001). Similarly, ApoB/ApoA-I ratio was considerably decreased in REG rather than CG (-0.32 ± 0.09 vs 0.02 ± 0.01, p < 0.001). Notably, ApoA-I, Lp(a), hsCRP, fibrinogen, the rest of lipid parameters, body weight and exercise capacity remained unaltered in both groups (p > 0.05). Among variables, HOMA-IR reduction was found to be an independent predictor of changes in ApoB/ApoA-I ratio (R 2 = 0.406, p = 0.041) in REG. Long-term RT ameliorated glycemic control, insulin sensitivity and ApoB/ApoA-I ratio in individuals with T2DM. Although we did not observe significant benefits in the rest of cardiovascular risk factors, our results indicate a merely beneficial impact of RT. © 2012 Springer Science+Business Media, LLC.

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