Chandrasekaran Krish, Choi Joungil, Salimian Mohammad, Hedayat Ahmad F, Russell James W
Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
Int J Mol Sci. 2024 Dec 25;26(1):80. doi: 10.3390/ijms26010080.
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O/min in HFD vs. 220 ± 20 nmol O/min in control diet (CD); < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O/min in HFD+AICAR). However, AICAR's protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN.
糖尿病周围神经病变（DPN）是1型糖尿病（T1D）和2型糖尿病（T2D）常见的并发症。虽然目前尚无预防或治疗DPN的特效药物，但某些策略有助于阻止其进展。在T1D中，通过胰岛素治疗维持严格的血糖控制可有效预防或延缓DPN的发生。然而，在T2D中，尽管运动显然有益，但总体血糖控制对DPN可能仅有中度影响。不幸的是，由于神经性足部疼痛和平衡能力差，最佳运动对许多DPN患者可能并不可行。运动对健康参数有若干有利影响，包括体重、血糖控制、血脂谱和血压。我们研究了一种运动模拟物5-氨基咪唑-4-甲酰胺核糖核苷酸（AICAR）对DPN的影响。AICAR治疗可预防或逆转T2D和T1D小鼠模型中的实验性DPN。高脂饮食（HFD喂养）小鼠中的AICAR增加了背根神经节（DRG）神经元提取物中AMPK的磷酸化，磷酸化AMPK与总AMPK的比值增加了3倍（HFD组与HFD + AICAR组相比；<0.001）。磷酸化AMP增加了动力相关蛋白1（，一种线粒体分裂标记物）的水平，增加了丝氨酸555位点的磷酸化自噬激活激酶1（ULK1），并使微管相关蛋白轻链3-II（LC3-II，自噬体组装标记物）增加了2倍。从HFD喂养的小鼠DRG神经元中分离的线粒体，其ADP刺激的状态3呼吸作用降低（HFD组为120±20 nmol O/min，对照饮食（CD）组为220±20 nmol O/min；<0.001）。从HFD + AICAR处理的小鼠中分离的线粒体，其状态3呼吸作用增加（HFD + AICAR组为240±30 nmol O/min）。然而，AICAR对T2D小鼠DPN的保护作用也通过其对胰岛素敏感性、葡萄糖代谢和脂质代谢的影响介导。增强AMPK磷酸化的药物可能对DPN的治疗有益。
