title: Sensory nerve inactivation by resiniferatoxin improves insulin sensitivity in male obese Zucker rats.
abstract: 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.
authors.affiliation: Discovery, Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: Sophia G
authors.initials: SG
authors.lastname: Moesgaard
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Jeppe
authors.initials: J
authors.lastname: Sturis
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.forename: Michael
authors.initials: M
authors.lastname: Wilken
authors.forename: Jan
authors.initials: J
authors.lastname: Fleckner
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carr
authors.forename: Ove
authors.initials: O
authors.lastname: Svendsen
authors.forename: Anker J
authors.initials: AJ
authors.lastname: Hansen
authors.forename: Dorte X
authors.initials: DX
authors.lastname: Gram
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes / Q000494:pharmacology*; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010477:Perfusion; D011897:Random Allocation; D051381:Rats; D011924:Rats, Zucker
chemical_list: D004224:Diterpenes; D007328:Insulin; D009498:Neurotoxins; C024353:resiniferatoxin; D005947:Glucose