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Excess of glucocorticoids during late gestation impairs the recovery of offspring’s β-cell function after a postnatal injury

dos Santos, Cristiane ; Rafacho, Alex ; Ferreira, Sandra Mara ; Vettorazzi, Jean Franciesco ; dos Reis Araújo, Thiago ; Mateus Gonçalves, Luciana ; Ruhrmann, Sabrina LU ; Bacos, Karl LU orcid ; Ling, Charlotte LU orcid and Boschero, Antônio Carlos , et al. (2021) In FASEB Journal 35(8).
Abstract

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower β-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the β-cell mass was partially... (More)

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower β-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the β-cell mass was partially recovered in the STZ-treated mice, but they remained glucose-intolerant, irrespective of being insulin sensitive. Prenatal exposition to DEX predisposed adult offspring to sustained hyperglycemia and perturbed islet function (lower insulin and higher glucagon response to glucose) in parallel with exacerbated glucose intolerance. β-cell-specific knockdown of the Hnf4α in mice from the DS group resulted in exacerbated glucose intolerance. We conclude that high GC exposure during the prenatal period exacerbates the metabolic dysfunctions in adult life of mice exposed to STZ early in life, resulting in a lesser ability to recover the islets’ function over time. This study alerts to the importance of proper management of exogenous GCs during pregnancy and a healthy postnatal lifestyle since the combination of adverse factors during the prenatal and postnatal period accentuates the predisposition to metabolic disorders in adult life.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
beta-cell regeneration, glucocorticoid, Hnf4-α, low birth weight, offspring
in
FASEB Journal
volume
35
issue
8
article number
e21828
publisher
Wiley
external identifiers
  • scopus:85111542080
  • pmid:34325494
ISSN
0892-6638
DOI
10.1096/fj.202100841R
language
English
LU publication?
yes
id
ad1d8d39-c085-406e-8581-4cda2c3271c8
date added to LUP
2021-08-27 12:49:10
date last changed
2024-06-15 15:11:10
@article{ad1d8d39-c085-406e-8581-4cda2c3271c8,
  abstract     = {{<p>Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower β-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the β-cell mass was partially recovered in the STZ-treated mice, but they remained glucose-intolerant, irrespective of being insulin sensitive. Prenatal exposition to DEX predisposed adult offspring to sustained hyperglycemia and perturbed islet function (lower insulin and higher glucagon response to glucose) in parallel with exacerbated glucose intolerance. β-cell-specific knockdown of the Hnf4α in mice from the DS group resulted in exacerbated glucose intolerance. We conclude that high GC exposure during the prenatal period exacerbates the metabolic dysfunctions in adult life of mice exposed to STZ early in life, resulting in a lesser ability to recover the islets’ function over time. This study alerts to the importance of proper management of exogenous GCs during pregnancy and a healthy postnatal lifestyle since the combination of adverse factors during the prenatal and postnatal period accentuates the predisposition to metabolic disorders in adult life.</p>}},
  author       = {{dos Santos, Cristiane and Rafacho, Alex and Ferreira, Sandra Mara and Vettorazzi, Jean Franciesco and dos Reis Araújo, Thiago and Mateus Gonçalves, Luciana and Ruhrmann, Sabrina and Bacos, Karl and Ling, Charlotte and Boschero, Antônio Carlos and Jorge dos Santos, Gustavo}},
  issn         = {{0892-6638}},
  keywords     = {{beta-cell regeneration; glucocorticoid; Hnf4-α; low birth weight; offspring}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{Wiley}},
  series       = {{FASEB Journal}},
  title        = {{Excess of glucocorticoids during late gestation impairs the recovery of offspring’s β-cell function after a postnatal injury}},
  url          = {{http://dx.doi.org/10.1096/fj.202100841R}},
  doi          = {{10.1096/fj.202100841R}},
  volume       = {{35}},
  year         = {{2021}},
}