Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme

J Steroid Biochem Mol Biol. 2016 Jan;155(Pt A):1-8. doi: 10.1016/j.jsbmb.2015.09.020. Epub 2015 Sep 16.


Objectives: Glucocorticoid treatment induces insulin resistance (IR), which is counteracted by a compensatory hyperinsulinemia, due to increased pancreatic β-cell function. There is evidence for also reduced hepatic insulin clearance, but whether this correlates with altered activity of insulin-degrading enzyme (IDE) in the liver, is not fully understood. Here, we investigated whether hyperinsulinemia, in glucocorticoid-treated rodents, is associated with any alteration in the insulin clearance and activity of the IDE in the liver.

Materials/methods: Adult male Swiss mice and Wistar rats were treated with the synthetic glucocorticoid dexamethasone intraperitoneally [1mg/kg body weight (b.w.)] for 5 consecutive days.

Results: Glucocorticoid treatment induced IR and hyperinsulinemia in both species, but was more impactful in rats that also displayed glucose intolerance and hyperglycemia. Insulin clearance was reduced in glucocorticoid-treated rats and mice, as judged by the reduction of insulin decay rate and increased insulin area-under-the-curve (47% and 87%, respectively). These results were associated with reduced activity (35%) of hepatic IDE in rats and a tendency to reduction (p=0.068) in mice, without alteration in hepatic IDE mRNA content, in both species.

Conclusion: In conclusion, the reduced insulin clearance in glucocorticoid-treated rodents was due to the reduction of hepatic IDE activity, at least in rats, which may contributes to the compensatory hyperinsulinemia. These findings corroborate the idea that short-term and/or partial inhibition of IDE activity in the liver could be beneficial for the glycemic control.

Keywords: Dexamethasone; Glucocorticoid; Glucose homeostasis; Insulin clearance; Insulin sensitivity; Insulin-degrading enzyme (IDE).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dexamethasone / adverse effects*
  • Dexamethasone / pharmacology
  • Glucocorticoids / adverse effects
  • Glucocorticoids / pharmacology
  • Glucose Tolerance Test
  • Hyperinsulinism / chemically induced*
  • Hyperinsulinism / metabolism
  • Insulin / metabolism*
  • Insulin Resistance
  • Insulysin / genetics
  • Insulysin / metabolism*
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Rats, Wistar


  • Glucocorticoids
  • Insulin
  • Dexamethasone
  • Insulysin