Endocrine Abstracts

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral anti-diabetic medications that improve glycaemia by reducing the amount of glucose being absorbed in the kidneys. SGLT2 inhibitors have been proven to improve blood pressure, cardiovascular health and kidney disease. Despite their beneficial clinical effects, their exact mechanism of action is not fully explored. The aim of this project was to investigate the effect of SGLT2 inhibitors in cortisol secretion and action, a hormone secreted by the adrenal glands and activated by the enzyme 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1), which can cause hyperglycaemia and insulin resistance when in high concentration.

Methods: SGLT2 knockout mice were generated on a C57/BL6 background using CRISPR/Cas9. Cortisol, cytokines and 11βHSD1 levels were measured in plasma and tissue in high-fat-fed male SGLT2−/− (knockout) mice and SGLT2+/+ (wild type-WT) mice chronically treated with the SGLT2 inhibitor dapagliflozin. Human kidney cells (HK2) were treated with cytokines found to be elevated in SGLT2-/- and dapagliflozin treated mice.

Results: Both WT dapagliflozin-treated and SGLT2-/- mice demonstrated same levels of glycosuria. However, glucose tolerance and insulin secretion was more pronounced in the latter. Cortisol secretion in plasma, and 11βHSD1 expression in liver and adipose tissue, was significantly reduced only in SGLT2-/- mice. Cytokines interleukin-6 (IL-6), leptin and Transforming growth factor beta (TGF-β) were significantly inhibited in plasma in SGLT2-/- mice, while anti-inflammatory peptides FGF-21 and IL-10 were increased. HK-2 cells treated with ascending concentrations of these IL-6, leptin and TGFβ demonstrated an increase in SGLT2 expression at gene level, while a decrease was observed when treated with IL-10 and FGF21.

Conclusion: SGLT2 inhibition appears to regulate cortisol secretion by reducing its tissular activation in the liver and adipose tissue. This effect may be mediated by a reduction in inflammatory cytokines and an improvement in glucose tolerance and insulin secretion.