Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage
Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage
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DOI：
10.1530/joe-17-0505
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发表时间：
2018-04-01
影响因子：
4
通讯作者：
Johnson, James D.
中科院分区：
文献类型：
--
作者：
Dommerholt, Marleen B.;Dionne, Derek A.;Johnson, James D.
热量限制（CR）是唯一有强有力证据表明它可以延长寿命并延缓衰老症状的环境干预措施，但其机制尚未完全了解。基于敲除模型的寿命延长，假设胰岛素-IGF途径可能是开发CR模拟物的靶点。本研究旨在测试CR是否对胰岛素基因剂量减少的小鼠的葡萄糖稳态和β细胞功能具有累加效应。为了研究具有一系列基础胰岛素水平的模型，将野生型C57 BL/6 J和Ins 2（-/-）背景的小鼠在不同年龄进行8周的40%CR。由于WAT质量减少，雄性和雌性小鼠的体重都迅速减轻。在野生型和45周龄和70周龄的Ins 2（-/-）小鼠中，CR改善了葡萄糖耐量，降低了空腹血糖水平。在20周龄的小鼠中，CR和胰岛素减少对葡萄糖耐量的影响是非累加的。有趣的是，CR小鼠在注射胰岛素后通常表现出无法进一步降低血糖，这表明胰岛素敏感性可能发生变化。总之，我们的研究结果表明，CR可以导致体重减轻的背景下，减少胰岛素的生产，但CR改善葡萄糖稳态不会发生在附近的“胰岛素地板”在年轻的小鼠。总的来说，这些数据进一步阐明了CR、胰岛素和葡萄糖稳态之间的关系。
Caloric restriction (CR) is the only environmental intervention with robust evidence that it extends lifespan and delays the symptoms of aging, but its mechanisms are incompletely understood. Based on the prolonged longevity of knockout models, it was hypothesized that the insulin-IGF pathway could be a target for developing a CR mimic. This study aimed to test whether CR has additive effects on glucose homeostasis and beta-cell function in mice with reduced insulin gene dosage. To study models with a range of basal insulin levels, wild-type C57BL/6J and mice on an Ins2(-/-) background, were put on 8 weeks of 40% CR at various ages. Both male and female mice rapidly lost weight due to a reduced WAT mass. Glucose tolerance was improved and fasting glucose levels were reduced by CR in both wild type and 45- and 70-week-old Ins2(-/-) mice. The effects of CR and reduced insulin on glucose tolerance were non-additive in 20-week-old mice. Interestingly, mice on CR generally exhibited an inability to further depress blood glucose after insulin injection, pointing to possible alterations in insulin sensitivity. In conclusion, our results demonstrate that CR can cause weight loss in the context of reduced insulin production, but that CR-improved glucose homeostasis does not occur near the 'insulin floor' in young mice. Collectively, these data shed further light on the relationships between CR, insulin and glucose homeostasis.