17-β Estradiol regulates proglucagon-derived peptide secretion in mouse and human α- and L cells
Sandra Handgraaf, Rodolphe Dusaulcy, Florian Visentin, Jacques Philippe, Yvan Gosmain
Sandra Handgraaf, Rodolphe Dusaulcy, Florian Visentin, Jacques Philippe, Yvan Gosmain
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Research Article Endocrinology Metabolism

17-β Estradiol regulates proglucagon-derived peptide secretion in mouse and human α- and L cells

Abstract

Clinical and experimental data indicate a beneficial effect of estrogens on energy and glucose homeostasis associated with improved insulin sensitivity and positive effects on insulin secretion. The aim of the study was to investigate the impact of estrogens on proglucagon-producing cells, pancreatic α cells, and enteroendocrine L cells. The consequences of sexual hormone deprivation were evaluated in ovariectomized mice (ovx). Ovx mice exhibited impaired glucose tolerance during oral glucose tolerance tests (OGTT), which was associated with decreased GLP-1 intestinal and pancreatic secretion and content, an effect that was reversed by estradiol (E2) treatment. Indeed, E2 increased oral glucose–induced GLP-1 secretion in vivo and GLP-1 secretion from primary culture of mouse and human α cells through the activation of all 3 estrogen receptors (ERs), whereas E2-induced GLP-1 secretion from mouse and human intestinal explants occurred only by ERβ activation. Underlying the implication of ERβ, its selective agonist WAY20070 was able to restore glucose tolerance in ovx mice at least partly through plasma GLP-1 increase. We conclude that E2 directly controls both α- and L cells to increase GLP-1 secretion, in addition to its effects on insulin and glucagon secretion, highlighting the potential beneficial role of the estrogenic pathway and, more particularly, of ERβ agonists to prevent type 2 diabetes.

Authors

Sandra Handgraaf, Rodolphe Dusaulcy, Florian Visentin, Jacques Philippe, Yvan Gosmain

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Figure 4

Estradiol directly affects α- and β cells from ovx mice in vitro.

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Estradiol directly affects α- and β cells from ovx mice in vitro. Both α...
Both α- and β cells isolated from ovx mice were cultured with vehicle (white bars), or 17β-estradiol (E2, 1 × 10–8 mol/l) (red bars). Relative mRNA levels were quantified in sorted α cells (n = 11 in each group) (A). Glucagon (B) and GLP-1 (C) contents were assessed in sorted α cells treated for 48 hours with vehicle (white, n = 11) or with E2, 1 × 10–8 mol/l (red, n = 13). Contents are normalized to total protein. Ratios of GLP-1 to glucagon content of sorted α cells are represented in D. Glucagon (E) and GLP-1 (F) levels were quantified in supernatants relative to the contents of glucagon and GLP-1, respectively, after 6 hours of continuous release in complete medium of purified α cells (vehicle, n = 11; E2, n = 13). Relative mRNA level quantification was assessed in sorted β cells (n = 12 in each group) (G), as well as insulin contents relative to total protein amount (H) and release relative to insulin content (I) (vehicle, n = 15; E2, n = 15). Purified α- and β cells isolated from ovx mice were cultured in 2 separate drops, and only α cells were treated either with vehicle (white bars, n = 5) or 17β-estradiol (E2, 1 × 10–8 mol/l) (red bars, n = 5); both drops were then joined during the secretion tests. Insulin (J) and GLP-1 (K) levels were assessed in response to glucose and a GLP-1 receptor antagonist (Ex9-39). Two-tailed Student’s t test statistical analyses. *P ≤ 0.05 for vehicle- vs. E2-treated cells.