Hyperinsulinemia and autonomic nervous system dysfunction in obesity - Effects of weight loss

Background-Because hyperinsulinemia acutely stimulates adrenergic activity, it has been postulated that chronic hyperinsulinemia may lead to enhanced sympathetic tone and cardiovascular risk. Methods and Results-In 21 obese (body mass index, 35+/-1 kg/m(2)) and 17 lean subjects, we measured resting cardiac output (by 3-dimensional echocardiography), plasma concentrations and timed (diurnal versus nocturnal) urinary excretion of catecholamines, and 24-hour heart rate variability (by spectral analysis of ECG). In the obese versus lean subjects, cardiac output was increased by 22% (P<0.03), and the nocturnal drop in urinary norepinephrine output was blunted (P=0.01). Spectral power in the low-frequency range was depressed throughout 74 hours (P<0.04). During the afternoon and early night, ie, the postprandial phase, high-frequency power was lower, heart rate was higher; and the ratio of low to high frequency. an index of sympathovagal balance, was increased in direct proportion to the degree of hyperinsulinemia independent of body mass index (partial r=0.43. P=0.01). In 9 obese subjects who lost 10% to 18% of their body weight, cardiac output decreased and low-frequency power returned toward normal (P<0.05). Conclusions-in free-living subjects with uncomplicated obesity, chronic hyperinsulinemia is associated with a high-output, low-resistance hemodynamic state, persistent baroreflex downregulation, and episodic (postprandial) sympathetic dominance. Reversal of these changes by weight loss suggests a causal role for insulin.