title: Autonomic blockade improves insulin sensitivity in obese subjects.
abstract: Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce 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. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake (MBW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m(2) body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P=0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects (MBW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P=0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation.
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Gamboa
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Okamoto
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Arnold
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Rocio A
authors.initials: RA
authors.lastname: Figueroa
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: André
authors.initials: A
authors.lastname: Diedrich
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Satish R
authors.initials: SR
authors.lastname: Raj
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Sachin Y
authors.initials: SY
authors.lastname: Paranjape
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Ginnie
authors.initials: G
authors.lastname: Farley
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN.
authors.forename: Naji
authors.initials: N
authors.lastname: Abumrad
authors.affiliation: From the Division of Clinical Pharmacology, Departments of Medicine (A.G., L.E.O., A.C.A., R.A.F., A.D., S.R.R., S.Y.P., G.F., I.B.), Pharmacology (S.R.R., I.B.), Biomedical Engineering (A.D.), and Surgery (N.A.), Vanderbilt University, Nashville, TN. italo.biaggioni@vanderbilt.edu.
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
mesh_terms: D000328:Adult; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology*; D015309:Glucose Clamp Technique / Q000379:methods; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000294:innervation; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D014294:Trimethaphan / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005730:Ganglionic Blockers; D007328:Insulin; D019323:omega-N-Methylarginine; D014294:Trimethaphan; D019001:Nitric Oxide Synthase
keywords: autonomic nervous system; insulin resistance; obesity