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17-β Estradiol regulates proglucagon-derived peptide secretion in mouse and human α- and L cells
First published April 5, 2018
https://insight.jci.org/articles/view/98569
Introduction
The control of glucose homeostasis predominantly depends on the coordinated secretion of insulin by pancreatic β cells and proglucagon-derived peptides, glucagon, and glucagon-like peptide-1 (GLP-1) produced by pancreatic α- and gut L cells. Type 2 diabetes (T2D) has been attributed to insulin resistance and alterations of insulin secretion, but it is also characterized by a disrupted coordination between glucagon, insulin, and GLP-1 secretions. Glucagon regulates glycemia mainly through the stimulation of glucose production by the liver (1), whereas GLP-1 increases insulin and decreases glucagon levels (2). A newly developed model shows that GLP-1 production by pancreatic α cells plays a key role in the regulation of glucose homeostasis by acting on GLP-1 receptors of adjacent β cells, whereas GLP-1 produced by the enteroendocrine L cells acts on GLP-1 receptors located on vagal afferent nerves, thereby controlling hepatic glucose production (3, 4). Thus, the understanding of proglucagon-derived peptide biosynthesis and secretion appears to be highly relevant for a better design of therapeutic approaches for diabetes care.
Beside their pivotal role in sexual development and reproduction, estrogens prevent the occurrence of visceral adiposity, insulin resistance, and glucose intolerance in both humans and animal models (5, 6). Supporting the beneficial effects of estrogens on glucose homeostasis, women of reproductive age present higher sensitivity to insulin than age-matched men (7). Furthermore, estrogen-based replacement therapies reduce T2D incidence in postmenopausal women (8, 9). Importantly, women also exhibit about 20% higher GLP-1 responses to glucose than age-matched men, suggesting that sexual hormones may control GLP-1 release (10).
In rodent models, the beneficial effect of sexual hormones on glucose homeostasis is mediated by estradiol (E2), the main endogenous reproductive hormone; its administration to ovariectomized (ovx) mice prevents diet-induced obesity and stimulates insulin secretion (11, 12). The beneficial effects of estrogens on energy balance, insulin sensitivity, and glucose homeostasis result from their combined actions both centrally and peripherally (13). Estrogens exert specific actions in insulin-sensitive tissues, notably by modulating the expression of key genes of glucose and lipid metabolism (14). It has been well established that E2 improves β cell function and viability (11); however, E2 effects in proglucagon cells are unclear. In rodent models, ovariectomy increases plasma glucagon concentrations, and estrogen administration decreases the hepatic portal vein insulin/glucagon ratio (15). Furthermore, in vitro, E2-treatment decreases glucagon secretion from male and female mice islets (16). Thus, better characterization of E2 effects on proglucagon-producing cells is highly relevant to more fully understand the beneficial effects of hormonal treatment on metabolism, and it could lead to new therapeutic approaches to treat, or prevent, glucose homeostasis dysregulation occurring during and after menopause.
We have explored the regulation of glucose homeostasis by estrogens through their action on proglucagon-producing cells. We first investigated the metabolic phenotype of 1-week-old ovx adult female mice, compared with their littermate intact controls (sham), and showed that hormonal deprivation led to an alteration of glucose tolerance, along with a decrease in plasma GLP-1 levels. Short-term E2 treatment reversed these effects. Then, we showed that E2 directly controls pancreatic α- and intestinal L cells to stimulate GLP-1 production. Interestingly, whereas all estrogen receptors (ERs) appear to mediate the effect in α cells, only the ERβ pathway is involved in L cells. Finally, we demonstrated that E2 effects were also observed on human α cells and intestinal explants from nondiabetic female donors.
17-β Estradiol regulates proglucagon-derived peptide secretion in mouse and human α- and L cells
First published April 5, 2018
https://insight.jci.org/articles/view/98569
Introduction
The control of glucose homeostasis predominantly depends on the coordinated secretion of insulin by pancreatic β cells and proglucagon-derived peptides, glucagon, and glucagon-like peptide-1 (GLP-1) produced by pancreatic α- and gut L cells. Type 2 diabetes (T2D) has been attributed to insulin resistance and alterations of insulin secretion, but it is also characterized by a disrupted coordination between glucagon, insulin, and GLP-1 secretions. Glucagon regulates glycemia mainly through the stimulation of glucose production by the liver (1), whereas GLP-1 increases insulin and decreases glucagon levels (2). A newly developed model shows that GLP-1 production by pancreatic α cells plays a key role in the regulation of glucose homeostasis by acting on GLP-1 receptors of adjacent β cells, whereas GLP-1 produced by the enteroendocrine L cells acts on GLP-1 receptors located on vagal afferent nerves, thereby controlling hepatic glucose production (3, 4). Thus, the understanding of proglucagon-derived peptide biosynthesis and secretion appears to be highly relevant for a better design of therapeutic approaches for diabetes care.
Beside their pivotal role in sexual development and reproduction, estrogens prevent the occurrence of visceral adiposity, insulin resistance, and glucose intolerance in both humans and animal models (5, 6). Supporting the beneficial effects of estrogens on glucose homeostasis, women of reproductive age present higher sensitivity to insulin than age-matched men (7). Furthermore, estrogen-based replacement therapies reduce T2D incidence in postmenopausal women (8, 9). Importantly, women also exhibit about 20% higher GLP-1 responses to glucose than age-matched men, suggesting that sexual hormones may control GLP-1 release (10).
In rodent models, the beneficial effect of sexual hormones on glucose homeostasis is mediated by estradiol (E2), the main endogenous reproductive hormone; its administration to ovariectomized (ovx) mice prevents diet-induced obesity and stimulates insulin secretion (11, 12). The beneficial effects of estrogens on energy balance, insulin sensitivity, and glucose homeostasis result from their combined actions both centrally and peripherally (13). Estrogens exert specific actions in insulin-sensitive tissues, notably by modulating the expression of key genes of glucose and lipid metabolism (14). It has been well established that E2 improves β cell function and viability (11); however, E2 effects in proglucagon cells are unclear. In rodent models, ovariectomy increases plasma glucagon concentrations, and estrogen administration decreases the hepatic portal vein insulin/glucagon ratio (15). Furthermore, in vitro, E2-treatment decreases glucagon secretion from male and female mice islets (16). Thus, better characterization of E2 effects on proglucagon-producing cells is highly relevant to more fully understand the beneficial effects of hormonal treatment on metabolism, and it could lead to new therapeutic approaches to treat, or prevent, glucose homeostasis dysregulation occurring during and after menopause.
We have explored the regulation of glucose homeostasis by estrogens through their action on proglucagon-producing cells. We first investigated the metabolic phenotype of 1-week-old ovx adult female mice, compared with their littermate intact controls (sham), and showed that hormonal deprivation led to an alteration of glucose tolerance, along with a decrease in plasma GLP-1 levels. Short-term E2 treatment reversed these effects. Then, we showed that E2 directly controls pancreatic α- and intestinal L cells to stimulate GLP-1 production. Interestingly, whereas all estrogen receptors (ERs) appear to mediate the effect in α cells, only the ERβ pathway is involved in L cells. Finally, we demonstrated that E2 effects were also observed on human α cells and intestinal explants from nondiabetic female donors.
