Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance

•Continuous administration of a COC, composed of EE and DRSP, causes hyperinsulinemia in female mice.•This effect was due to the chronic actions of EE and DRSP on pancreatic β-cells, ledding to insulin hypersecretion.•COC-treated mice had reduced insulin clearance that contributed to IR downregulati...

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Published in:	The Journal of steroid biochemistry and molecular biology Vol. 190; pp. 54 - 63
Main Authors:	Oliveira, Cremilda Amaral Roso de, dos Reis Araujo, Thiago, Aguiar, Gésily de Souza, da Silva Junior, Joel Alves, Vettorazzi, Jean Franciesco, Freitas, Israelle Netto, Oliveira, Kênia Moreno de, Boschero, Antonio Carlos, Bonfleur, Maria Lúcia, Clarke, Júlia Rosauro, Henriques, Helene Nara, Ribeiro, Rosane Aparecida
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-06-2019 Elsevier BV
Subjects:	17β-Estradiol Adipose tissue Blood glucose Body weight Contraception Cytotoxicity Down-regulation Drospirenone Endocrine disrupters Ethinylestradiol Females Glucose Glucose homeostasis Glucose tolerance Homeostasis Hormonal contraception Hyperinsulinemia Insulin Insulin degradation Insulin resistance Insulin secretion Liver Lymphocytes T Menstruation Oral contraceptives Pancreas Secretion Steroid hormones Thinyl estradiol Uterus Endocrine disrupters Hormonal contraception Insulin degradation Drospirenone Glucose homeostasis Thinyl estradiol
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Summary:	•Continuous administration of a COC, composed of EE and DRSP, causes hyperinsulinemia in female mice.•This effect was due to the chronic actions of EE and DRSP on pancreatic β-cells, ledding to insulin hypersecretion.•COC-treated mice had reduced insulin clearance that contributed to IR downregulation in the liver.•Our study may provide a warning that the prolongation of COC treatment may cause insulin resistance. Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 μg EE and 60 μg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperinsulinemia and lower plasma C-peptide/insulin ratio, indicating reduced insulin clearance. Furthermore, COC mice displayed reduced protein content of the β subunit of the insulin receptor (IRβ) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperinsulinemia, due to enhancement of insulin secretion and the reduction of insulin degradation, which possibly lead to the down-regulation of hepatic IRβ. These findings suggest that the continuous administration of COC could cause insulin resistance with the prolongation of treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-0760 1879-1220
DOI:	10.1016/j.jsbmb.2019.03.018