Translational Medicine and Surgery, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Division of Internal Medicine and Endocrine and Metabolic Sciences (MISEM), Laboratory for Endocrine Cell Transplants and Biohybrid Organs, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Front Immunol. 2023 Nov 20;14:1163288. doi: 10.3389/fimmu.2023.1163288. eCollection 2023.
Immune cells and other cells respond to nutrient deprivation by the classic catabolic pathway of AMPK (Adenosine monophosphate kinase). This kinase is a pivotal regulator of glucose and fatty acids metabolism, although current evidence highlights its role in immune regulation. Indeed AMPK, through activation of Foxo1 (Forkhead box O1) and Foxo3 (Forkhead box O3), can regulate FOXP3, the key gene for differentiation and homeostasis of Tregs (T regulators lymphocytes). The relevance of Tregs in the onset of T1D (Type 1 diabetes) is well-known, while their role in the pathogenesis of T2D (Type 2 diabetes) is not fully understood yet. However, several studies seem to indicate that Tregs may oppose the progression of diabetic complications by mitigating insulin resistance, atherosclerosis, and damage to target organs (as in kidney disease). Hence, AMPK and AMPK-activating agents may play a role in the regulation of the immune system. The connection between metformin and AMPK is historically known; however, this link and the possible related immune effects are less studied about SGLT2i (Sodium-glucose co-transport 2 inhibitors) and GLP1-RAs (Glucagon-like peptide-1 receptor agonists). Actual evidence shows that the negative caloric balance, induced by SGLT2i, can activate AMPK. Conversely and surprisingly, an anabolizing agent like GLP-1RAs can also upregulate this kinase through cAMP (Cyclic adenosine monophosphate) accumulation. Therefore, both these drugs can likely lead to the activation of the AMPK pathway and consequential proliferation of Tregs. These observations seem to confirm not only the metabolic but also the immunoregulatory effects of these new antidiabetic agents.
免疫细胞和其他细胞通过 AMPK（腺苷单磷酸激酶）的经典分解代谢途径对营养缺乏做出反应。这种激酶是葡萄糖和脂肪酸代谢的关键调节剂，尽管目前的证据强调了它在免疫调节中的作用。事实上，AMPK 通过激活 Foxo1（叉头框 O1）和 Foxo3（叉头框 O3），可以调节 FOXP3，FOXP3 是 Treg（调节性 T 淋巴细胞）分化和稳态的关键基因。Treg 在 T1D（1 型糖尿病）发病机制中的相关性是众所周知的，而它们在 T2D（2 型糖尿病）发病机制中的作用尚未完全阐明。然而，几项研究似乎表明，Treg 通过减轻胰岛素抵抗、动脉粥样硬化和靶器官损伤（如肾病），可能在对抗糖尿病并发症的进展中发挥作用。因此，AMPK 和 AMPK 激活剂可能在免疫系统的调节中发挥作用。二甲双胍与 AMPK 的联系在历史上是已知的；然而，关于 SGLT2i（钠-葡萄糖共转运蛋白 2 抑制剂）和 GLP1-RAs（胰高血糖素样肽-1 受体激动剂），这种联系和可能相关的免疫作用研究较少。实际证据表明，SGLT2i 诱导的负热量平衡可以激活 AMPK。相反，令人惊讶的是，像 GLP-1RAs 这样的合成代谢剂也可以通过 cAMP（环磷酸腺苷）积累来上调这种激酶。因此，这两种药物都可能导致 AMPK 途径的激活和 Treg 的后续增殖。这些观察结果不仅证实了这些新型抗糖尿病药物的代谢作用，也证实了它们的免疫调节作用。
