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Pioglitazone treatment enhances the sympathetic nervous system response to oral carbohydrate load in obese individuals with metabolic syndrome.
Straznicky, NE, Grima, MT, Sari, CI, Eikelis, N, Lambert, GW, Nestel, PJ, Richards, K, Dixon, JB, Schlaich, MP, Lambert, EA
Metabolism: clinical and experimental. 2015;(7):797-803
Abstract
CONTEXT Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis. OBJECTIVE This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome. METHODS Un-medicated individuals (n=42, mean age 56±0.8 yrs, body mass index 34±0.6 kg/m(2)) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index. RESULTS PIO increased clamp derived glucose utilisation by 35% (P<0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P<0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all <0.05). The overall norepinephrine spillover response (AUC(0-120)) increased significantly in the PIO group (group × time interaction, P=0.04), with greatest increment at 30 minutes post-glucose (101±38 ng/min at baseline versus 241±48 ng/min post treatment, P=0.04) and correlated with percent improvement in M. CONCLUSIONS PIO enhances the early postprandial SNS response to carbohydrate ingestion.
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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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Pioglitazone Randomised Italian Study on Metabolic Syndrome (PRISMA): effect of pioglitazone with metformin on HDL-C levels in Type 2 diabetic patients.
Genovese, S, Passaro, A, Brunetti, P, Comaschi, M, Cucinotta, D, , , Egan, CG, Chinea, B, Bravi, F, Di Pietro, C
Journal of endocrinological investigation. 2013;(8):606-16
Abstract
BACKGROUND Previous evidence indicates that pioglitazone may improve dyslipidemia in patients with Type 2 diabetes mellitus (T2DM). AIM: The primary objective of this study was to evaluate the effect of either pioglitazone or placebo with metformin on levels of serum HDL cholesterol (HDL-C) in patients with T2DM. A secondary objective evaluated changes in metabolic syndrome (MS)-specific parameters. SUBJECTS AND METHODS This multicenter, double-blind, randomized study was performed in patients with T2DM treated with metformin and hemoglobin A1c (HbA1c) levels between 6-8%, central obesity and reduced HDL-C. MS was evaluated from global changes in parameter values and expressed as a single factorial score following multivariate analysis of each parameter. 213 patients (110 in the pioglitazone group and 103 in the placebo group) were available for intention-to-treat analysis. RESULTS Pioglitazone-treated patients showed a significant increase in HDL-C compared to placebo group (6.3 mg/dl vs 3.0 mg/dl; p<0.01) in addition to a greater reduction in the extent of MS (-13.2 vs -4.9; p=0.0055). Upon study completion, patients treated with pioglitazone had lower levels of HbA1c (6.41±0.65 vs 6.96±0.74%; p<0.001) and homeostasis model assessment-insulin resistance (HOMA-IR) (2.88±1.95 vs 4.68±3.63; p=0.013) and a reduction of the atherogenic LDL subfraction (pattern B) (-5.7%). CONCLUSIONS The beneficial effects observed in pioglitazone-treated patients in the present study, (i.e. the increase in HDL-C and the reduction of insulin resistance and atherogenic LDL subfractions), support findings from the PROactive trial, where pioglitazone showed pleiotropic effects and reduced death, fatal myocardial infarction (MI) and non-fatal MI in T2DM patients with MS. Furthermore, medication used in this study showed good tolerability.
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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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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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Low-dose pioglitazone, flutamide, metformin plus an estro-progestagen for non-obese young women with polycystic ovary syndrome: increasing efficacy and persistent safety over 30 months.
Ibáñez, L, López-Bermejo, A, Díaz, M, Enríquez, G, Del Río, L, De Zegher, F
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2010;(12):869-73
Abstract
CONTEXT Therapy of androgen excess should not only confer cosmetic benefit, but also improve long-term markers of endocrine-metabolic and cardiovascular health. Here we report on our pilot experience with a low-dose polytherapy for 30 months. DESIGN, PATIENTS, INTERVENTION Unblinded extension (24-30 months) of a double-placebo study exploring low-dose polytherapy over 24 months. Between 24 and 30 months, women with hyperinsulinemic androgen excess (N = 36; mean age: 19.4 year; BMI: 23.7 kg/m(2)) received metformin (850 mg/day), flutamide (62.5 mg/day), pioglitazone (7.5 mg/day), ethinylestradiol (20 μg/day) plus drospirenone (3 mg/day) for 24/28 days. MAIN OUTCOMES Carotid IMT, body composition (by absorptiometry), abdominal fat (by magnetic resonance), hirsutism score, fasting glycaemia, insulin, androgens, HDL cholesterol, C-reactive protein and hepatic safety indices. RESULTS Low-dose polytherapy for 30 months was not accompanied by a change in body weight or bone mineral density, but it was associated with a marked rise of insulin sensitivity (p < 0.00001), with a loss of visceral fat (mean: -27%; p < 0.00001) and with a lowering of IMT (-0.16 mm; p < 0.00001). Aspartate aminotransferase, gamma-glutamyl transferase and lactate dehydrogenase levels decreased slightly over 30 months. CONCLUSION Low-dose polytherapy (24/28 day) with pioglitazone, flutamide, metformin and estro-progestagen was found to improve, without changing weight, a spectrum of long-term health markers in young women with hyperinsulinemic androgen excess.
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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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Changes in insulin resistance and cardiovascular risk induced by PPARgamma activation have no impact on RBP4 plasma concentrations in nondiabetic patients.
Pfützner, A, Schöndorf, T, Hanefeld, M, Lübben, G, Kann, PH, Karagiannis, E, Wilhelm, B, Forst, T
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2009;(3):202-6
Abstract
Retinol binding protein 4 (RBP4) has recently been suggested as a good biomarker for insulin resistance and the metabolic syndrome. With this study, we wanted to investigate the effect of pioglitazone (PIO) and simvastatin (SIMVA) on insulin resistance and RBP4 plasma concentrations in nondiabetic patients with metabolic syndrome and increased risk for cardiovascular complications. The prospective, parallel, randomized, double-blind clinical trial was performed with 125 nondiabetic patients with increased cardiovascular risk (78 females, 47 males, age (mean+/-STD): 58.6+/-7.8 years, BMI: 30.8+/-4.2 kg/m (2)). They were randomized to either receive PIO (45 mg)+placebo, SIMVA (40 mg)+placebo, or PIO+SIMVA for 3 months. Key outcome measures were the HOMA (IR)-Score, an oral glucose tolerance test, adiponectin, hsCRP, and RBP4 at baseline and endpoint. No correlation could be detected between the HOMA (IR) values or the impaired fasting glucose tolerance status and RBP-4. Treatment with PIO alone or in combination with SIMVA resulted in a significant improvement of the HOMA (IR)-Score and the adiponectin values, while no change in HOMA (IR) and a decrease in adiponectin (p<0.05) were observed with SIMVA monotherapy. Reductions of hsCRP were seen in all three treatment arms (p<0.001). No changes of the plasma RBP4 concentrations were observed in any of the treatment groups (PIO: 35.6+/-7.2/36.3+/-8.7 ng/ml, PIO+SIMVA 36.5+/-10.8/36.5+/-8 ng/ml, SIMVA 36.1+/-8.1/36.6+/-11.1 ng/ml, all n.s. vs. baseline). Despite a partial or comprehensive improvement in insulin resistance and/or cardiovascular risk indicators in all treatment arms, no change in RBP4-levels could be observed. The regulation of RBP4 expression and secretion occurs through biochemical pathways independent from those influenced by pioglitazone or simvastatin.
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Total and high molecular weight (HMW) adiponectin levels and measures of glucose and lipid metabolism following pioglitazone treatment in a randomized placebo-controlled study in polycystic ovary syndrome.
Glintborg, D, Frystyk, J, Højlund, K, Andersen, KK, Henriksen, JE, Hermann, AP, Hagen, C, Flyvbjerg, A, Andersen, M
Clinical endocrinology. 2008;(2):165-74
Abstract
OBJECTIVE Recent studies suggested that the effect of adiponectin on insulin-stimulated glucose metabolism is mediated primarily by the high molecular weight (HMW) form of adiponectin. In the present study we evaluated total and HMW adiponectin in polycystic ovary syndrome (PCOS) patients and controls and examined possible mechanisms for increased insulin sensitivity during pioglitazone treatment. STUDY SUBJECTS Thirty PCOS patients randomized to pioglitazone, 30 mg/day, or placebo for 16 weeks and 14 weight-matched healthy females were studied. DESIGN Total and HMW adiponectin levels were measured, and euglycaemic hyperinsulinaemic clamps and indirect calorimetry were performed. Delta-values denoted changes during pioglitazone treatment (16 weeks--basal). RESULTS Pretreatment adiponectin levels were decreased in PCOS patients vs. controls (P < 0.05), whereas no significant differences were found in HMW adiponectin levels. Following pioglitazone treatment, total and HMW adiponectin increased (all P < 0.05), whereas no significant changes were observed with placebo. Delta-total adiponectin levels correlated positively with the rate of Delta-insulin-stimulated glucose disposal (R(d)) (r = 0.89) and Delta-oxidative glucose metabolism (r = 0.71) and inversely with Delta-fasting free fatty acid (FFA) levels (r = -0.69) and Delta-lipid oxidation (r = -0.73) during insulin stimulation (all P < 0.01). Weaker correlations were found between Delta-HMW adiponectin levels and Delta-measures of glucose and lipid metabolism during insulin stimulation than with Delta-total adiponectin. CONCLUSION A close correlation between increased total adiponectin levels and increased insulin-stimulated glucose metabolism during pioglitzone treatment supports the hypothesis that the insulin-sensitizing effect of pioglitazone in PCOS is, at least in part, mediated by adiponectin. Measures of changes in HMW adiponectin did not add further information to this relationship.
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Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and metabolic syndrome treated with metformin.
Derosa, G, D'Angelo, A, Ragonesi, PD, Ciccarelli, L, Piccinni, MN, Pricolo, F, Salvadeo, SA, Montagna, L, Gravina, A, Ferrari, I, et al
Internal medicine journal. 2007;(2):79-86
Abstract
BACKGROUND Metformin is considered the gold standard for type 2 diabetes treatment as monotherapy and in combination with sulphonylureas and insulin, whereas the combination of metformin with thiazolidinediones is relatively less studied. The aim of the present study was to assess the differential effect on glycaemic metabolism and lipid variables of the combination of metformin plus pioglitazone or metformin plus rosiglitazone in diabetic patients with metabolic syndrome. METHODS All patients began metformin and were randomized to receive pioglitazone or rosiglitazone for 12 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, homeostasis model assessment index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and apolipoprotein B. RESULTS Significant decreases in glycated haemoglobin, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, and postprandial plasma insulin were seen after 9 and 12 months in both groups. Homeostasis model assessment index improved at 12 months in both groups. Significant total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, and apolipoprotein B improvement was observed in pioglitazone group after 12 months, but not in the rosiglitazone group. These variations were significant between groups. CONCLUSION The combination of metformin plus thiazolidinediones was able to improve glycaemic control compared with previous therapy. Pioglitazone was associated with a significant improvement in lipid and lipoprotein variables.