Dexamethasone enhances intestinal glucose absorption and TMPRSS2 expression with implications for hyperglycaemia and infection risk

Long-term corticosteroid use, including dexamethasone, is associated with an increased risk of type 2 diabetes, leading to enhanced hepatic gluconeogenesis and peripheral insulin resistance. This study reveals that dexamethasone additionally acts as a potent inducer of the main intestinal glucose transporter, sodium-dependent glucose cotransporter 1 (SGLT1). In differentiated human Caco-2/TC7 intestinal cell monolayers, dexamethasone dose-dependently increased glucose transport by upregulating SGLT1 mRNA despite a reduction in glucose transporter 2 (GLUT2) mRNA. Dexamethasone similarly elevated SGLT1 expression in ileal enterocytes and induced GLUT2 mRNA in mice, supporting its role in enhancing intestinal glucose uptake. Given the extensive use of dexamethasone to treat COVID-19, we further assessed its impact on SARS-CoV-2 entry receptors in the intestine. Dexamethasone increased transmembrane protease, serine 2 (TMPRSS2) mRNA expression while decreasing angiotensin-converting enzyme 2 (ACE2) mRNA and protein levels, potentially exacerbating viral spread in the gut. Our findings suggest that dexamethasone promotes glucose absorption in the intestine, contributing to hyperglycaemia, and modulates expression of intestinal SARS-CoV-2 receptors.