Glucocorticoid Receptor ß Overexpression Has Agonist-Independent Insulin-Mimetic Effects on HepG2 Glucose Metabolism.

Glucocorticoids (GC) are steroids hormones that drive circulating glucose availability through gluconeogenesis in the liver. However, alternative splicing of the GR mRNA produces two isoforms, termed GRα and GRß. GRα is the classic receptor that binds to GCs and mediates the most described actions of GCs. GRß does not bind GCs and acts as a dominant-negative inhibitor of GRα. Moreover, GRß has intrinsic and GRα-independent transcriptional activity. To date, it remains unknown if GRß modulates glucose handling in hepatocytes. Therefore, the study aims to characterize the impact of GRß overexpression on glucose uptake and storage using an in vitro hepatocyte model. Here we show that GRß overexpression inhibits the induction of gluconeogenic genes by dexamethasone. Moreover, GRß activates the Akt pathway, increases glucose transports mRNA, increasing glucose uptake and glycogen storage as an insulin-mimetic. Our results suggest that GRß has agonist-independent insulin-mimetic actions in HepG2 cells.

Hydrogen sulfide disrupts insulin-induced glucose uptake in L6 skeletal muscle cells.

Hydrogen sulfide (H2S) has been known for its toxicity. However, recent studies have focused on the mechanisms involved in endogenous production and function. To date, the H2S role in insulin signaling and glucose homeostasis is unclear. This uncertainty is even more evident in skeletal muscle, a physiological niche highly relevant for regulating glycemia in response to insulin. This study aimed to investigate the role of H2S on insulin signaling and glucose uptake in the L6 skeletal muscle cell line. We evaluated the endogenous synthesis with the fluorescent dye, 7-azido-4-methyl coumarin (7-AzMC). Glucose restriction-induced an increase in the endogenous levels of H2S, likely through stimulation of cystathionine γ-lyase activity, as its specific inhibitor, PAG (5 mM) prevented this increase, and mRNA levels of CSE decreased with glucose and amino acid restriction. Exogenous H2S reduced insulin-induced glucose uptake at 0.5 up to 24 h, an effect dissociated from the level of Akt phosphorylation. Our results show that glucose restriction induces endogenous production of H2S via CSE. In addition, H2S disrupts insulin-induced glucose uptake independent of the Akt pathway. These results suggest that H2S antagonism over insulin-induced glucose uptake could help maintain the plasmatic glucose levels in conditions that provoke hypoglycemia, which could serve as an H2S-regulated mechanism for maintaining glucose plasmatic levels through the inhibition of the skeletal muscle insulin-depended glucose uptake.