Abstract Most important factors leading to the development of diabetic encephalopathy in type 1 diabetes mellitus (T1DM) are impaired energy metabolism and mitochondrial dynamics, as well as activation of apoptosis in brain neurons, which is largely due to insulin and C-peptide deficiency in the CNS. In T1DM, hypothalamic neuronal dysfunctions lead to disturb both feeding behavior and central regulation of energy metabolism. One of the approaches to compensate for insulin and C-peptide deficiency in the brain is their intranasal administration. However, its influence on the functional state of hypothalamic neurons has not yet been studied. The aim of the work was to study the effect of intranasally administered insulin and C-peptide on the activity of AMP-activated protein kinase (AMPK) and expression of Drp-1 and mitofusins (Mfn-1 and Mfn-2) responsible for the biogenesis of mitochondria, pro- and anti-apoptotic proteins Bax and Bcl-2, autophagy-associated protein Beclin-1, and melanocortin receptors (MCR) in the hypothalamus of male rats with T1DM induced by 50 mg/kg of streptozotocin. We studied a 7-day intranasal administration to diabetic rats (D) of insulin (20 µg/rat/day, DI), C-peptide (36 µg/rat/day, DC), and insulin combined with C-peptide at two doses of 12 and 36 µg/rat/day (DIC12, DIC36). In the hypothalamus of the DI and DIC36 rat groups, there were observed normalization of AMPK activity and the Bax/Bcl-2 ratio (typically increased in T1DM), restoration of Drp-1, Mfn-2 and Beclin-1 expression, and increased expression of type 4 MCR responsible for transduction of anorexigenic signals, with all changes being associated in these groups with attenuated hyperphagia. In the DIС12 and DС rat groups, the restorative effects of the intranasal treatment were less pronounced. Thus, intranasal administration of insulin and C-peptide, to the greatest extent at a 1:3 molar ratio, restores energetic balance and mitochondrial dynamics, as well as suppresses pro-apoptotic processes in the hypothalamus of rats with severe T1DM. These effects appear to underlie their neuroprotective action.

中文翻译：

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鼻内注射胰岛素和 C 肽对链脲佐菌素诱导的糖尿病大鼠下丘脑 AMP 激活蛋白激酶活性、线粒体动力学和细胞凋亡标志物的影响

摘要 导致 1 型糖尿病 (T1DM) 发生糖尿病脑病的最重要因素是能量代谢和线粒体动力学受损，以及脑神经元凋亡的激活，这主要是由于脑神经元中的胰岛素和 C 肽缺乏所致。中枢神经系统。在 T1DM 中，下丘脑神经元功能障碍导致摄食行为和能量代谢的中枢调节受到干扰。补偿大脑中胰岛素和 C 肽缺乏的方法之一是鼻内给药。然而，尚未研究其对下丘脑神经元功能状态的影响。这项工作的目的是研究鼻内注射胰岛素和 C 肽对 AMP 活化蛋白激酶 (AMPK) 活性和 Drp-1 和丝裂蛋白 (Mfn-1 和 Mfn-2) 表达的影响。 50 mg/kg 链脲佐菌素诱导的 T1DM 雄性大鼠下丘脑中线粒体、促凋亡和抗凋亡蛋白 Bax 和 Bcl-2、自噬相关蛋白 Beclin-1 和黑皮质素受体 (MCR) 的生物发生。我们研究了对糖尿病大鼠 (D) 的 7 天鼻内给药胰岛素（20 µg/大鼠/天，DI）、C-肽（36 µg/大鼠/天，DC）和胰岛素与 C-肽在 2剂量为 12 和 36 µg/大鼠/天（DIC12、DIC36）。在 DI 和 DIC36 大鼠组的下丘脑中，观察到 AMPK 活性和 Bax/Bcl-2 比率正常化（通常在 T1DM 中增加），Drp-1 恢复，Mfn-2 和 Beclin-1 的表达，以及负责转导厌食信号的 4 型 MCR 的表达增加，这些组中的所有变化都与减轻的食欲过盛有关。在 DIС12 和 DС 大鼠组中，鼻内治疗的修复效果不太明显。因此，以 1:3 的摩尔比鼻内给予胰岛素和 C 肽，最大程度地恢复能量平衡和线粒体动力学，并抑制严重 T1DM 大鼠下丘脑的促凋亡过程。这些作用似乎是其神经保护作用的基础。鼻内治疗的修复效果不太明显。因此，以 1:3 的摩尔比鼻内给予胰岛素和 C 肽，最大程度地恢复能量平衡和线粒体动力学，并抑制严重 T1DM 大鼠下丘脑的促凋亡过程。这些作用似乎是其神经保护作用的基础。鼻内治疗的修复效果不太明显。因此，以 1:3 的摩尔比鼻内给予胰岛素和 C 肽，最大程度地恢复能量平衡和线粒体动力学，并抑制严重 T1DM 大鼠下丘脑的促凋亡过程。这些作用似乎是其神经保护作用的基础。