The impact of type 2 diabetes and atorvastatin treatment on serum levels of MMP-7 and MMP-8.

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 (R(2)=0.648, p=0.017). Similarly, IL-18 changes emerged as an independent determinant of MMP-8 alterations (R(2)=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.

Effects of rosiglitazone/metformin fixed-dose combination therapy and metformin monotherapy on serum vaspin, adiponectin and IL-6 levels in drug-naïve patients with type 2 diabetes.

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.

Exercise ameliorates serum MMP-9 and TIMP-2 levels in patients with type 2 diabetes.

AIM: This study assessed the impact of regular exercise on inflammatory markers (high-sensitivity C-reactive protein [hsCRP], fibrinogen), and matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), in patients with type 2 diabetes mellitus (T2DM). PATIENTS: Fifty overweight patients with T2DM were randomly assigned to two groups: (A) an exercise group (EXG, n=25), with self-controlled exercise for at least 150 min/week and one additional supervised exercise session/week; and (B) a control group (COG, n=25), with no exercise instructions. All participants were taking oral antidiabetic drugs, and none had diabetic complications. Clinical parameters, exercise capacity (VO(2 peak)), ventilatory threshold (VT), insulin resistance indices (fasting insulin, HOMA-IR, HOMA%S), hsCRP, fibrinogen, MMP-2, MMP-9, TIMP-1 and TIMP-2 were assessed at baseline and after 16 weeks. RESULTS: No significant changes were found in body mass index, waist/hip ratio, insulin-resistance indices, MMP-2 and TIMP-1 throughout the study in either group (P>0.05). Compared with controls, the EXG showed a significant decrease in systolic and mean blood pressure, total and LDL cholesterol, and HbA(1c) (P<0.05). Also, exercise significantly suppressed levels of fibrinogen (P=0.047), hsCRP (P=0.041) and MMP-9 (P=0.028), and the MMP-9-to-TIMP-1 ratio (P=0.038), whereas VO(2 peak) (P=0.011), VT (P=0.008) and plasma TIMP-2 levels (P=0.022) were considerably upregulated in the EXG vs. COG. Standard multiple-regression analyses revealed that MMP-9 changes were independently associated with fibrinogen and HbA(1c) changes, while fibrinogen changes independently predicted TIMP-2 alterations with exercise. CONCLUSION: Mostly self-controlled exercise of moderate intensity ameliorated serum levels of pro- and anti-atherogenic markers in patients with T2DM, with no effects on body weight. These data offer further insight into the cardioprotective mechanisms of exercise in patients with T2DM.

Visfatin (nampt) and ghrelin as novel markers of carotid atherosclerosis in patients with type 2 diabetes.

OBJECTIVE: Visfatin (nampt) and ghrelin are the most recently identified adipocytokines, but their role in atherosclerosis is poorly clarified. In our study we investigated their association with advanced carotid atherosclerosis and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (T2DM). METHODS: 122 patients (50 males) with T2DM, aged 55-70 were enrolled. Sixty-four age- and sex-matched healthy individuals served as controls (group A). CIMT was assayed in all participants by ultrasound. Among diabetic patients, 47 appeared with carotid plaques (group B), while 75 without plaques (group C). Anthropometric parameters, blood pressure, glycemic and lipid profile, high-sensitivity CRP (hsCRP), insulin resistance (HOMA-IR), fibrinogen, nampt and ghrelin were measured. RESULTS: Diabetic patients had a higher mean-CIMT, increased body-mass index, worse lipid profile, elevated blood pressure and higher levels of white blood cells count, nampt and hsCRP with respect to controls (p<0.01). Among diabetic patients, groups B and C were comparable in anthropometric, glycemic and lipid parameters. Serum nampt was significantly higher in group B rather than in groups A and C (p<0.05). On the other hand, ghrelin levels were considerably lower only in diabetic patients with carotid atherosclerosis compared with healthy individuals. In univariate analysis, mean-CIMT correlated with age (r=0.312; p=0.003), nampt (r=0.341; p<0.001) and ghrelin (r=-0.421; p=0.002) and the latter associations remained significant in multiple regression analysis. CONCLUSIONS: High nampt and low ghrelin serum levels are significantly associated with advanced carotid atherosclerosis in patients with T2DM. Moreover these adipocytokines are independently associated with CIMT, implicating their role as novel atherosclerotic biomarkers and providing another important link between adiposity and atherosclerosis.

Intensive lipid-lowering therapy ameliorates novel calcification markers and GSM score in patients with carotid stenosis.

OBJECTIVES/DESIGN: Carotid plaque echogenicity quantified by the Gray-Scale Median (GSM) score has been associated with plaque vulnerability. The aim of this study was to assess whether intensive lipid-lowering treatment with atorvastatin in patients with carotid artery stenosis ameliorates novel vascular calcification inhibitors, such as osteopontin (OPN) and osteoprotegerin (OPG), and improves GSM score. METHODS: Ninety-seven patients with carotid stenosis (>40%), but without indication for intervention, were treated for 6 months with atorvastatin (10mg-80mg) to target LDL<100mg/dl. Fifty-two age-and sex-matched healthy individuals served as the control group. Blood samples and GSM were obtained at the beginning and after 6 months. RESULTS: Systolic blood pressure, hsCRP, fibrinogen, OPN and OPG levels differed significantly between patients with carotid stenosis and healthy controls at baseline (p<0.05). Atorvastatin treatment improved lipid profile and significantly reduced hsCRP (p=0.002), WBC count (p=0.041), OPN (p<0.001) and OPG levels (p<0.001). GSM score increased considerably after atorvastatin therapy (from 58.33+/-24.38 to 79.33+/-22.3; p<0.001) and that effect appeared related to OPN (p=0.001), OPG (p=0.013) and LDL (p=0.01) reduction. CONCLUSIONS: In patients with carotid stenosis, intensive lipid-lowering therapy with statins attenuates serum OPN and OPG levels and enhances carotid plaque echogenicity, outlining their beneficial effects on plaque stability.

[Arterial tortuosity syndrome]. / Das Arterial-Tortuosity-Syndrom.

The arterial tortuosity syndrome is a rare congenital disorder characterized by elongation and generalized tortuosity of the major arteries including the aorta. Associated clinical features consist of excessively stretchable skin and joint laxity which is indicative of a connective tissue disorder such as Ehlers-Danlos or Cutis laxa syndrome. The gene locus of the arterial tortuosity syndrome has recently been localised on chromosome 20q13; inheritance ist autosomal recessive. - We report on a newborn with arterial tortuosity syndrome and hiatal hernia, bilateral hip dislocation, inguinal hernias and diffuse tortuosity of the great arteries including the aorta. Known gene loci involved in Ehlers-Danlos syndrome, cutis laxa syndrome and other connective tissue disorders were excluded by specific DNA markers. By homozygosity mapping with polymorphic microsatellite markers it was possible to confirm the gene locus for the ATS on chromosome 20q13. In addition to the presentation of this patient, a review of the literature is presented.