Insulin at the Intersection of Thermoregulation and Glucose Homeostasis.
Insulin at the Intersection of Thermoregulation and Glucose Homeostasis.
复制标题
胰岛素处于体温调节和血糖稳态的交叉点。
DOI：
10.1101/2023.11.17.566254
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Wasserman,DavidH
中科院分区：
文献类型：
--
作者：
Winn,NathanC;Schleh,MichaelW;Garcia,JamieN;Lantier,Louise;McGuinness,OwenP;Blair,JoslinA;Hasty,AlyssaH;Wasserman,DavidH
哺乳动物通过改变产生热量的能量过程来保护自己不受环境温度变化的影响。胰岛素是葡萄糖摄取和代谢的主要刺激物，这是产热过程的基础。这项工作的目的是确定环境温度诱导的能量消耗（EE）变化对葡萄糖通量胰岛素敏感性的相互作用。研究了小鼠对热中性温度（TN, ~ 28°C）和室内（实验室）温度（RT, ~ 22°C）的短期和适应性反应。这个温度范围不会引起循环儿茶酚胺或寒战的可检测变化，并维持吸收后的葡萄糖稳态。我们验证了一种假设，即TN引起的EE减少会导致胰岛素抵抗，并且胰岛素作用和EE的减少会在短期（<12小时）转变为rt后逆转。结合同位素示踪剂和高胰岛素-正糖钳评估胰岛素刺激的葡萄糖处置（Rd）和组织特异性葡萄糖代谢指数。与rt适应小鼠相比，tn适应小鼠的EE和胰岛素刺激Rd均降低（约50%）。当rt适应小鼠切换到TN时，EE迅速降低，Rd降低约50%。tn适应小鼠转到RT后，EE迅速增加，但全身胰岛素刺激的Rd仍然保持在tn适应小鼠的低率。相反，全身糖酵解通量随EE升高而升高。这种较高的EE并不会增加从血液中摄取的葡萄糖，而是将葡萄糖从葡萄糖储存转移到糖酵解。除了胰岛素作用的适应性外，棕色脂肪中“胰岛素独立”的葡萄糖摄取对体温调节非常敏感。这些结果表明，胰岛素的作用可以适应环境温度的非应激变化，从而在不影响葡萄糖稳态的情况下支持体温稳态。
Mammals are protected from changes in environmental temperature by altering energetic processes that modify heat production. Insulin is the dominant stimulus of glucose uptake and metabolism, which are fundamental for thermogenic processes. The purpose of this work was to determine the interaction of ambient temperature induced changes in energy expenditure (EE) on the insulin sensitivity of glucose fluxes. Short-term and adaptive responses to thermoneutral temperature (TN, ∼28 °C) and room (laboratory) temperature (RT, ∼22 °C) were studied in mice. This range of temperature does not cause detectable changes in circulating catecholamines or shivering and postabsorptive glucose homeostasis is maintained. We tested the hypothesis that a decrease in EE that occurs with TN causes insulin resistance and that this reduction in insulin action and EE is reversed upon short term (<12h) transition to RT. Insulin-stimulated glucose disposal (Rd) and tissue-specific glucose metabolic index were assessed combining isotopic tracers with hyperinsulinemic-euglycemic clamps. EE and insulin-stimulated Rd are both decreased (∼50%) in TN-adapted vs RT-adapted mice. When RT-adapted mice are switched to TN, EE rapidly decreases and Rd is reduced by ∼50%. TN-adapted mice switched to RT exhibit a rapid increase in EE, but whole-body insulin-stimulated Rd remains at the low rates of TN-adapted mice. In contrast, whole body glycolytic flux rose with EE. This higher EE occurs without increasing glucose uptake from the blood, but rather by diverting glucose from glucose storage to glycolysis. In addition to adaptations in insulin action, ‘insulin-independent’ glucose uptake in brown fat is exquisitely sensitive to thermoregulation. These results show that insulin action adjusts to non-stressful changes in ambient temperature to contribute to the support of body temperature homeostasis without compromising glucose homeostasis.