We have recently shown that in the intact rat, at 10 min after vincristine treatment, glucose-induced insulin release and glucose tolerance were potentiated, but at 60 and 120 min after vincristine treatment, glucose-induced insulin release and glucose tolerance were significantly impaired. The present study further evaluated the mechanisms of these observations by examining the in vivo effect of vincristine on (1) the pancreatic /3-cell microtubular structures and (2) insulin release in response to arginine, an insulin secretogogue other than glucose. In the first series of studies, the pancreases were removed from the rats at 60 and 120 min after vincristine (0.15 mg/kg; i.v.) or vehicle (control) administration for electron microscopy. Morphometric analysis revealed that the number of /3-cell microtubules was similar in the vincristinetreated and the control rats. Furthermore, the mean microtubular length in vincristine-treated rats was also similar to that observed in the control rats. In the next series of studies, at 10, 60, or 120 min after vincristine (0.15 mg/kg; i.v.), insulin levels in response to an i.v. arginine pulse were similar in the vincristinetreated and in the control rats at all time intervals between 2 and 30 min. A parallel study once again demonstrated that glucose-induced insulin release and glucose tolerance were significantly impaired at 120 min after vincristine treatment. These findings indicate that (1) In the intact rat, inhibition of glucose-induced insulin release by vincristine occurs in the absence of any demonstrable changes in the /3-cell microtubular structure; and (2) even though vincristine inhibits glucose-induced insulin release, it has no effect on arginine-induced insulin release. Therefore, in
SUMMARYWe have previously shown that in the intact rat: (1) the inhibition of glucose-induced insulin release caused by vincristine occurred in the presence or absence of morphologic disruption of the beta-cell microtubules; and (2) vincristine, however, failed to inhibit arginine-induced insulin release, even in the presence of a marked disruption of the beta-cell microtubules. The present study further evaluated the mechanism of inhibition of vincristine on glucose-induced insulin release in the intact rat. In the first series of studies, glucose (500 mg/kg) was infused over 1 min into fasting rats with indwelling vascular catheters. Five minutes later, vincristine (0.15 mg/kg i.v.) or vehicle (control) was injected. Sixty minutes after vincristine or vehicle treatment, insulin release in response to a 150-mg i.v. glucose pulse was examined. Serum insulin and glucose levels were similar at all time intervals in the vincristine-treated and the control rats. In the next series of studies, the experiments were repeated as above, except arginine (100 mg/kg), instead of glucose, was infused over 1 min before vincristine or vehicle treatment. In these studies, serum insulin in response to a glucose pulse was significantly inhibited in the vincristine-treated rats as compared with control rats. Therefore, in the intact rat, prior exposure to glucose but not arginine protected the beta-cell from the inhibitory effect of vincristine on glucose-induced insulin release. These findings, along with our previous observations, support the concept that arginine-induced insulin release is mediated via mechanisms other than those involved in glucose-induced insulin release and suggest that the in vivo effect of vincristine on glucose-induced insulin release is mediated via alteration of the beta-cell glucose receptors rather than microtubular structures. DIABETES
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