Li Bing-Wei, Li Yuan, Zhang Xu, Fu Sun-Jing, Wang Bing, Zhang Xiao-Yan, Liu Xue-Ting, Wang Qin, Li Ai-Ling, Liu Ming-Ming
Institute of Microcirculation, Diabetes Research Center, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Laboratory of Electron Microscopy, Ultrastructural Pathology Center, Peking University First Hospital, Beijing 100005, China.
World J Diabetes. 2022 Sep 15;13(9):765-775. doi: 10.4239/wjd.v13.i9.765.
The pancreatic islet microcirculation adapts its metabolism to cope with limited oxygen availability and nutrient delivery. In diabetes, the balance between oxygen delivery and consumption is impaired. Insulin has been proven to exert complex actions promoting the maintenance of homeostasis of the pancreas under glucotoxicity.
To test the hypothesis that insulin administration can improve the integrated pancreatic microcirculatory oxygen profile and bioenergetics.
The pancreatic microcirculatory partial oxygen pressure (PO), relative hemoglobin (rHb) and hemoglobin oxygen saturation (SO) were evaluated in nondiabetic, type 1 diabetes mellitus (T1DM), and insulin-treated mice. A three-dimensional framework was generated to visualize the microcirculatory oxygen profile. Ultrastructural changes in the microvasculature were examined using transmission electron microscopy. An Extracellular Flux Analyzer was used to detect the real-time changes in bioenergetics by measuring the oxygen consumption rate and extracellular acidification rate in islet microvascular endothelial cells (IMECs).
Significantly lower PO, rHb, and SO values were observed in T1DM mice than in nondiabetic controls. Insulin administration ameliorated the streptozotocin-induced decreases in these microcirculatory oxygen parameters and improved the mitochondrial ultrastructural abnormalities in IMECs. Bioenergetic profiling revealed that the IMECs did not have spare respiratory capacity. Insulin-treated IMECs exhibited significantly greater basal respiration than glucotoxicity-exposed IMECs ( < 0.05). An energy map revealed increased energetic metabolism in insulin-treated IMECs, with significantly increased ATP production, non-mitochondrial respiration, and oxidative metabolism (all < 0.05). Significant negative correlations were revealed between microcirculatory SO and bioenergetic parameters.
Glucotoxicity deteriorates the integrated pancreatic microcirculatory oxygen profile and bioenergetics, but this deterioration can be reversed by insulin administration.
胰岛微循环会调整其代谢以应对有限的氧气供应和营养输送。在糖尿病中，氧气供应与消耗之间的平衡受到损害。胰岛素已被证明能发挥复杂作用，促进在糖毒性作用下胰腺内稳态的维持。
检验胰岛素给药可改善胰腺整体微循环氧分布和生物能量学这一假说。
在非糖尿病小鼠、1型糖尿病（T1DM）小鼠和接受胰岛素治疗的小鼠中评估胰腺微循环的局部氧分压（PO）、相对血红蛋白（rHb）和血红蛋白氧饱和度（SO）。构建三维框架以可视化微循环氧分布。使用透射电子显微镜检查微血管的超微结构变化。通过测量胰岛微血管内皮细胞（IMECs）中的氧消耗率和细胞外酸化率，使用细胞外通量分析仪检测生物能量学的实时变化。
T1DM小鼠的PO、rHb和SO值显著低于非糖尿病对照组。胰岛素给药改善了链脲佐菌素诱导的这些微循环氧参数的降低，并改善了IMECs中的线粒体超微结构异常。生物能量学分析显示IMECs没有备用呼吸能力。接受胰岛素治疗的IMECs表现出比暴露于糖毒性的IMECs显著更高的基础呼吸（<0.05）。能量图显示接受胰岛素治疗的IMECs的能量代谢增加，ATP产生、非线粒体呼吸和氧化代谢均显著增加（均<0.05）。微循环SO与生物能量学参数之间存在显著负相关。
糖毒性会使胰腺整体微循环氧分布和生物能量学恶化，但这种恶化可通过胰岛素给药逆转。
