Section of Endocrinology and Metabolism, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.
Neuroscience Program, Tulane University, New Orleans, LA.
Diabetes. 2019 Mar;68(3):490-501. doi: 10.2337/db18-0293. Epub 2018 Oct 10.
Estrogens favor glucose homeostasis primarily through the estrogen receptor-α (ERα), but the respective importance of nuclear ERα (NOER) and membrane ERα (MOER) pools to glucose homeostasis are unknown. We studied glucose homeostasis, insulin secretion, and insulin sensitivity in male and female mice expressing either the NOER or the MOER. Male and female MOER mice exhibited fasting and fed hyperglycemia and glucose intolerance. Female MOER mice displayed impaired central insulin signaling associated with hyperinsulinemia and insulin resistance due to unrestrained hepatic gluconeogenesis, without alterations in glucose-stimulated insulin secretion (GSIS). In contrast, male MOER mice did not exhibit detectable insulin resistance, but showed impaired GSIS associated with reduced brain glucose sensing. Female NOER mice exhibited milder hepatic insulin resistance and glucose intolerance. In conclusion, nuclear ERα signaling is predominant in maintaining glucose homeostasis in mice of both sexes. Lack of nuclear ERα alters the central control of insulin sensitivity in females and predominantly impairs the central regulation of insulin secretion in males.
雌激素主要通过雌激素受体-α（ERα）促进葡萄糖稳态，但核 ERα（NOER）和膜 ERα（MOER）池对葡萄糖稳态的各自重要性尚不清楚。我们研究了表达 NOER 或 MOER 的雄性和雌性小鼠的葡萄糖稳态、胰岛素分泌和胰岛素敏感性。雄性和雌性 MOER 小鼠表现出空腹和进食后高血糖和葡萄糖不耐受。由于肝糖异生不受限制，雌性 MOER 小鼠表现出中枢胰岛素信号受损，伴有高胰岛素血症和胰岛素抵抗，但葡萄糖刺激的胰岛素分泌（GSIS）没有改变。相比之下，雄性 MOER 小鼠没有表现出可检测到的胰岛素抵抗，但表现出与脑葡萄糖感知降低相关的 GSIS 受损。雌性 NOER 小鼠表现出较轻的肝胰岛素抵抗和葡萄糖不耐受。总之，核 ERα 信号在维持雌雄两性小鼠的葡萄糖稳态中占主导地位。缺乏核 ERα 会改变女性中枢胰岛素敏感性的控制，并主要损害男性中枢胰岛素分泌的调节。
