Mendez Armando J, Szeto Angela, Boulina Maria, Westwright Jesica, Rahman Hafsha, Abushamma Sarah, Schneider Riley, McCabe Philip M
Diabetes Research Institute, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States.
Department of Psychology, University of Miami, Coral Gables, FL, United States.
Front Endocrinol (Lausanne). 2024 Dec 23;15:1465818. doi: 10.3389/fendo.2024.1465818. eCollection 2024.
The neuropeptide oxytocin (OXT) and its receptor (OXTR) have been shown to play an important role in glucose metabolism, and pancreatic islets express this ligand and receptor. In the current study, OXTR expression was identified in α-, β-, and δ-cells of the pancreatic islet by RNA hybridization, and OXT protein expression was observed only in β-cells. In order to examine the contribution of islet OXT/OXTR in glycemic control and islet β-cell heath, we developed a β-cell specific OXTR knock-out (β-KO) mouse. In isolated islets from control mice, OXT enhanced glucose stimulated secretion of insulin, but this response was abolished in the β-KO mice. , supraphysiological doses of OXT reduced blood glucose levels in hyperglycemic Control mice and during a glucose tolerance test. Once again, this response was abolished in the β-KO mice, suggesting that β-cell OXTR may play a role in glycemic regulation. Despite these findings, β-cell deletion of OXTR had no effect on fasting glucose, fasting insulin or glucose tolerance in mice fed a low fat- or high fat-diet for 23 weeks. The low fat or high fat diets did not alter β-cell mass by immundetection or a measure of apoptosis, however, β-KO mice on a high fat diet did exhibit increased β-cell proliferation. In mice treated with the cytotoxic agent, streptozotocin, deletion of OXTR resulted in greater hyperglycemia in β-KO mice relative control mice, suggesting that β-cell OXTR may provide some cytoprotection. In conclusion, the present study provides mixed support for a role of the β-cell OXTR in glycemic regulation. On one hand, experiments and pharmacologic experiments provided evidence that under hyperglycemia, OXTR activation can potentiate insulin secretion and glucose suppression. On the other hand, β-KO followed by chronic dietary manipulation had no effect on whole body glucose regulation . In terms of β-cell health, our data suggests a role of the OXTR in β-cell proliferation and cytoprotection following metabolic or cytotoxic challenge.
神经肽催产素（OXT）及其受体（OXTR）已被证明在葡萄糖代谢中起重要作用，并且胰岛表达这种配体和受体。在当前研究中，通过RNA杂交在胰岛的α细胞、β细胞和δ细胞中鉴定出OXTR表达，而仅在β细胞中观察到OXT蛋白表达。为了研究胰岛OXT/OXTR在血糖控制和胰岛β细胞健康中的作用，我们培育了一种β细胞特异性OXTR基因敲除（β-KO）小鼠。在来自对照小鼠的分离胰岛中，OXT增强了葡萄糖刺激的胰岛素分泌，但这种反应在β-KO小鼠中消失了。此外，超生理剂量的OXT降低了高血糖对照小鼠在葡萄糖耐量试验期间的血糖水平。同样，这种反应在β-KO小鼠中消失了，这表明β细胞OXTR可能在血糖调节中起作用。尽管有这些发现，但在低脂或高脂饮食喂养23周的小鼠中，β细胞中OXTR的缺失对空腹血糖、空腹胰岛素或葡萄糖耐量没有影响。低脂或高脂饮食并未通过免疫检测或细胞凋亡测量改变β细胞质量，然而，高脂饮食的β-KO小鼠确实表现出β细胞增殖增加。在用细胞毒性剂链脲佐菌素处理的小鼠中，OXTR的缺失导致β-KO小鼠相对于对照小鼠出现更严重的高血糖，这表明β细胞OXTR可能提供一些细胞保护作用。总之，本研究为β细胞OXTR在血糖调节中的作用提供了喜忧参半的证据。一方面，体内实验和药理学实验提供了证据，表明在高血糖情况下，OXTR激活可增强胰岛素分泌和血糖抑制。另一方面，β-KO后进行慢性饮食干预对全身葡萄糖调节没有影响。就β细胞健康而言，我们的数据表明OXTR在代谢或细胞毒性攻击后的β细胞增殖和细胞保护中起作用。
