Sensory nerve inactivation by resiniferatoxin improves insulin sensitivity in male obese Zucker rats

1 Discovery, Novo Nordisk A/S, Maaloev; 2 Department of Pharmacology and Pathobiology, The Royal Veterinary and Agricultural University, Copenhagen, Denmark; and 3 Department of Medicine, Lund University, Lund, Sweden Submitted 4 August 2004 ; accepted in final form 9 January 2005 Recent studies have suggested that sensory nerves may influence insulin secretion and action. The present study investigated the effects of resiniferatoxin (RTX) inactivation of sensory nerves (desensitization) on oral glucose tolerance, insulin secretion and whole body insulin sensitivity in the glucose intolerant, hyperinsulinemic, and insulin-resistant obese Zucker rat. After RTX treatment (0.05 mg/kg RTX sc given at ages 8, 10, and 12 wk), fasting plasma insulin was reduced ( P < 0.0005), and oral glucose tolerance was improved ( P < 0.005). Pancreas perfusion showed that baseline insulin secretion (7 mM glucose) was lower in RTX-treated rats ( P = 0.01). Insulin secretory responsiveness to 20 mM glucose was enhanced in the perfused pancreas of RTX-treated rats ( P < 0.005) but unaffected in stimulated, isolated pancreatic islets. At the peak of spontaneous insulin resistance in the obese Zucker rat, insulin sensitivity was substantially improved after RTX treatment, as evidenced by higher glucose infusion rates (GIR) required to maintain euglycemia during a hyperinsulinemic euglycemic (5 mU·kg –1 ·min –1 ) clamp (GIR 60–120min : 5.97 ± 0.62 vs. 11.65 ± 0.83 mg·kg –1 ·min –1 in RTX-treated rats, P = 0.003). In conclusion, RTX treatment and, hence, sensory nerve desensitization of adult male obese Zucker rats improved oral glucose tolerance by enhancing insulin secretion, and, in particular, by improving insulin sensitivity. capsaicin; hyperinsulinemic euglycemic clamp; obesity Address for reprint requests and other correspondence: D. X. Gram, Pharmacology Research 3, Novo Nordisk A/S, Novo Nordisk Park, F6.1.30, 2760 Maaloev, Denmark (E-mail: dxg{at}novonordisk.com )