Catecholamine-induced insulin resistance of glucose transport in isolated rat adipocytes

Abstract

The effects of pre-incubation with isoprenaline and noradrenaline on insulin binding and insulin stimulation of D-glucose transport in isolated rat adipocytes are reported. (1) Pre-incubation of the cells with isoprenaline (0.1-10 microM) in Krebs-Ringer-Hepes [4-(2-hydroxyethyl)-1-piperazine-ethanesulphonic acid] buffer (30 min, 37 degrees C) at D-glucose concentrations of 16 mM, in which normal ATP levels were maintained, caused a rightward-shift in sensitivity of D-glucose transport to insulin stimulation by 50% and a decrease in maximal responsiveness by 30% (2) [A14-125I]insulin binding was reduced significantly by 35% at insulin concentrations less than 100 mu-units/ml and Scatchard analysis showed that this consisted mainly of a decrease in high-affinity binding. (3) Pre-incubation with catecholamines under the same conditions but at low glucose concentrations (0-5 mM) caused a fall in intracellular ATP levels of 65 and 45% respectively. (4) The fall in ATP additionally lowered insulin binding by 50% at all insulin concentrations and a parallel shift of the binding curves in the Scatchard plot showed that this was due to a decrease in the number of receptors. (5) At low and high ATP concentrations the insulin stimulation of D-glucose transport was inhibited to a similar extent. (6) Pre-incubation with catecholamines thus inhibited insulin stimulation of D-glucose transport in rat adipocytes mainly by a decrease in high-affinity binding of insulin, which was not mediated by low ATP levels. This mechanism may play a role in the pathogenesis of catecholamine-induced insulin resistance in vivo.

Reduced insulin binding to human fat cells following beta-adrenergic stimulation ? experimental evidence and studies in patients with a phaeochromocytoma

“…This finding is similar to recent results with rat adipocytes where catecholamines, via a fl-adrenergic mechanism, rapidly reduced insulin binding [6][7][8].…”

“…In agreement with our previous results with rat adipocytes [6], the decreased insulin binding was mainly due to an apparent reduction of the number of receptors. This finding is somewhat at variance with the results of Pessin et al [7] and Kirsch et al [8], who attributed the decreased binding to affinity changes or a decreased number of high affinity sites. In a recent study with human adipocytes, Arner et al [20] reported that high isoproterenol concentrations (6 ~mol/1) reduced the affinity of binding sites in the absence of glucose in the incubation medium.…”

“…In addition, catecholamines were found to induce a marked inhibition of insulin-stimulated glucose transport in these cells [8][9][10][11]. The time course of both events is similar, suggesting that they may be elicited by the same mechanism [11].…”

“…Recently, we and others independently reported that fl-adrenergic stimulation leads to a rapid reduction of insulin binding to rat adipocytes [6][7][8]. In addition, catecholamines were found to induce a marked inhibition of insulin-stimulated glucose transport in these cells [8][9][10][11].…”

The regulation of glucose transport in insulin-sensitive cells

“…When adipocytes incubated at a high cell concentration were exposed to isoproterenol, the affinity of insulin receptors was reduced [80,81]. Similar data were obtained by stimulation of adenylate cyclase with the adenosine antagonist, theophylline [82].…”