title: A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Laboratories of Human Neurotransmitters (N.E.S., M.T.G., C.L.S., N.E., G.W.L., K.R., J.B.D., E.A.L.), Cardiovascular Nutrition (P.J.N.), and Neurovascular Hypertension and Kidney Disease (P.M., M.P.S.) and Alfred Baker Medical Unit (S.K., C.W.), Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 8008, Australia; Faculty of Medicine, Nursing, and Health Sciences (G.W.L., M.P.S.) and the Departments of Physiology (E.A.L.) and Primary Health Care (J.B.D.), Monash University, Melbourne, Victoria 3800, Australia; and the Department of Physiology (E.A.L.), University of Melbourne, Melbourne 3010, Australia.
authors.forename: Nora E
authors.initials: NE
authors.lastname: Straznicky
authors.forename: Mariee T
authors.initials: MT
authors.lastname: Grima
authors.forename: Carolina I
authors.initials: CI
authors.lastname: Sari
authors.forename: Nina
authors.initials: N
authors.lastname: Eikelis
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Lambert
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Nestel
authors.forename: Sofie
authors.initials: S
authors.lastname: Karapanagiotidis
authors.forename: Chiew
authors.initials: C
authors.lastname: Wong
authors.forename: Katrina
authors.initials: K
authors.lastname: Richards
authors.forename: Petra
authors.initials: P
authors.lastname: Marusic
authors.forename: John B
authors.initials: JB
authors.lastname: Dixon
authors.forename: Markus P
authors.initials: MP
authors.lastname: Schlaich
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lambert
mesh_terms: D001794:Blood Pressure / Q000187:drug effects*; D003971:Diastole / Q000187:drug effects; D004311:Double-Blind Method; D015150:Echocardiography, Doppler; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D008954:Models, Biological; D009638:Norepinephrine / Q000097:blood / Q000493:pharmacokinetics; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D000077205:Pioglitazone; D010919:Placebos; D013564:Sympathetic Nervous System / Q000187:drug effects*; D045162:Thiazolidinediones / Q000008:administration & dosage*; D014316:Tritium
chemical_list: D007004:Hypoglycemic Agents; D010919:Placebos; D045162:Thiazolidinediones; D014316:Tritium; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol; D000077205:Pioglitazone; D009638:Norepinephrine