One of the most distressing side effects for patients treated long term with glucocorticoids is weight gain, often with disfiguring fat deposition. In humans treated with glucocorticoids, the accumulation of adipocytes occurs primarily in the visceral fat and interscapular depots, leading to a characteristic “buffalo hump” and truncal obesity. This occurs through effects of glucocorticoids on differentiation of preadipocytes into mature adipocytes (2
). Glucocorticoids also induce insulin resistance, hyperglycemia, and hyperlipidemia. While increases in visceral fat contribute to the insulin resistance that occurs with glucocorticoid therapy, direct actions of glucocorticoids on muscle, liver, and other tissues also play a role.
Glucocorticoids have been shown to inhibit a number of steps in the insulin signaling network through several different mechanisms (Figure ). Insulin acts by binding to its receptor (IR), leading to increased kinase activity and tyrosine phosphorylation of several downstream signaling molecules, including IRS-1 through IRS-4. These proteins then activate the PI3K and MAPK pathways, leading to a range of downstream effects (3
). In skeletal muscle, glucocorticoids cause insulin resistance by decreasing transcription of IRS-1, while increasing transcription of two proteins that counter insulin action, protein tyrosine phosphatase type 1B (PTP1B) and p38MAPK (4
). A similar increase in transcription of p38MAPK is observed in liver (5
). Glucocorticoids also decrease IRS-1 and IRS-2 levels in fat (6
), while there is a decrease in IR and IRS-1 phosphorylation in response to glucocorticoids in liver (6
). In the 3T3-L1 mouse adipocyte cell line, there is upregulation of MAPK phosphatases, leading to downregulation of p38MAPK phosphorylation (8
Mechanisms leading to glucocorticoid-mediated insulin resistance.
Factors secreted by adipose tissue, referred to as adipokines, also act to modify insulin sensitivity of tissues. One of these, adiponectin, promotes insulin sensitivity in tissues and is suppressed by glucocorticoid treatment, serving as yet another component in the insulin resistance seen with glucocorticoid therapy (9
). Glucocorticoids also promote proteolysis, lipolysis, free fatty acid production, and fat accumulation in the liver, which can contribute to insulin resistance (9
). In addition, glucocorticoids directly promote hepatic gluconeogenesis, increasing hyperglycemia. Pancreatic β cell dysfunction allows further hyperglycemia to develop, likely contributing to the progression to frank diabetes sometimes seen with chronic glucocorticoid therapy (9
In this issue of the JCI
, Brennan-Speranza and colleagues provide evidence for a new mechanism of glucocorticoid-induced insulin resistance in which glucocorticoid action on bone decreases the levels of the osteoblast-derived peptide osteocalcin, which in turn contributes to the insulin resistance and metabolic derangements associated with glucocorticoid therapy (10