Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor

Abstract

Aims/hypothesis: Treatment with glucocorticoids, especially at high doses, induces insulin resistance. The aims of the present study were to identify the potential defects in insulin signalling that contribute to dexamethasone-induced insulin resistance in skeletal muscles, and to investigate whether the glycogen synthase-3 (GSK-3) inhibitor CHIR-637 could restore insulin-stimulated glucose metabolism. Materials and methods: Skeletal muscles were made insulin-resistant by treating male Wistar rats with dexamethasone, a glucocorticoid analogue, for 12 days. Insulin-stimulated glucose uptake, glycogen synthesis and insulin signalling were studied in skeletal muscles in vitro. Results: Dexamethasone treatment decreased the ability of insulin to stimulate glucose uptake, glycogen synthesis and glycogen synthase fractional activity. In addition, the dephosphorylation of glycogen synthase by insulin was blocked. These defects were paralleled by reduced insulin-stimulated protein kinase B (PKB) and GSK-3 phosphorylation. While expression of PKB, GSK-3 and glycogen synthase was not reduced by dexamethasone treatment, expression of the p85α subunit of phosphatidylinositol 3-kinase (PI 3-kinase) was increased. Inhibition of GSK-3 by CHIR-637 increased glycogen synthase fractional activity in soleus muscle from normal and dexamethasone-treated rats, although the effect was more pronounced in control rats. CHIR-637 did not improve insulin-stimulated glucose uptake in muscles from dexamethasone-treated rats. Conclusions/interpretation: We demonstrated that chronic dexamethasone treatment impairs insulin-stimulated PKB and GSK-3 phosphorylation, which may contribute to insulin resistance in skeletal muscles. Acute pharmacological inhibition of GSK-3 activated glycogen synthase in muscles from dexamethasone-treated rats, but GSK-3 inhibition did not restore insulinstimulated glucose uptake.

Experimental model of glucocorticoid-induced insulin resistance

“…Several studies show that glucocorticoids induce peripheral insulin resistance, in vivo and in vitro 5,8,[23][24][25][26] , by increasing hepatic glucose output and decreasing the peripheral glucose uptake. There are evidences that ROS' production plays a fundamental role on developing insulin resistance by being responsible for the smaller capture of glucose on muscle 27 and on adipose tissue 28 .…”

“…Alteration in protein profile 8 and in lipid panel 9 . However the efects over insulinemia are still controversial.…”

Role of aldosterone and angiotensin II in insulin resistance: an update

“…As glucocorticoids and mineralocorticoids have similar affinity for MR, it is possible that MR blockade decreases clearance of cortisol, leading to impaired insulin action in numerous tissues such as skeletal muscle, adipose, hepatic and cardiovascular tissues, 43 whole-body insulin resistance and impaired glucose homeostasis. Glucocorticoids in turn are known to cause insulin resistance through numerous mechanisms, including increased fatty acids oxidation, 43 decreased insulin-mediated glucose uptake in skeletal muscle, 44 decreased serine phosphorylation of Akt/protein kinase B (PKB), 45 impaired insulin receptor tyrosine phosphorylation and insulin receptor substrate 1 (IRS-1) expression, 46 as well as increased hepatic glucose output. 47 The findings of augmented Ang II and cortisol during MR block might explain not only the deleterious effects on insulin sensitivity, but also the lack of benefit in terms of endothelial function observed in these studies.…”

Steroid-Induced Diabetic Ketoacidosis in a Patient with Type 2 Diabetes Mellitus

“…For example, steroids can interfere with signaling cascades (mainly involving glucose transporter type 4) in muscle cells, leading to a reduction in insulinmediated glucose uptake and glycogen synthesis (15,16). Steroids can also induce lipolysis and proteolysis, enhance the effects of counterregulatory hormones such as glucagon and epinephrine, and also induce insulin resistance via the nuclear peroxisome proliferator-activated receptor (13,16).…”