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The Effects of Aging on Male Mouse Pancreatic β-Cell Function Involve Multiple Events in the Regulation of Secretion: Influence of Insulin Sensitivity
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences ( IF 5.1 ) Pub Date : 2021-09-25 , DOI: 10.1093/gerona/glab276
Eva Tudurí 1, 2 , Sergi Soriano 2, 3 , Lucía Almagro 2 , Anabel García-Heredia 2 , Alex Rafacho 4 , Paloma Alonso-Magdalena 1, 2 , Ángel Nadal 1, 2 , Ivan Quesada 1, 2
Affiliation  

Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of β-cell adaptations and/or alterations during aging are still a matter of debate. In this study, we investigated the effects of aging on β-cell function from control (3-month-old) and aged (20-month-old) mice. Aged animals were further categorized into 2 groups: high insulin sensitive (aged-HIS) and low insulin sensitive (aged-LIS). Aged-LIS mice were hyperinsulinemic, glucose intolerant, and displayed impaired glucose-stimulated insulin and C-peptide secretion, whereas aged-HIS animals showed characteristics in glucose homeostasis similar to controls. In isolated β cells, we observed that glucose-induced inhibition of KATP channel activity was reduced with aging, particularly in the aged-LIS group. Glucose-induced islet NAD(P)H production was decreased in aged mice, suggesting impaired mitochondrial function. In contrast, voltage-gated Ca2+ currents were higher in aged-LIS β cells, and pancreatic islets of both aged groups displayed increased glucose-induced Ca2+ signaling and augmented insulin secretion compared with controls. Morphological analysis of pancreas sections also revealed augmented β-cell mass with aging, especially in the aged-LIS group, as well as ultrastructural β-cell changes. Altogether, these findings indicate that aged mouse β cells compensate for the aging-induced alterations in the stimulus-secretion coupling, particularly by adjusting their Ca2+ influx to ensure insulin secretion. These results also suggest that decreased peripheral insulin sensitivity exacerbates the effects of aging on β cells.

中文翻译:

衰老对雄性小鼠胰腺 β 细胞功能的影响涉及分泌调节中的多个事件:胰岛素敏感性的影响

衰老与外周胰岛素敏感性下降以及糖耐量受损和 2 型糖尿病的风险增加有关。在胰岛素敏感性降低的情况下,胰腺β细胞经历适应性反应以增加胰岛素分泌并维持血糖正常。然而,衰老过程中 β 细胞适应和/或改变的存在和性质仍然存在争议。在这项研究中,我们研究了衰老对对照(3 个月大)和老年(20 个月大)小鼠的 β 细胞功能的影响。老年动物进一步分为两组:高胰岛素敏感性(老年-HIS)和低胰岛素敏感性(老年-LIS)。老年 LIS 小鼠存在高胰岛素血症、葡萄糖不耐受,并表现出葡萄糖刺激的胰岛素和 C 肽分泌受损,而老年HIS动物表现出与对照组相似的葡萄糖稳态特征。在分离的 β 细胞中,我们观察到葡萄糖诱导的 KATP 通道活性抑制随着年龄的增长而降低,特别是在老年 LIS 组中。葡萄糖诱导的胰岛 NAD(P)H 产量在老年小鼠中减少,表明线粒体功能受损。相比之下,老年 LIS β 细胞中的电压门控 Ca2+ 电流较高,与对照组相比,两个老年组的胰岛显示出葡萄糖诱导的 Ca2+ 信号传导和胰岛素分泌增加。胰腺切片的形态学分析还揭示了随着年龄增长而增加的 β 细胞量,尤其是在老年 LIS 组中,以及超微结构 β 细胞的变化。共,这些发现表明,衰老的小鼠 β 细胞补偿了衰老引起的刺激-分泌耦合变化,特别是通过调整其 Ca2+ 流入以确保胰岛素分泌。这些结果还表明,外周胰岛素敏感性降低会加剧衰老对 β 细胞的影响。
更新日期:2021-09-25
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