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

Author(s):Show less -

dos Santos, Cristiane ^[1] ; Rafacho, Alex ^[2] ; Ferreira, Sandra Mara ^[1] ; Vettorazzi, Jean Franciesco ^[1] ; dos Reis Araujo, Thiago ^[1] ; Mateus Goncalves, Luciana ^[1] ; Ruhrmann, Sabrina ^[3] ; Bacos, Karl ^[3] ; Ling, Charlotte ^[3] ; Boschero, Antonio Carlos ^[1] ; Jorge dos Santos, Gustavo ^[2]

Affiliation

^[1] Campinas State Univ UNICAMP, Dept Struct & Funct Biol, Lab Endocrine Pancreas & Metab LAPEM, Inst Biol, Campinas - Brazil

^[2] Fed Univ Santa Catarina UFSC, Ctr Biol Sci, Dept Physiol Sci, Lab Invest Chron Dis LIDoC, BR-88040900 Florianopolis, SC - Brazil

^[3] Scania Univ Hosp, Lund Univ Diabet Ctr, Dept Clin Sci Malmo, Epigenet & Diabet Unit, Malmo - Sweden

• Document type: Journal article
• Source: FASEB JOURNAL; v. 35, n. 8 AUG 2021.
• Web of Science Citations: 0

Abstract

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on beta-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 beta-cell mass, in parallel with higher a-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the beta-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. beta-cell-specific knockdown of the Hnf4 alpha 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. (AU)

• FAPESP's process: 19/10543-8 - Investigation on epigenetic mechanisms involved in islet dysfunction by prenatal glucocorticoid treatment
• Grantee: Cristiane dos Santos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 16/23140-0 - Endocrine pancreas plasticity of mice offspring after maternal treatment with glucocorticoid during late gestation
• Grantee: Cristiane dos Santos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/12611-0 - Molecular mechanisms involved in pancreatic beta cell disfunction and dead in diabetes mellitus: strategies for the inhibition of these processes and restoration of the insular mass
• Grantee: Antonio Carlos Boschiero
• Support Opportunities: Research Projects - Thematic Grants