title: Lacking of estradiol reduces insulin exocytosis from pancreatic β-cells and increases hepatic insulin degradation.
abstract: Low levels of plasma estrogens are associated with weight-gain, android fat distribution, and a high prevalence of obesity-related comorbidities such as glucose intolerance and type II diabetes. The mechanisms underlying the association between low levels of estrogens and impaired glucose homeostasis are not completely understood. To begin to test this, we used three-month-old female C57BL/6J mice that either underwent ovariectomy (OVX) or received a sham surgery (Sham), and we characterized glucose homeostasis. In a subsequent series of experiments, OVX mice received estradiol treatment (OVX+E2) or vehicle (OVX) for 6 consecutive days. As has been previously reported, lack of ovarian hormones resulted in dysregulated glucose homeostasis. To begin to explore the mechanisms by which this occurs, we characterized the impact of estrogens on insulin secretion and degradation in these mice. Insulin secretion and plasma insulin levels were lower in OVX mice. OVX mice had lower levels of pancreatic Syntaxin 1-A (Synt-1A) protein, which is involved in insulin extrusion from the pancreas. In the liver, OVX mice had higher levels of insulin-degrading enzyme (IDE) and this was associated with higher insulin clearance. Estradiol treatment improved glucose intolerance in OVX mice and restored insulin secretion, as well as normalized the protein content of pancreatic Synt-1A. The addition of estrogens to OVX mice reduced IDE protein to that of Sham mice. Our data suggest loss of ovarian estradiol following OVX led to impaired glucose homeostasis due to pancreatic β-cell dysfunction in the exocytosis of insulin, and upregulation of hepatic IDE protein content resulting in lower insulinemia, which was normalized by estradiol replacement.
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil; Biomedical Research Department, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, CA, United States. Electronic address: santosrds1@gmail.com.
authors.forename: Roberta S
authors.initials: RS
authors.lastname: Santos
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Batista
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Camargo
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Priscila N
authors.initials: PN
authors.lastname: Morato
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Patrícia C
authors.initials: PC
authors.lastname: Borck
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Nayara C
authors.initials: NC
authors.lastname: Leite
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Mirian A
authors.initials: MA
authors.lastname: Kurauti
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Amarylis C B A
authors.initials: AC
authors.lastname: Wanschel
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Universidad Miguel Hernández de Elche, Elche, Alicante, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Nadal
authors.affiliation: Biomedical Research Department, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Beverly Hills, CA, United States.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Clegg
authors.affiliation: Departamento de Biologia Estrutural e Funcional, Instituto de Biologia, e Centro de Pesquisa em Obesidade e Comorbidades, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Everardo M
authors.initials: EM
authors.lastname: Carneiro
mesh_terms: D000818:Animals; D004958:Estradiol / Q000097:blood / Q000627:therapeutic use*; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D050600:SNARE Proteins / Q000378:metabolism
chemical_list: D007328:Insulin; D050600:SNARE Proteins; D004958:Estradiol
keywords: Estradiol; IDE; Insulin degradation; Insulin secretion; SNARE proteins