title: Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: André Otávio Peres
authors.initials: AO
authors.lastname: Protzek
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Luiz Fernando
authors.initials: LF
authors.lastname: Rezende
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: José Maria
authors.initials: JM
authors.lastname: Costa-Júnior
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Sandra Mara
authors.initials: SM
authors.lastname: Ferreira
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Ana Paula Gameiro
authors.initials: AP
authors.lastname: Cappelli
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Flávia Maria Moura
authors.initials: FM
authors.lastname: de Paula
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Jane Cristina
authors.initials: JC
authors.lastname: de Souza
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Mirian Ayumi
authors.initials: MA
authors.lastname: Kurauti
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil.
authors.forename: Everardo Magalhães
authors.initials: EM
authors.lastname: Carneiro
authors.affiliation: Department of Physiological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil; Multicenter Graduate Program in Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, Brazil. Electronic address: alex.rafacho@ufsc.br.
authors.forename: Alex
authors.initials: A
authors.lastname: Rafacho
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, Campinas State University (UNICAMP), Campinas, Brazil. Electronic address: boschero@unicamp.br.
authors.forename: Antonio Carlos
authors.initials: AC
authors.lastname: Boschero
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000139:chemically induced* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D017208:Rats, Wistar
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D003907:Dexamethasone; D007339:Insulysin
keywords: Dexamethasone; Glucocorticoid; Glucose homeostasis; Insulin clearance; Insulin sensitivity; Insulin-degrading enzyme (IDE)