Glucocorticoids decrease the production of glucagon-like peptide-1 at the transcriptional level in intestinal L-cells

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Glucocorticoids are vital anti-inflammatory drugs but can cause hyperglycemia.
• Glucagon-like peptide-1 (GLP-1) is key for glucose homeostasis, produced in intestinal L cells.
• The direct impact of glucocorticoids on GLP-1 production in L cells is not fully understood.

Purpose of the Study:

• To investigate the direct effects of glucocorticoids on GLP-1 production in L cells.
• To elucidate the molecular mechanisms underlying glucocorticoid-induced changes in GLP-1 synthesis.

Main Methods:

• In vitro studies using L cell lines treated with glucocorticoids (dexamethasone, budesonide) and mifepristone.
• In vivo studies administering dexamethasone or budesonide to mice.
• Analysis of proglucagon (GLP-1 precursor) mRNA and protein levels.
• Assessment of glucose-stimulated GLP-1 secretion.
• Evaluation of a dissociated glucocorticoid receptor modulator (Compound A).

Main Results:

• Glucocorticoids significantly decreased GLP-1 release and proglucagon expression (mRNA and protein) in L cell lines.
• These effects were blocked by mifepristone, an antagonist.
• In mice, dexamethasone and budesonide reduced ileal proglucagon mRNA and impaired glucose-stimulated GLP-1 secretion.
• Compound A did not alter proglucagon expression, suggesting a role for glucocorticoid receptor dimerization.

Conclusions:

• Glucocorticoids directly suppress GLP-1 production at the transcriptional level in intestinal L cells.
• The mechanism involves glucocorticoid receptor dimerization.
• These findings offer insights into glucocorticoid-induced hyperglycemia and potential therapeutic targets.