Lacking of estradiol reduces insulin exocytosis from pancreatic beta-cells and increases hepatic insulin degradation

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Santos, Roberta S. ; Batista, Thiago M. ; Camargo, Rafael L. ; Morato, Priscila N. ; Borck, Patricia C. ; Leite, Nayara C. ; Kurauti, Mirian A. ; Wanschel, Amarylis C. B. A. ; Nadal, Angel ; Clegg, Deborah J. ; Carneiro, Everardo M.

• Document type: Journal article
• Source: Steroids; v. 114, p. 9-pg., 2016-10-01.

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 + E-2) 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 beta-cell dysfunction in the exocytosis of insulin, and upregulation of hepatic IDE protein content resulting in lower insulinemia, which was normalized by estradiol replacement. (C) 2016 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center
• Grantee: Licio Augusto Velloso
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/05801-7 - Investigation of 17 alfa-estradiol´s role in increasing inflammation in the central nervous system
• Grantee: Roberta de Souza Santos
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor