PDF(Pubmed)
Abstract：
Insulin secretion from pancreatic β cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that β-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced β-cell injury in aging. β-cell-specific-Ghsr-deficient (Ghsr-βKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected β-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-βKO mice were subjected to STZ. We found that middle-aged and old Ghsr-βKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that β-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced β-cell injury in aging.
摘要：
胰岛β细胞分泌胰岛素是葡萄糖稳态的重要支柱,在肥胖和衰老的情况下受损。生长激素促分泌素受体（GHSR）是营养敏感激素ghrelin的受体。以前,我们表明β细胞GHSR调节年轻小鼠的葡萄糖刺激的胰岛素分泌（GSIS）。在目前的研究中,我们进一步研究了GHSR对饮食诱导的肥胖（DIO）和链脲佐菌素（STZ）诱导的衰老β细胞损伤的雄性小鼠胰岛素分泌的影响。β细胞特异性Ghsr缺陷型（Ghsr-βKO）小鼠在DIO下没有表现出血糖表型，但在衰老中显示出离体GSIS显着改善。我们还检测到体内和离体衰老过程中胰岛素敏感性降低和胰岛素分泌受损。因此，葡萄糖转运蛋白的表达有年龄相关的改变，胰岛素信号通路,和炎症基因。为了进一步确定GHSR缺乏是否影响β细胞对急性损伤的易感性，年轻,中年,和老年Ghsr-βKO小鼠接受STZ。我们发现中年和老年Ghsr-βKO小鼠受到STZ诱导的高血糖和胰岛素分泌受损的保护，与胰岛中胰岛素信号调节因子表达增加相关，但促炎细胞因子降低。总的来说，我们的发现表明，β细胞GHSR对衰老而不是肥胖的胰岛素分泌有重要影响，和GHSR缺乏保护STZ诱导的衰老中的β细胞损伤。
