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We wish to thank Dr. Frontoni (1) for her insightful comments regarding the disparate relationship of glucose utilization to two indices of sympathetic nervous system activity—whole-body norepinephrine spillover rate and muscle sympathetic nerve activity (MSNA), within our cohort of obese metabolic syndrome subjects (2). Both arterial norepinephrine concentration and norepinephrine spillover rate showed a strong inverse relationship with clamp-derived glucose utilization (M/I value, r = −0.47, P = 0.008), whereas MSNA was not significantly associated with glucose utilization. Rather, total MSNA was influenced by the prevailing insulin concentration as indicated by positive associations with fasting C-peptide levels (r = 0.37, P = 0.04) and insulin area under the curve between 0 and 120 min during an oral glucose tolerance test (r = 0.33, P = 0.07), which was amplified within the type 2 diabetic subgroup (r = 0.70, P = 0.004) that comprised both hyperinsulinemic and hypoinsulinemic subjects. This is consistent with clinical experimental data showing that hyperinsulinemia stimulates central sympathetic outflow (3).
Glucose uptake during insulin clamp occurs primarily in skeletal muscle and encompasses nonoxidative glucose disposal and glucose oxidation. Acute administration of norepinephrine has been shown to impair glucose uptake by both hemodynamic (α-adrenergic vasoconstriction) and direct β-adrenoceptor–mediated metabolic effects (inhibition of net glycogen synthesis and stimulation of hepatic glucose production) (4). Sympathetic activation also increases adipose tissue lipolysis, with resultant elevation in circulating nonesterified fatty acids and competitive inhibition of glucose oxidation. A number of factors may modulate the reciprocal interrelationships between sympathetic activity, hyperinsulinemia, and insulin resistance. As pointed out by Frontoni, these factors, and therefore the nature of interactions, will change dynamically along the diabetes pathogenic pathway. Key modulators are the presence or absence of obesity, insulin resistance (5), or hyperglycemia; β-adrenoceptor sensitivity, which plays a pivotal role in basal and postprandial energy expenditure, and which in turn is influenced by genetics and duration of chronic sympathetic activation; familial disposition; and background lifestyle habits (diet and exercise).
Our study highlights neuroadrenergic dysfunction at multiple levels in newly diagnosed type 2 diabetic subjects. Increased central sympathetic drive was accompanied by blunted nutritional sympathetic responsiveness and reduced neuronal norepinephrine uptake and plasma clearance. These findings portend adverse clinical implications for target organ damage, postprandial thermogenesis, body weight homeostasis, and cardiovascular risk. Further long-term prospective studies, using robust measures of sympathetic activity, are warranted to better delineate temporal relationships with insulin resistance and type 2 diabetes. There also remains a gap in knowledge regarding the benefits of weight loss on neuroadrenergic parameters within diabetic patient groups and subgroups (hyper- vs. hypoinsulinemic) prior to the onset of neuropathy. This should be addressed as a matter of priority. Pharmacological intervention may offer another avenue for interrupting the feedback loop between sympathetic activity and insulin resistance. To this end, treatment with the insulin-sensitizing drug pioglitazone has been shown to decrease MSNA in patients with type 2 diabetes (6).
N.E.S. is funded by a Heart Foundation Grant-in-Aid (G11M5892).
The authors’ laboratory currently receives research funding from Medtronic Inc., Abbott Pharmaceuticals, Allergan Inc., and Servier. No other potential conflicts of interest relevant to this article were reported.