Abstract Sensory nerve desensitization by capsaicin has been shown to improve the diabetic condition in Zucker Diabetic Fatty rats. However, administration of capsaicin to adult rats is associated with an increased mortality. Therefore, in this experiment, we examined the influence of resiniferatoxin, a tolerable analogue of capsaicin suitable for in vivo use, on the diabetic condition of Zucker Diabetic Fatty rats. A single subcutaneous injection of resiniferatoxin (0.01 mg/kg) to these rats was tolerable, with no mortality. When administered to early diabetic rats at 15 weeks of age, the further deterioration of glucose homeostasis was prevented by resiniferatoxin. Further, when administered to overtly diabetic rats at 19 weeks of age, resiniferatoxin markedly improved glucose tolerance at two weeks after administration and this was accompanied by an increased insulin response to oral glucose as well as a reduction in the plasma levels of dipeptidyl peptidase IV. Therefore, resiniferatoxin is a safe alternative to capsaicin for further investigations of the role of the sensory nerves in experimental diabetes.