Dexamethasone pretreatment of rat insulinoma cells decreases binding of glucagon-like peptide-1(7–36)amide

Abstract

The effect of dexamethasone on binding of glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) to rat insulinoma-derived cells (RINm5F) was investigated. Preincubation of RINm5F cells with dexamethasone (100 nmol/l) for 24 h resulted in a decrease of GLP-1(7-36)amide binding to 55.0 +/- 8.16% (mean +/- S.E.M.), incubation for 48 h to 39.1 +/- 1.76%, and for 72 h to 15.5 +/- 4.35% of maximal binding. The GLP-1(7-36)amide-induced stimulation of cyclic AMP (cAMP) production was significantly decreased to 61.03 +/- 7.4% of maximum production in cells pretreated with dexamethasone (100 nmol/l) for 48 h. The decreased binding was due to a reduction of the receptor number while the receptor affinity remained unchanged. These inhibitory effects on binding and cAMP formation induced by dexamethasone were completely abolished when the antiglucocorticoid RU 38486 (100 nmol/l) was added during preincubation with dexamethasone. RU 38486 alone had no effects. Our data suggest that the biological action of GLP-1(7-36)amide at the B-cell may be modified by glucocorticoids.

Glucagon‐like peptide‐1(7–36) amide is a new incretin/enterogastrone candidate

“…Further analysis of the binding data revealed a reduction of the receptor number while the receptor affinity remained unchanged [60]. From these results it was speculated that the effect of GLP-l(7-36) amide receptors induced by glucocorticoids could contribute to the impaired glucose tolerance in glucocorticoid-induced diabetes [60].…”

“…Further analysis of the binding data revealed a reduction of the receptor number while the receptor affinity remained unchanged[60]. From these results it was speculated that the effect of GLP-l(7-36) amide receptors induced by glucocorticoids could contribute to the impaired glucose tolerance in glucocorticoid-induced diabetes[60]. However, this suggestion remains rather specula-tive and needs further confirmation.Up to now, clinical studies considering physiological and pathophysiological implications of GLP-I (7-36) amide are clearly lacking.…”

High-Level Expression of the GLP-I Receptor Results in Receptor Desensitization

“…In B cells the signal is transduced into the cell by coupling of the receptor to the adenylate cyclase. The number of GLP-I receptors present on B cells can be regulated by several intracellular signal transduction pathways (18)(19)(20). This impacts on B-cell function and may influence therapeutic strategies.…”

Regulation of glucagon receptor expression

“…Glucocorticoids were found to reduce both glucagon and GLP-1 receptor mRNA expression in islets which is in agreement with previously reported binding studies. Calle et al (1987) found that in isolated adipocytes from cortisol treated rats, the number of glucagon receptors was reduced by 50 % (Calle et al 1987), and in a separate study by Richter et al (1990), treatment of rat insulinoma cells (RINm5F) with dexamethasone was found to decrease GLP-1 receptor binding (Richter et al 1990). Although it remains to be determined whether changes in glucagon receptor mRNA expression are reflected at the protein level, it appears that despite their high degree of homology, glucagon and GLP-1 receptor mRNA expression in pancreatic islets are differentially regulated.…”

“…This suggests that following long-term metabolic changes as might occur during diabetes, glucagon receptors may be upregulated making the islets more sensitive to glucagon. Calle et al (1987) found that in isolated adipocytes from cortisol treated rats, the number of glucagon receptors was reduced by 50 % (Calle et al 1987), and in a separate study by Richter et al (1990), treatment of rat insulinoma cells (RINm5F) with dexamethasone was found to decrease GLP-1 receptor binding (Richter et al 1990). Agents such as forskolin and IBMX which increase intracellular cAMP levels were found to decrease glucagon receptor mRNA expression dramatically but had no effect on GLP-1 receptor mRNA levels in rat islets.…”