Effects of Tolbutamide Pretreatment on the Rate of Conversion of Newly Synthesized Proinsulin to Insulin and the Compartmental Characteristics of Insulin Storage in Isolated Rat Islets

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Abstract
Toibutamide (1 g/kg body wt) was administered to male rats for 3 days to determine the effects of this pretreatment on subsequent insulin biosynthesis and compartmental storage characteristics of freshly isolated islets. Islets were isolated 16 h after the last toibutamide administration, at a time when fed plasma glucose concentrations were normal. Islet glucagon was unchanged but insulin content was significantly reduced (38 ± 1.2 ng IRI/islet from seven untreated rats versus 7.9 ± 1.2 ng IRI/islet from eight treated rats). After toibutamide pretreatment, the rate of incorporation of 3Hleucine into islet proinsulin was unchanged, but the t1/2 of labeled proinsulin-to-insulin conversion was significantly (P < 0.001) decreased from 36 to 20 min. After treatment, actual rates of glucose-stimulated insulin secretion were 50% lower, however, because due to the proportionately greater depletion of islet insulin content, the fractional rate of secretion was increased twofold. After treatment, there was evidence of compartmental, heterogeneous insulin storage, and glucose still marked newly synthesized insulin for preferential release; however, the differential release of new and old insulin converged rapidly with time. Mathematical integration of the data suggested dilution of the newly synthesized insulin compartment with unlabeled insulin during the chase period, but additionally indicated more rapid mixing of newly synthesized with previously stored, unlabeled insulin. Thus, tolbutamide-treated rats partially compensated for acute insulin depletion by (1) increasing the rate of proinsulin-to-insulin conversion, but not increasing the rate of proinsulin biosynthesis; (2) doubling the glucose-stimulated fractional secretory rate of the depleted cellular insulin storage compartment; and (3) retaining compartmental storage characteristics but mixing newly synthesized insulin more rapidly with the compartment of previously stored, unlabeled insulin.

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