Long-Term Actions of Sulfonylureas on (Pro-)Insulin Biosynthesis and Secretion[*] - II. Studies after Administration of Tolbutamide and Glibenclamide to Rats In Vivo

Abstract

Sulfonylureas, especially tolbutamide, inhibit insulin biosynthesis when added in vitro to isolated pancreatic islets. It was the aim of the present study to evaluate the significance of this effect in vivo.

Tolbutamide and glibenclamide were administered orally to rats for 10 months at a daily dose of 90 and 0.3 mg/kg, respectively. Islets isolated by collagenase 16 hours after the last dose of sulfonylureas were used for estimating total insulin content of the islets as well as for studying release and synthesis of (pro-)insulin by incubation of the islets with ³H-leucine at 100 and 200 mg/100 ml glucose for 3 hours. (Pro-)Insulin biosynthesis was judged by measuring ³H-leucine incorporation into the proinsulin and insulin fractions separated on Sephadex G50.

Weight and serum levels of glucose and insulin were significantly higher in rats treated with tolbutamide and glibenclamide for 10 months compared with control rats. Insulin content of the islets was significantly lowered after tolbutamide whereas no changes were found after glibenclamide. Insulin release from islets of tolbutamide-treated rats tended to be reduced, however, no significant differences existed when insulin release was related to insulin content of the islets. ³H-leucine incorporation into proinsulin and insulin was significantly reduced after glibenclamide treatment and unchanged after tolbutamide.

Long-term administration of sulfonylureas to rats increase serum levels of insulin which might cause the weight gain of the animals. Tolbutamide diminishes insulin biosynthesis also in vivo concluded from the reduced insulin content of the islets. Such an action could not be demonstrated for glibenclamide. Inhibition of hormone synthesis appears, however, to be short-lasting for tolbutamide whereas glibenclamide exerts a late, mild reduction of ³H-leucine incorporation also 16 hours after the end of treatment. The secretory capacity of the islets was not seriously disturbed.

In conclusion: Long-term administration to rats of tolbutamide, at variance to glibenclamide, diminishes pancreatic insulin content by inhibiting hormone synthesis. This action is, however, quickly reversible and does not result in a permanently impaired secretory mechanism of the beta-cell.

Key words

Isolated Rat Islets - Sulfonylureas - Tolbutamide - Glibenclamide - Proinsulin/Insulin Biosynthesis - Insulin Content - Insulin Secretion - Body Weight - Cholesterol - Triglycerides

1 Supported by Deutsche Forschungsgemeinschaft Bonn-Bad Godesberg

1 Supported by Deutsche Forschungsgemeinschaft Bonn-Bad Godesberg