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Effect of pioglitazone versus metformin on cardiovascular risk markers in type 2 diabetes.
Genovese, S, De Berardis, G, Nicolucci, A, Mannucci, E, Evangelista, V, Totani, L, Pellegrini, F, Ceriello, A
Advances in therapy. 2013;(2):190-202
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Abstract
INTRODUCTION Besides its critical role in metabolic homeostasis, peroxisome proliferator-activated receptor (PPAR)-γ modulates several cellular responses involved in atherothrombosis. This multicenter, double-blind, randomized study investigated the effects of two oral hypoglycemic agents on markers of inflammation, platelet activation, thrombogenesis, and oxidative stress in patients with type 2 diabetes. METHODS AND RESULTS The primary objective of this study was to evaluate the effect on C-reactive protein (CRP) after a 16-week treatment period with either pioglitazone or metformin. Additionally, markers of vascular inflammatory response, platelet activation, thrombogenesis, oxidative stress, glucose, and lipid metabolism, as well as liver function, were measured. In total, 50 patients completed the study. Pioglitazone-treated patients were found to have statistically significantly larger decreases in mean CRP levels (-0.4 mg/dL) compared to those treated with metformin (-0.2 mg/dL) (P=0.04), as well as greater reductions in levels of mean fasting plasma glucose (-27 vs. -9 mg/dL; P=0.01), serum insulin (-2 vs. -1.9 mU/L; P=0.014), homeostatic model assessment (HOMA) (-1.2 vs. -0.9; P=0.015), and E-selectin (-12.4 vs. +3.4 μg/mL; P=0.01). Mean glycated hemoglobin (HbA1c) levels decreased in both treatment groups from baseline to week 16 (-0.4% in the pioglitazone group, -0.2% in the metformin group; P=0.36). Pioglitazone treatment was also found to be associated with a statistically significant increase in total cholesterol levels (+10 mg/dL in the pioglitazone arm, -3 mg/dL in the metformin arm; P=0.05) and a decrease in liver enzyme levels. CONCLUSIONS The favorable changes in markers of systemic and vascular inflammatory response with pioglitazone suggest that it may positively influence the atherothrombotic process in type 2 diabetes.
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The ubiquitin-proteasome system and inflammatory activity in diabetic atherosclerotic plaques: effects of rosiglitazone treatment.
Marfella, R, D'Amico, M, Esposito, K, Baldi, A, Di Filippo, C, Siniscalchi, M, Sasso, FC, Portoghese, M, Cirillo, F, Cacciapuoti, F, et al
Diabetes. 2006;(3):622-32
Abstract
The role of ubiquitin-proteasome system in the accelerated atherosclerotic progression of diabetic patients is unclear. We evaluated ubiquitin-proteasome activity in carotid plaques of asymptomatic diabetic and nondiabetic patients, as well as the effect of rosiglitazone, a peroxisome proliferator-activated receptor (PPAR)-gamma activator, in diabetic plaques. Plaques were obtained from 46 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Diabetic patients received 8 mg rosiglitazone (n = 23) or placebo (n = 23) for 4 months before scheduled endarterectomy. Plaques were analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLA-DR), ubiquitin, proteasome 20S activity, nuclear factor (NF)-kappaB, inhibitor of kappaB (IkappaB)-beta, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP)-9, and collagen content (immunohistochemistry and enzyme-linked immunosorbent assay). Compared with nondiabetic plaques, diabetic plaques had more macrophages, T-cells, and HLA-DR+ cells (P < 0.001); more ubiquitin, proteasome 20S activity (TNF-alpha), and NF-kappaB (P < 0.001); and more markers of oxidative stress (nitrotyrosine and O2(-) production) and MMP-9 (P < 0.01), along with a lesser collagen content and IkappaB-beta levels (P < 0.001). Compared with placebo-treated plaques, rosiglitazone-treated diabetic plaques presented less inflammatory cells (P < 0.01); less ubiquitin, proteasome 20S, TNF-alpha, and NF-kappaB (P < 0.01); less nitrotyrosine and superoxide anion production (P < 0.01); and greater collagen content (P < 0.01), indicating a more stable plaque phenotype. Similar findings were obtained in circulating monocytes obtained from the two groups of diabetic patients and cultured in the presence or absence of rosiglitazone (7.0 micromol/l). Ubiquitin-proteasome over-activity is associated with enhanced inflammatory reaction and NF-kappaB expression in diabetic plaques. The inhibition of ubiquitin-proteasome activity in atherosclerotic lesions of diabetic patients by rosiglitazone is associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by downregulating NF-kappaB-mediated inflammatory pathways.