Ishino Seigo, Sugita Taku, Kondo Yusuke, Okai Mika, Tsuchimori Kazue, Watanabe Masanori, Mori Ikuo, Hosoya Masaki, Horiguchi Takashi, Kamiguchi Hidenori
Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi, 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.
CVM-DDU, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Ann Nucl Med. 2017 Jun;31(5):413-423. doi: 10.1007/s12149-017-1169-0. Epub 2017 Apr 11.
One of the major causes of diabetes and obesity is abnormality in glucose metabolism and glucose uptake in the muscle and adipose tissue based on an insufficient action of insulin. Therefore, many of the drug discovery programs are based on the concept of stimulating glucose uptake in these tissues. Improvement of glucose metabolism has been assessed based on blood parameters, but these merely reflect the systemic reaction to the drug administered. We have conducted basic studies to investigate the usefulness of glucose uptake measurement in various muscle and adipose tissues in pharmacological tests using disease-model animals.
A radiotracer for glucose, F-2-deoxy-2-fluoro-D-glucose (F-FDG), was administered to Wistar fatty rats (type 2 diabetes model), DIO mouse (obese model), and the corresponding control animals, and the basal glucose uptake in the muscle and adipose (white and brown) tissues were compared using biodistribution method. Moreover, insulin and a β3 agonist (CL316,243), which are known to stimulate glucose uptake in the muscle and adipose tissues, were administered to assess their effect. F-FDG uptake in each tissue was measured as the radioactivity and the distribution was confirmed by autoradiography.
In Wistar fatty rats, all the tissues measured showed a decrease in the basal level of glucose uptake when compared to Wistar lean rats. On the other hand, the same trend was observed only in the white adipose tissue in DIO mice, while brown adipose tissue showed increments in the basal glucose uptake in this model. Insulin administration stimulated glucose uptake in both Wistar lean and fatty rats, although the responses were inhibited in Wistar fatty rats. The same tendency was shown also in control mice, but clear increments in glucose uptake were not observed in the muscle and brown adipose tissue of DIO mice after insulin administration. β3 agonist administration showed the similar trend in Wistar lean and fatty rats as insulin, while the responses were inhibited in the adipose tissues of Wistar fatty rats.
A system to monitor tissue glucose uptake with F-FDG enabled us to detect clear differences in basal glucose uptake between disease-model animals and their corresponding controls. The responses in the tissues to insulin or β3 agonist could be identified. Taken as a whole, the biodistribution method with F-FDG was confirmed to be useful for pharmacological evaluation of anti-diabetic or anti-obesity drugs using disease-model animals.
糖尿病和肥胖的主要原因之一是基于胰岛素作用不足导致的肌肉和脂肪组织中葡萄糖代谢及葡萄糖摄取异常。因此，许多药物研发项目都基于刺激这些组织中葡萄糖摄取的概念。葡萄糖代谢的改善已根据血液参数进行评估，但这些仅反映了对所给药药物的全身反应。我们进行了基础研究，以调查在使用疾病模型动物的药理试验中，测量各种肌肉和脂肪组织中葡萄糖摄取的实用性。
将葡萄糖放射性示踪剂F-2-脱氧-2-氟-D-葡萄糖（F-FDG）给予Wistar肥胖大鼠（2型糖尿病模型）、饮食诱导肥胖（DIO）小鼠（肥胖模型）及相应的对照动物，采用生物分布法比较肌肉和脂肪（白色和棕色）组织中的基础葡萄糖摄取。此外，给予已知可刺激肌肉和脂肪组织中葡萄糖摄取的胰岛素和β3激动剂（CL316,243），以评估其效果。通过测量各组织中F-FDG摄取的放射性，并通过放射自显影确认其分布。
与Wistar瘦大鼠相比，Wistar肥胖大鼠中所有测量组织的基础葡萄糖摄取水平均降低。另一方面，在DIO小鼠中仅白色脂肪组织观察到相同趋势，而在此模型中棕色脂肪组织的基础葡萄糖摄取增加。给予胰岛素可刺激Wistar瘦大鼠和肥胖大鼠的葡萄糖摄取，尽管Wistar肥胖大鼠的反应受到抑制。对照小鼠也表现出相同趋势，但给予胰岛素后，DIO小鼠的肌肉和棕色脂肪组织中未观察到明显的葡萄糖摄取增加。给予β3激动剂在Wistar瘦大鼠和肥胖大鼠中显示出与胰岛素相似的趋势，而Wistar肥胖大鼠脂肪组织中的反应受到抑制。
用F-FDG监测组织葡萄糖摄取的系统使我们能够检测疾病模型动物与其相应对照之间基础葡萄糖摄取的明显差异。可以确定组织对胰岛素或β3激动剂的反应。总体而言，证实F-FDG生物分布法对于使用疾病模型动物进行抗糖尿病或抗肥胖药物的药理评价是有用的。
