Neuroadrenergic Dysfunction Along the Diabetes Continuum

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 = −0.47; 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.

Insulin- and glucagon-like peptide-1-induced changes in heart rate and vagosympathetic activity: why they matter

“…This suggests that chronic marked hyperinsulinaemia may prevent further enhancement of cardiac sympathetic tone during an acute rise in insulin. A similar trend towards a limited increase in sympathetic activity in obese and type 2 diabetic patients has been reported during other tests, including deep breathing, exercise and oral glucose challenge [12,39,40], suggesting a reduction in sympathetic reserve when sympathetic activity is relatively high at baseline. A blunted sympathetic response may result from impaired insulin transport across the blood-brain barrier, which has been shown in experimentally induced insulin resistance in dogs [41], and from lower cerebrospinal fluid insulin levels, as reported in obese insulin-resistant humans [42].…”

“…Thus, a vagosympathetic imbalance may occur prior to diabetes as a result of overweight and insulin resistance. This is strongly supported by the recent demonstration that progression to type 2 diabetes is associated with increased central sympathetic drive, blunted sympathetic responsiveness and altered noradrenaline (norepinephrine) disposition [12]. In addition to obesity and diabetes, several factors associated with these conditions, such as insulin, proinsulin, C-peptide, glucose, leptin, adiponectin and NEFA, have been shown to affect the autonomic nervous system [13,14].…”

Is diabetic cardiomyopathy a specific entity?

“…There are reports of overactivation of the sympathetic system in the pre-diabetic and diabetic condition that further contributes to metabolic abnormalities. Straznicky observed the association of blunted sympathetic responsiveness and insulin resistance, and disturbed sympathetic neurobiology is characterized by augmented resting sympathetic nervous activity and blunted sympathetic responsiveness to oral glucose ingestion [35] .…”

Lifestyle Modification Is the First Line Treatment for Type 2 Diabetes

“…Those observations provide evidence of a strong linkage between the activity of the sympathetic nervous system and insulin levels over glucose metabolisms. Straznicky et al [68] reported that the progress from metabolic syndrome to type 2 diabetes might be associated with increased central sympathetic drive, blunted sympathetic responsiveness, and altered norepinephrine disposition.…”