Acute Tolbutamide Administration Alone or Combined With Insulin Enhances Glucose Intake in the Perfused Rat Hindlimb

Abstract

We examined the effects of acute administration of tolbutamide on glucose uptake in the non-cyclically perfused rat hindlimb. During the hour of study, 500 microunits boluses of insulin were given every ten min in the presence or absence of 3 X 10(-3)M tolbutamide. Tolbutamide by itself increased glucose uptake; however at no time was this increase significantly different from that seen in the group which received insulin alone. After 42 min of perfusion, the insulin-stimulated uptake was 26% and the tolbutamide was 20% greater than control (1.90 +/- 0.08, 1.80 +/- 0.06, and 1.50 +/- 0.05 mumol/min/100 g respectively). After 20 min of perfusion, the increase in glucose uptake seen with the combination of insulin + tolbutamide was significantly greater than that obtained with either tolbutamide or insulin alone. At the termination of perfusion, the glucose uptake with the combined treatment was 59% greater than control, 35% greater than tolbutamide, and 19% greater than insulin alone (2.67 +/- 0.10, vrs. 1.68 +/- 0.07 vrs. 1.97 +/- 0.07 vrs. 2.16 +/- 0.07 mumol/min/100 g). These results demonstrate not only a direct effect of tolbutamide, but also a potentiation of insulin-stimulated glucose uptake in the rat hindlimb. Therefore, tolbutamide has extra-pancreatic effects which probably contribute to the hypoglycemic action of this sulfonylurea.

Stimulation of glucose utilization in 3T3 adipocytes and rat diaphragm in vitro by the sulphonylureas, glimepiride and glibenclamide, is correlated with modulations of the cAMP regulatory cascade

“…A large number of studies during the past three decades have demonstrated multiple effects of sulphonylurea drugs on isolated normal and insulinresistant rat [12,[37][38][39][40][41][42][43] and mouse 3T3 adipocytes [44][45][46], cultured myocytes [47][48][49][50][51], isolated rat diaphragms [52] and perfused rat hind limbs [53] (for a review see Ref. [54]).…”

“…[54]). Among them are the stimulation of glucose transport [12,37,38,41,[44][45][46][47][48][49][50][51][52][53], lipogenesis [40] and glycogenesis [43], as well as the inhibition of lipolysis [39]. The multiple effects of sulphonylureas on glucose utilization in vitro suggest the induction of one or several basic molecular mechanism(s) which is(are) responsible for the regulation of key metabolic pathways.…”

The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro

“…It will be inter esting to see in future studies whether glimepiride will compensate the lower number of GLUT4 in PM of muscle cells in the basal and insulin-stimulated state. The direct stimulation of glucose transport in the isolated rat dia phragm (67), perfused rat hindlimb (68), and cultured muscle cells (7,8) by sulfonylurea drugs suggests similar modes of action of these compounds in muscle and adipose tissue.…”

Differences Between the Tolbutamide-Boosted and the Insulin-Modified Minimal Model Protocols

“…It is unlikely that tolbutamide itself contributed to the observed prolongation of insulin action. Although in vitro studies have suggested a direct tolbutamide action on glucose metabolism (27)(28)(29), a recent in vivo human study did not show such an effect (30). Nevertheless, tolbutamide-induced proinsulin release could play a role (Fig.…”