Pankov Y A
Endocrinology Research Centre,Mosсow, Russia.
Biomed Khim. 2016 Jan-Feb;62(1):5-13. doi: 10.18097/PBMC20166201005.
Studies on experimental animals with knockout of the insulin receptor gene Insr (in the whole body or in certain tissues) and/or related genes encoding proteins involved in realization of insulin signal transduction in target cells, have made an important contribution to the elucidation of insulin regulation of metabolism, particularly fat metabolism. Since the whole insulin secreted by b-cells, together with the products of gastrointestinal tract digestion of proteins, fats, and carbohydrates reach the liver, the latter is the first organ on which this hormone acts. The liver employs released amino acids for synthesis of proteins, including apoproteins for various lipoproteins. Glucose is used for synthesis of glycogen, fatty acids, and triglycerides, which enter all the organs in very low density lipoproteins (VLDL). The LIRKO mice with knockout of the Insr gene in the liver demonstrated inhibition of synthesis of macromolecular compounds from amino acids, glucose, and fatty acids. Low molecular weight substances demonstrated increased entry to circulation, and together with other disorders induced hyperglycemia. In LIRKO mice blood glucose levels and glucose tolerance demonstrated time-dependent normalization and at later stages the increase in glucose levels was replaced by hypoglycemia. These changes can be well explained if we take into consideration that one of the main functions of insulin consists in stimulation of energy accumulation by means of activation of triglyceride deposition in adipose tissue. FIRKO mice with selective knockout of adipose tissue Insr were characterized by decreased uptake of glucose in adipocytes, and its transformation into lipids. However, the level of body fat in animals remained normal, possibly due to preserved insulin receptor in the liver and insulin-induced activation of triglyceride production which maintained normal levels of body fat stores, the effective functioning of adipose tissue and secretion of leptin by adipocytes during inhibition of glucose transformation into triglyceride in adipose tissue. Knockout of the Insr gene in muscles blocked glucose uptake by myocytes, but it did not induce hyperglycemia, probably due to the increase in glucose uptake by other organs, which retained the insulin receptor, and induced some increase in fat resources in adipose tissue. Similar results were obtained in mice with knockout the glucose transporter 4 GLUT4 in muscle and/or adipose tissue. Insulin microinjections in the brain, in the cerebral ventricle 4 (ICV) and mediobasal hypothalamus (MBH) did not affect the insulin levels in the general circulation, but effectively activated lipogenesis and inhibited lipolysis in adipose tissue. They induced obesity, similar to conventional obesity when the insulin levels increased. These results may serve as additional evidence for importance of the adipogenic insulin function in mechanisms of regulation of general metabolism.
对胰岛素受体基因Insr（全身或特定组织中）以及/或编码参与靶细胞胰岛素信号转导相关蛋白质的基因进行敲除的实验动物研究，为阐明胰岛素对代谢尤其是脂肪代谢的调节作用做出了重要贡献。由于β细胞分泌的全部胰岛素，连同蛋白质、脂肪和碳水化合物在胃肠道消化的产物都会到达肝脏，所以肝脏是该激素作用的首个器官。肝脏利用释放的氨基酸来合成蛋白质，包括各种脂蛋白的载脂蛋白。葡萄糖则用于合成糖原、脂肪酸和甘油三酯，这些物质以极低密度脂蛋白（VLDL）的形式进入所有器官。肝脏中Insr基因敲除的LIRKO小鼠表现出从氨基酸、葡萄糖和脂肪酸合成大分子化合物的过程受到抑制。低分子量物质进入循环的量增加，与其他紊乱一起导致了高血糖。在LIRKO小鼠中，血糖水平和葡萄糖耐量呈现出随时间的正常化，在后期血糖水平的升高被低血糖所取代。如果考虑到胰岛素的主要功能之一在于通过激活脂肪组织中甘油三酯的沉积来刺激能量积累，那么这些变化就可以得到很好的解释。脂肪组织Insr选择性敲除的FIRKO小鼠的特征是脂肪细胞对葡萄糖的摄取减少以及葡萄糖向脂质的转化减少。然而，动物体内的脂肪水平保持正常，这可能是由于肝脏中胰岛素受体的保留以及胰岛素诱导的甘油三酯生成的激活，从而维持了正常的体脂储存水平、脂肪组织的有效功能以及脂肪细胞在脂肪组织中葡萄糖向甘油三酯转化受抑制期间瘦素的分泌。肌肉中Insr基因的敲除阻断了肌细胞对葡萄糖的摄取，但并未诱发高血糖，这可能是由于其他保留胰岛素受体的器官对葡萄糖摄取增加，并导致脂肪组织中脂肪储备有所增加。在肌肉和/或脂肪组织中葡萄糖转运蛋白4 GLUT4敲除的小鼠中也获得了类似的结果。向脑室内4（ICV）和中基底下丘脑（MBH）进行胰岛素微量注射不会影响全身循环中的胰岛素水平，但能有效激活脂肪组织中的脂肪生成并抑制脂肪分解。它们诱发了肥胖，类似于胰岛素水平升高时的传统肥胖。这些结果可以作为胰岛素促脂肪生成功能在全身代谢调节机制中重要性的额外证据。
