Glucocorticoids induce insulin resistance independent of GR in the liver

Glucocorticoids (GC) are potent anti-inflammatory drugs which are widely used in steroid therapy for autoimmune diseases. But besides their beneficial effects, long term treatment induces insulin resistance leading to type 2 diabetes. Until now, the precise molecular mechanisms how GCs induce insulin resistance are ill-defined. GCs act via the glucocorticoid receptor (GR) that can alter gene expression via two different modes of action: either by protein-protein interaction of the monomeric GR with transcription factors such as AP-1 and NF-κB or by direct binding as a homodimer to glucocorticoid response elements (GREs) in the promoter region of target genes. Traditionally GRE induced expression of gluconeogenetic enzymes in the liver by the GR was assumed to be responsible for insulin resistance due to excessive gluconeogenesis.

To test this hypothesis we investigated GC-induced insulin resistance in GR dimerization deficient (GRdim) and tissue specific GR mutant mice (GRMckCre and GRAlfCre). Using GRdim mice we could show that GR dimerization is required for GC-induced insulin resistance. On the molecular level, GC treatment lead to a strong impairment of insulin signaling in wild type mice, but not in GRdim mice.

In wild type mice GC treatment caused a highly reduced phosphorylation of AKT/PKB in muscle and white adipose tissue upon insulin stimulation.

Interestingly, insulin resistant wild type mice developed also a strong steatosis in liver that did not occur in GC treated GRdim mice.

Surprisingly, liver specific GR knock out (GRAlfCre) mice became insulin resistant after GC treatment. Thus, for GC-induced insulin resistance the GR in liver seems to be dispensable. In contrast muscle specific GR knockout (GRMckCre) mice showed less severe insulin resistance after GC treatment compared to wild type mice.

Taken together GC-induced insulin resistance requires GR dimerization in part in muscle whereas the GR in liver is dispensable.