title: Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism.
abstract: Progesterone has been associated with the development of gestational diabetes (GD) due to the enhancement of insulin resistance. As β-cell apoptosis participates in type 1 and type 2 diabetes pathophysiology, we proposed the hypothesis that progesterone might contribute to the development of GD through a mechanism that also involves β-cell death. To address this question, RINm5F insulin-producing cells were incubated with progesterone (25-100 μM), in the presence or absence of α-tocopherol (40 μM). After 24 or 48 h, membrane integrity and DNA fragmentation were analyzed by flow cytometry. Caspase activity was used to identify the mode of cell death. The involvement of endoplasmic reticulum stress in the action of progesterone was investigated by western blotting. Oxidative stress was measured by 2',7'-dichlorofluorescein diacetate (DCFDA) oxidation. Isolated rat islets were used in similar experiments in order to confirm the effect of progesterone in primary β-cells. Incubation of RINm5F cells with progesterone increased the number of cells with loss of membrane integrity and DNA fragmentation. Progesterone induced generation of reactive species. Pre-incubation with α-tocopherol attenuated progesterone-induced apoptosis. Western blot analyses revealed increased expression of CREB2 and CHOP in progesterone-treated cells. Progesterone caused apoptotic death of rat islet cells and enhanced generation of reactive species. Our results show that progesterone can be toxic to pancreatic β-cells through an oxidative-stress-dependent mechanism that induces apoptosis. This effect may contribute to the development of GD during pregnancy, particularly under conditions that require administration of pharmacological doses of this hormone.
authors.affiliation: School of Arts, Sciences and Humanities Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil Department of Biochemistry of Federal University of Sao Paulo, Sao Paulo, Brazil Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
authors.forename: V A
authors.initials: VA
authors.lastname: Nunes
authors.forename: E P
authors.initials: EP
authors.lastname: Portioli-Sanches
authors.forename: M P
authors.initials: MP
authors.lastname: Rosim
authors.forename: M S
authors.initials: MS
authors.lastname: Araujo
authors.forename: P
authors.initials: P
authors.lastname: Praxedes-Garcia
authors.forename: M M R
authors.initials: MM
authors.lastname: Valle
authors.forename: L P
authors.initials: LP
authors.lastname: Roma
authors.forename: C
authors.initials: C
authors.lastname: Hahn
authors.forename: E
authors.initials: E
authors.lastname: Gurgul-Convey
authors.forename: S
authors.initials: S
authors.lastname: Lenzen
authors.forename: A K
authors.initials: AK
authors.lastname: Azevedo-Martins
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016640:Diabetes, Gestational / Q000139:chemically induced*; D004964:Estriol / Q000494:pharmacology; D005260:Female; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D011374:Progesterone / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D011374:Progesterone; D004964:Estriol
keywords: apoptosis; gestational diabetes; insulin-producing cells; oestriol; oxidative stress; progesterone