A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome

Nora E. Straznicky, Mariee T. Grima, Carolina I. Sari, Nina Eikelis, Gavin W. Lambert, Paul J. Nestel, Sofie Karapanagiotidis, Chiew Wong, Katrina Richards, Petra Marusic, John B. Dixon, Markus P. Schlaich, Elisabeth A. Lambert

Research output: Contribution to journalArticle

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Abstract

Context: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. Copyright

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/m2) whoreceived 12 weeks of pioglitazone (PIO; 15mgfor 6 wk, then 30mgdaily) 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 ([3H]-DHPG to [3H]-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 [3H]-DHPG to [3H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [3H]-DHPG to [3H]-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 curve0-120during 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 [3H]-DHPG to [3H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

Original languageEnglish
Pages (from-to)E1701-E1707
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number9
DOIs
Publication statusPublished - 1 Sep 2014
Externally publishedYes

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pioglitazone
Sympathetic Nervous System
Neurology
Norepinephrine
Randomized Controlled Trials
Blood Pressure
Blood pressure
Baroreflex
Placebos
Insulin
Glucose Tolerance Test
Glucose
Muscle
Insulin Resistance
Therapeutics
Echocardiography
Muscles
Glucose Clamp Technique
Deceleration
Doppler Echocardiography

Cite this

Straznicky, Nora E. ; Grima, Mariee T. ; Sari, Carolina I. ; Eikelis, Nina ; Lambert, Gavin W. ; Nestel, Paul J. ; Karapanagiotidis, Sofie ; Wong, Chiew ; Richards, Katrina ; Marusic, Petra ; Dixon, John B. ; Schlaich, Markus P. ; Lambert, Elisabeth A. / A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome. In: Journal of Clinical Endocrinology and Metabolism. 2014 ; Vol. 99, No. 9. pp. E1701-E1707.
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abstract = "Context: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. CopyrightObjective: 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/m2) whoreceived 12 weeks of pioglitazone (PIO; 15mgfor 6 wk, then 30mgdaily) 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 ([3H]-DHPG to [3H]-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 [3H]-DHPG to [3H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [3H]-DHPG to [3H]-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 curve0-120during 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 [3H]-DHPG to [3H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.",
author = "Straznicky, {Nora E.} and Grima, {Mariee T.} and Sari, {Carolina I.} and Nina Eikelis and Lambert, {Gavin W.} and Nestel, {Paul J.} and Sofie Karapanagiotidis and Chiew Wong and Katrina Richards and Petra Marusic and Dixon, {John B.} and Schlaich, {Markus P.} and Lambert, {Elisabeth A.}",
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language = "English",
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Straznicky, NE, Grima, MT, Sari, CI, Eikelis, N, Lambert, GW, Nestel, PJ, Karapanagiotidis, S, Wong, C, Richards, K, Marusic, P, Dixon, JB, Schlaich, MP & Lambert, EA 2014, 'A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome' Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 9, pp. E1701-E1707. https://doi.org/10.1210/jc.2014-1976

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, Nora E.; Grima, Mariee T.; Sari, Carolina I.; Eikelis, Nina; Lambert, Gavin W.; Nestel, Paul J.; Karapanagiotidis, Sofie; Wong, Chiew; Richards, Katrina; Marusic, Petra; Dixon, John B.; Schlaich, Markus P.; Lambert, Elisabeth A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 99, No. 9, 01.09.2014, p. E1701-E1707.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome

AU - Straznicky, Nora E.

AU - Grima, Mariee T.

AU - Sari, Carolina I.

AU - Eikelis, Nina

AU - Lambert, Gavin W.

AU - Nestel, Paul J.

AU - Karapanagiotidis, Sofie

AU - Wong, Chiew

AU - Richards, Katrina

AU - Marusic, Petra

AU - Dixon, John B.

AU - Schlaich, Markus P.

AU - Lambert, Elisabeth A.

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Context: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. CopyrightObjective: 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/m2) whoreceived 12 weeks of pioglitazone (PIO; 15mgfor 6 wk, then 30mgdaily) 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 ([3H]-DHPG to [3H]-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 [3H]-DHPG to [3H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [3H]-DHPG to [3H]-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 curve0-120during 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 [3H]-DHPG to [3H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

AB - Context: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. CopyrightObjective: 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/m2) whoreceived 12 weeks of pioglitazone (PIO; 15mgfor 6 wk, then 30mgdaily) 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 ([3H]-DHPG to [3H]-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 [3H]-DHPG to [3H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [3H]-DHPG to [3H]-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 curve0-120during 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 [3H]-DHPG to [3H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

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