The Diphasic Effect of Vincristine on Glucose-Induced Insulin Secretion and Glucose Tolerance in the Intact Rat*

Abstract

The effect of vincristine on glucose-induced insulin secretion and glucose tolerance was examined in intact, unanesthetized, and unrestrained rats with indwelling intravascular catheters. In the first series of studies, the insulin secretion in response to a 150-mg iv glucose pulse and the glucose disappearance rate (K_G) were evaluated 10 min after iv administration of vincristine in doses of 0.06, 0.15, and 0.5 mg/kg or of vehicle (control). The lower dose of vincristine (0.06 mg/kg) caused significant potentiation of glucose-induced insulin secretion and also caused marked enhancement of K_G compared with control rats. However, this potentiating effect of vincristine on glucoseinduced insulin secretion and K_G was less with the medium dose (0.15 mg/kg) and was completely abolished with the highest dose (0.5 mg/kg) of vincristine tested. Thus, a significant negative correlation was observed between the vincristine dose and its potentiating effect on glucose-induced insulin secretion and K_G. In the next series of studies, vincristine (0.06 and 0.15 mg/kg, iv) was administered, but the insulin secretion and K_G in response to a 150-mg iv glucose pulse were evaluated 60 and 120 min after the vincristine treatment. In contrast to the effect of the low dose of vincristine (0.06 mg/kg) at 10 min in the initial studies, a significant impairment of glucose-induced insulin secretion and K_G was observed 120 min after the same dose of vincristine. The glucose-induced insulin secretion and K_G were also impaired 60 and 120 min after a medium dose of vincristine (0.15 mg/kg). A significant negative correlation was also observed between the duration of vincristine treatment and the glucose-induced insulin secretion and K_G. Such a time-dependent change in glucose-induced insulin secretion and glucose tolerance was not observed in the control rats. Therefore, vincristine in the intact rat (in doses comparable on a weight basis to those used for cancer chemotherapy in humans) initially causes potentiation of glucose-induced insulin secretion and K_G but ultimately causes impairment of glucoseinduced insulin secretion and glucose tolerance