Objectives

The present study aims to verify the relationship between glucose consumption and uptake of ¹⁸F-2-deoxy-glucose (FDG) in the skeletal muscle (SM) of experimental models of streptozotocin-induced diabetes mellitus (STZ-DM).

Methods

The study included 36 Balb/c mice. Two weeks after intraperitoneal administration of saline (control group, n = 18) or 150 mg streptozotocin (STZ-DM group, n = 18), the two cohorts were submitted to an oral glucose tolerance test and were further subdivided into three groups (n = 6 each): untreated and treated with metformin (MTF) at low or high doses (10 or 750 mg/kg daily, respectively). Two weeks thereafter, all mice were submitted to dynamic micro–positron emission tomography (PET) imaging after prolonged fasting. After sacrifice, enzymatic pathways and response to oxidative stress were evaluated in harvested SM.

Results

On PET imaging, the FDG uptake rate in hindlimb SM was significantly lower in nondiabetic mice as compared with STZ-DM–untreated mice. MTF had no significant effect on SM FDG uptake in untreated mice; however, its high dose induced a significant decrease in STZ-DM animals. Upon conventional analysis, the SM standard uptake value was higher in STZ-DM mice, while MTF was virtually ineffective in either control or STZ-DM models. This metabolic reprogramming was not explained by any change in cytosolic glucose metabolism. By contrast, it closely agreed with the catalytic function of hexose-6P-dehydrogenase (H6PD; i.e., the trigger of a specific pentose phosphate pathway selectively located within the endoplasmic reticulum). In agreement with this role, the H6PD enzymatic response to both STZ-DM and MTF matched the activation of the NADPH-dependent antioxidant responses to the increased generation of reactive oxygen species caused by chronic hyperglycemia. Ex vivo analysis of tracer kinetics confirmed that the enhanced SM avidity for FDG occurred despite a significant reduction in glucose consumption, while it was associated with increased radioactivity transfer to the endoplasmic reticulum.

Conclusions

These data challenge the current dogma linking FDG uptake to the glycolytic rate. They instead introduce a new model considering a strict link between the uptake of this glucose analog, H6PD reticular activity, and oxidative damage in diabetes, at least under fasting condition.

中文翻译：

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实验研究表明，FDG的摄取可追踪糖尿病骨骼肌的氧化损伤。

目标

本研究旨在验证链脲佐菌素诱发的糖尿病（STZ-DM）实验模型中骨骼肌（SM）的葡萄糖消耗与摄取¹⁸ F-2-脱氧葡萄糖（FDG）之间的关系。

方法

该研究包括36只Balb / c小鼠。腹膜内注射生理盐水（对照组，n = 18）或150 mg链脲佐菌素（STZ-DM组，n = 18）两周后，将这两个队列进行口服葡萄糖耐量试验，并进一步分为三组（n每次= 6）：未经治疗或以低剂量或高剂量（分别为每日10或750 mg / kg）服用二甲双胍（MTF）。此后两周，所有小鼠长期禁食后接受动态微正电子发射断层扫描（PET）成像。处死后，在收获的SM中评估酶促途径和对氧化应激的响应。

结果

在PET成像中，与未治疗STZ-DM的小鼠相比，非糖尿病小鼠后肢SM的FDG摄取率显着降低。MTF对未经治疗的小鼠的SM FDG摄取没有显着影响。然而，其高剂量诱导了STZ-DM动物的显着减少。根据常规分析，STZ-DM小鼠的SM标准摄取值较高，而对照或STZ-DM模型中的MTF实际上无效。这种代谢重编程不能通过胞质葡萄糖代谢的任何变化来解释。相反，它与己糖-6P-脱氢酶（H6PD；即选择性地位于内质网内的特定戊糖磷酸途径的触发）的催化功能非常吻合。与此角色一致，H6PD对STZ-DM和MTF的酶促反应与NADPH依赖的抗氧化反应的激活与慢性高血糖引起的活性氧的产生增加相吻合。示踪动力学的离体分析证实，尽管葡萄糖消耗显着降低，但FDG的SM亲和力仍在增强，而这与向内质网的放射性转移增加有关。

结论

这些数据挑战了当前将FDG摄取与糖酵解速率联系起来的教条。相反，他们引入了一种新模型，考虑到至少在禁食的情况下，摄取这种葡萄糖类似物，H6PD网状活性与糖尿病中的氧化损伤之间存在严格的联系。