Neuroadrenergic dysfunction along the diabetes continuum: A comparative study in obese metabolic syndrome subjects

Nora E. Straznicky, Mariee T. Grima, Carolina I. Sari, Nina Eikelis, Elisabeth A. Lambert, Paul J. Nestel, Murray D. Esler, John B. Dixon, Reena Chopra, Alan J. Tilbrook, Markus P. Schlaich, Gavin W. Lambert

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Abstract

Neuroadrenergic function in type 2 diabetic (T2D) patients without neuropathy is poorly characterized. We therefore compared sympathetic nervous system activity at rest and during an oral glucose tolerance test in obese metabolic syndrome (MetS) subjects classified as glucose intolerant (impaired glucose tolerance [IGT]; n = 17) or treatment-naive T2D (n = 17). Untreated subjects, matched for age (mean 59 ± 1 year), sex, BMI (32.4 ± 0.6 kg/m2), and family history of diabetes were studied. We measured resting muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics by isotope dilution, insulin sensitivity by euglycemic-hyperinsulinemic clamp (steady-state glucose utilization adjusted for fat-free mass and steady-state insulin concentration [M/I]), and MetS components. T2D subjects had higher resting MSNA burst incidence (67 ± 4 versus 55 ± 3 bursts per 100 heartbeats; P = 0.05) and arterial norepinephrine levels (264 ± 33 versus 167 ± 16 pg/mL; P = 0.02), lower plasma norepinephrine clearance (by 17%; P = 0.03), and reduced neuronal reuptake compared with IGT subjects (by 46%; P = 0.04). Moreover, norepinephrine spillover responses to glucose ingestion were blunted in T2D subjects. The M/I value independently predicted whole-body norepinephrine spillover (r = 20.47; P = 0.008), whereas fasting insulin level related to neuronal norepinephrine reuptake (r = -0.35, P = 0.047). These findings demonstrate that progression to T2D is associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.

Original languageEnglish
Pages (from-to)2506-2516
Number of pages11
JournalDiabetes
Volume61
Issue number10
DOIs
Publication statusPublished - 2012
Externally publishedYes

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Straznicky, N. E., Grima, M. T., Sari, C. I., Eikelis, N., Lambert, E. A., Nestel, P. J., ... Lambert, G. W. (2012). Neuroadrenergic dysfunction along the diabetes continuum: A comparative study in obese metabolic syndrome subjects. Diabetes, 61(10), 2506-2516. https://doi.org/10.2337/db12-0138