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A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.
Straznicky, NE, Grima, MT, Sari, CI, Eikelis, N, Lambert, GW, Nestel, PJ, Karapanagiotidis, S, Wong, C, Richards, K, Marusic, P, et al
The Journal of clinical endocrinology and metabolism. 2014;(9):E1701-7
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CONTEXT Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. OBJECTIVE The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. PARTICIPANTS AND METHODS A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. RESULTS PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). CONCLUSIONS Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.
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Drospirenone/ethinyl estradiol versus rosiglitazone treatment in overweight adolescents with polycystic ovary syndrome: comparison of metabolic, hormonal, and cardiovascular risk factors.
Tfayli, H, Ulnach, JW, Lee, S, Sutton-Tyrrell, K, Arslanian, S
The Journal of clinical endocrinology and metabolism. 2011;(5):1311-9
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CONTEXT Adolescents with polycystic ovary syndrome (PCOS) have insulin resistance and higher rates of the metabolic syndrome. OBJECTIVE Our objective was to compare the effects of 6 months treatment with drospirenone/ethinyl estradiol (EE) (3 mg/30 μg) vs. rosiglitazone (4 mg) daily on the hormonal and cardiometabolic profiles of overweight/obese adolescents with PCOS. DESIGN We conducted a randomized, double-blinded, parallel clinical trial in an academic hospital, with n = 46 patients. OUTCOME MEASURES The primary outcome measure was insulin sensitivity, hepatic with [6,6-(2)H(2)]glucose and peripheral with a 3-h hyperinsulinemic-euglycemic clamp. Other outcome measures included plasma androgen profile and response to ACTH stimulation, glucose and insulin response to oral glucose tolerance test, insulin secretion with a 2-h hyperglycemic clamp, fasting lipid profile, inflammatory markers, intima media thickness, aortic pulse wave velocity, body composition by dual-energy x-ray absorptiometry, and abdominal adiposity by computed tomography scan. RESULTS Drospirenone/EE resulted in greater reductions in androgenemia. Neither treatment led to change in weight or body mass index, but rosiglitazone led to a significant decrease in visceral adiposity. Compared with drospirenone/EE, treatment with rosiglitazone improved hepatic and peripheral insulin sensitivity and lowered fasting and stimulated insulin levels during the oral glucose tolerance test. Treatment with drospirenone/EE was associated with elevations in total cholesterol, high-sensitivity C-reactive protein and leptin concentrations, whereas treatment with rosiglitazone led to lower triglycerides and higher adiponectin concentrations. Neither treatment affected intima media thickness or pulse wave velocity. CONCLUSIONS In overweight/obese adolescents with PCOS, 6 months treatment with rosiglitazone was superior to drospirenone/EE in improving the cardiometabolic risk profile, and effective but inferior in attenuating hyperandrogenemia. Additional studies are needed to test insulin sensitizers in the treatment of the reproductive and cardiometabolic aspects of PCOS.
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Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome.
Fujitaka, K, Otani, H, Jo, F, Jo, H, Nomura, E, Iwasaki, M, Nishikawa, M, Iwasaka, T
Endocrine journal. 2011;(6):425-32
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Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.
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Retinol-binding protein 4 in polycystic ovary syndrome--association with steroid hormones and response to pioglitazone treatment.
Aigner, E, Bachofner, N, Klein, K, De Geyter, C, Hohla, F, Patsch, W, Datz, C
The Journal of clinical endocrinology and metabolism. 2009;(4):1229-35
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CONTEXT Polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance. OBJECTIVE The aim of the study was to investigate a putative role of the adipokines retinol-binding protein 4 (RBP4), adiponectin, and visfatin in a cohort of patients with PCOS and their response to treatment with pioglitazone. DESIGN AND SETTING We conducted a randomized, controlled, double-blind study at a tertiary referral center. PATIENTS AND INTERVENTIONS Forty premenopausal women with PCOS were allocated to receive treatment with either pioglitazone (30 mg/d) or a placebo for a period of 3 months. MAIN OUTCOME MEASURES Serum concentrations of RBP4, adiponectin, and visfatin were determined along with metabolic and hormonal parameters before and after treatment. RESULTS Serum adiponectin concentrations were higher after treatment with pioglitazone (P = 0.003), whereas RBP4 levels tended to decrease (P = 0.06), and visfatin concentrations remained unchanged. We found RBP4 serum concentrations at baseline to be positively correlated with serum levels of testosterone (R = 0.446; P = 0.005), 17-OH progesterone (R = 0.345, P = 0.037), and dehydroepiandrosterone sulfate (R = 0.347; P = 0.041). However, these correlations were abolished after treatment with pioglitazone. Patients with high RBP4 levels had significantly higher hirsutism scores (P = 0.038 before and P = 0.034 after treatment). In contrast, serum adiponectin concentrations were related to parameters of impaired glucose metabolism, and no significant associations were detected for visfatin. CONCLUSIONS Our results suggest that RBP4 may contribute to endocrine changes and to the phenotypic manifestation of patients with PCOS because higher RBP4 concentrations are associated with higher androgen levels and higher clinical hirsutism scores independently of pioglitazone treatment. The molecular involvement of RBP4 in human steroid metabolism requires further clarification.
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Effect of pioglitazone on glucose metabolism and luteinizing hormone secretion in women with polycystic ovary syndrome.
Glintborg, D, Hermann, AP, Andersen, M, Hagen, C, Beck-Nielsen, H, Veldhuis, JD, Henriksen, JE
Fertility and sterility. 2006;(2):385-97
Abstract
OBJECTIVE To thoroughly examine the mechanisms for insulin resistance in polycystic ovary syndrome (PCOS) and to evaluate the effects of pioglitazone treatment on insulin resistance, beta-cell function, LH secretion, and glucose metabolism. DESIGN Randomized, blinded, placebo-controlled study. SETTING Outpatient clinic, at a university hospital in Denmark. PATIENT(S): Thirty obese women with PCOS and 14 weight-matched healthy females. INTERVENTION(S): Sixteen weeks of blinded treatment with pioglitazone (30 mg/d) or placebo. MAIN OUTCOME MEASURE(S): Fasting blood samples, 24-hour 20-minute integrated blood sampling (LH, insulin, and C-peptide), euglycemic hyperinsulinemic clamps including 3-(3)H glucose, and indirect calorimetry were performed before and after the intervention period. RESULT(S): Patients with PCOS had significantly lower insulin sensitivity compared with controls, including significantly decreased insulin-stimulated oxidative and nonoxidative glucose metabolism. Pioglitazone treatment resulted in significantly lower levels of fasting insulin and significantly higher insulin sensitivity, increased insulin-stimulated glucose oxidation, and increased insulin-stimulated inhibition of lipid oxidation. During 24-hour blood sampling, significantly lower area under-the-curve insulin and lower median insulin levels were observed. Secretion profiles of LH and E(2) and T levels did not change significantly. CONCLUSION(S): Insulin resistance in PCOS was characterized by hyperinsulinemia, impaired insulin-stimulated oxidative and nonoxidative glucose metabolism, which was partly reversed by pioglitazone treatment.
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Effect of metformin and rosiglitazone on lipid metabolism in HIV infected patients receiving protease inhibitor containing HAART.
Tomazic, J, Karner, P, Vidmar, L, Maticic, M, Sharma, PM, Janez, A
Acta dermatovenerologica Alpina, Pannonica, et Adriatica. 2005;(3):99-105
Abstract
AIMS: Insulin resistance may be the primary event in the protease inhibitor-associated metabolic syndrome. Treatment with insulin sensitizers (metformin, rosiglitazone) can ameliorate insulin resistance. So far, the effects of these agents on blood lipids have not been well determined. The aim of the present study was to evaluate the effects of metformin and rosiglitazone treatment on lipid metabolism in HIV infected patients receiving protease inhibitors containing HAART. DESIGN AND METHODS HIV infected male patients (>18 years) were eligible for the study if they had impaired glucose tolerance with insulin resistance, characterized by fasting insulin concentration greater then 20 mIU/L and if they were on stable antiretroviral therapy regimen including a protease inhibitor for at least 12 months prior to the study enrolment. The patients were randomly assigned to receive either 1g/day metformin (metformin group, n=30) or 4 mg/day rosiglitazone maleate (rosiglitazone group, n=30) or no treatment (control group, n=30). The primary efficacy parameters were fasting plasma lipids, glucose levels and fasting insulin levels compared between baseline and week 48, by treatment groups. RESULTS The total cholesterol concentration in rosiglitazone group increased from 5.76 -/+1.2 to 7.1-/+1.6 mmol/l (23% increase, p<0.05), HDL levels increased from 0.91-/+0.44 to 1.3-/+0.2 (38% increase, p<0.01) and LDL levels increased from 3.5-/+0.98 to 4.5-/+1.0 (28% increase, p<0.05). Treatment with metformin had no significant effect on total, HDL and LDL cholesterol. After 48 weeks of treatment, the fasting triglycerides concentration in the metformin group declined from 4.1-/+1.6 to 3.2-/+1.3 mmol/l (22% decrease,p<0.05) but in the rosiglitazone group no statistically significant effect on plasma triglycerides was noted. Furthermore, after 48 weeks of treatment the fasting insulin concentration in the rosiglitazone group declined by 49% and in the metformin group by 28%. This improvement in insulin secretion could be clearly demonstrated when the sums of insulin concentrations after oral glucose tolerance test were compared: 548-/+13 to 345-/+11.8 mIU/l in the rosiglitazone group (37% decrease, p<0.01) and from 552-/+15 to 420-/+12 mIU/l in the metformin group (24% decrease, p<0.01). CONCLUSIONS The study demonstrates that both therapies improve insulin resistance. However, treatment with metformin has no effect on total, HDL and LDL cholesterol, but significantly reduces triglycerides, which has beneficial effect on the lipid status in these patients. Rosiglitazone causes significant increases in total cholesterol, HDL and LDL, but has no effect on triglycerides concentrations.
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Long-term effect of glimepiride and rosiglitazone on non-conventional cardiovascular risk factors in metformin-treated patients affected by metabolic syndrome: a randomized, double-blind clinical trial.
Derosa, G, Gaddi, AV, Ciccarelli, L, Fogari, E, Ghelfi, M, Ferrari, I, Cicero, AF
The Journal of international medical research. 2005;(3):284-94
Abstract
We evaluated the effect of glimepiride plus metformin and rosiglitazone plus metformin on glucose, and on cardiovascular risk parameters such as lipoprotein(a) (Lp[a]) and homocysteine (HCT) in patients with type 2 diabetes and metabolic syndrome. Ninety-nine patients in the multicentre, randomized, double-blind study took metformin (1500 mg/day) plus glimepiride (2 mg/day) or rosiglitazone (4 mg/day) for 12 months. Changes in body mass index, glycosylated haemoglobin (HbA1c), Lp(a) and HCT were primary efficacy variables. Fasting plasma glucose (FPG), post-prandial plasma glucose (PPG) and homeostasis model assessment index were also used to assess efficacy. On average, HbA1c decreased by 9.1% and 8.1%, FPG decreased by 7.3% and 10.9%, and PPG decreased by 7.6% and 10.5%, respectively, in the glimepiride and rosiglitazone groups after 12 months. Patients receiving rosiglitazone experienced more rapid improvement in glycaemic control than those on glimepiride, and showed a significant improvement in insulin resistance-related parameters. There was a statistically significant decrease in basal homocysteinaemia in glimepiride-treated patients (-27.3%), but not in rosiglitazone-treated patients. Rosiglitazone plus metformin significantly improved long-term control of insulin resistance-related parameters compared with glimepiride plus metformin, although glimepiride treatment was associated with a slight improvement in cholesterolaemia, not observed in the rosiglitazone-treated patients, and with significant improvements in non-traditional risk factors for cardiovascular disease, such as basal homocysteinaemia and plasma Lp(a) levels.