Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis.
Effect of targeted estrogen delivery using glucagon-like peptide-1 on insulin secretion, insulin sensitivity and glucose homeostasis.
复制标题
使用胰高血糖素样肽-1 靶向雌激素输送对胰岛素分泌、胰岛素敏感性和葡萄糖稳态的影响。
DOI：
10.1038/srep10211
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发表时间：
2015
影响因子：
4.6
通讯作者：
Mauvais-Jarvis,Franck
中科院分区：
文献类型：
--
作者：
Tiano,JosephP;Tate,ChandraR;Yang,BinS;DiMarchi,Richard;Mauvais-Jarvis,Franck
雌性雌激素17β-雌二醇（E2）通过雌激素受体（ER）增强胰腺β细胞功能。然而，激素依赖性癌症的风险排除了使用一般雌激素疗法作为糖尿病的慢性治疗。为了使E2靶向β细胞而没有一般雌激素治疗的不良作用，我们创建了在单个分子中组合活性或非活性胰高血糖素样肽-1（GLP-1）和E2的融合肽（分别为aGLP 1-E2和iGLP 1-E2）。通过结合GLP-1和E2的活性，我们设想了这些分子对β细胞的协同促胰岛素活性。在培养的人胰岛和C57 BL/6小鼠中，与溶媒和iGLP 1-E2相比，aGLP 1和aGLP 1-E2均增强葡萄糖刺激的胰岛素分泌（GSIS），而aGLP 1-E2与单独的GLP-1相比无上级功效。然而，aGLP 1-E2降低空腹和餐后血糖的程度大于单独的aGLP 1和iGLP 1-E2。此外，与单独的aGLP 1和iGLP 1-E2相比，aGLP 1-E2表现出改善的胰岛素敏感性（HOMA-IR和胰岛素耐受性测试）。总之，在GLP-1存在下，靶向雌激素递送至非糖尿病胰岛不会增强GSIS。然而，在非糖尿病小鼠中，相对于单独的GLP-1，GLP-1与雌激素组合对胰岛素敏感性和葡萄糖稳态提供了额外的功效。
The female estrogen 17β-estradiol (E2) enhances pancreatic β-cell function via estrogen receptors (ERs). However, the risk of hormone dependent cancer precludes the use of general estrogen therapy as a chronic treatment for diabetes. To target E2 to β-cells without the undesirable effects of general estrogen therapy, we created fusion peptides combining active or inactive glucagon-like peptide-1 (GLP-1) and E2 in a single molecule (aGLP1-E2 and iGLP1-E2 respectively). By combining the activities of GLP-1 and E2, we envisioned synergistic insulinotropic activities of these molecules on β-cells. In cultured human islets and in C57BL/6 mice, both aGLP1 and aGLP1-E2 enhanced glucose-stimulated insulin secretion (GSIS) compared to vehicle and iGLP1-E2 without superior efficacy of aGLP1-E2 compared to GLP-1 alone. However, aGLP1-E2 decreased fasting and fed blood glucose to a greater extent than aGLP1 and iGLP1-E2 alone. Further, aGLP1-E2 exhibited improved insulin sensitivity compared to aGLP1 and iGLP1-E2 alone (HOMA-IR and insulin tolerance test). In conclusion, targeted estrogen delivery to non-diabetic islets in the presence of GLP-1 does not enhance GSIS. However, combining GLP-1 to estrogen delivers additional efficacy relative to GLP-1 alone on insulin sensitivity and glucose homeostasis in non-diabetic mice.