Abstract 475: Autonomic Blockade Improves Obesity-Associated Insulin Resistance
A hallmark of obesity is the development of insulin resistance. Increased secretion of insulin is an initial compensatory mechanism and is thought to contribute to sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance providing a negative feedback loop. To test this hypothesis we determined insulin sensitivity (hyperinsulinemic euglycemic clamp) in obese subjects (30<BMI<40 kg/m2) during intact and during pharmacologically induced autonomic blockade (trimethaphan 4 mg/min IV infusion). Blood pressure was clamped during autonomic blockade by concomitant titrated IV infusion of the NOS inhibitor L-NMMA. Eleven obese subjects (41±3.6 years, 35±0.8 kg/m2, 144±4/90±4 mm Hg) were studied on two separate occasions randomly assigned. Seven were found to be insulin resistance and four to be insulin sensitive (GIR>4.5 mg/kg/min). There were no differences in age, total fat percentage, blood pressure or muscle sympathetic activity between groups. GIR increased during autonomic blockade only among subjects with insulin resistance (2.96±0.54 to 4.03±0.67 mg/kg/min for the intact and blocked days, p=0.018, figure group A). No improvement was seen in the insulin sensitive group (6.08±0.88 to 5.99±1.34 mg/kg/min for the intact and blocked days, p=0.5, Group B). Our results support the concept that sympathetic activation has a detrimental effect on glucose utilization in obesity, and provides the rational to explore it as a therapeutic target.
- © 2012 by American Heart Association, Inc.