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GLP-1 RAs and SGLT2i: two antidiabetic agents associated with immune and inflammation modulatory properties through
Alessio Mazzieri1, Giuseppe Basta2, Riccardo Calafiore3,4
1Translational Medicine and Surgery, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
Abstract:
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.
Insights
Adenosine monophosphate kinase (AMPK) regulates immune cells and T regulatory lymphocytes (Tregs). New antidiabetic drugs like SGLT2 inhibitors and GLP-1 receptor agonists may activate AMPK, promoting Treg proliferation and offering immunoregulatory benefits.
Area of Science:
- Metabolic and Immunological Sciences
- Endocrinology and Diabetes Research
Background:
- Adenosine monophosphate kinase (AMPK) is a key regulator of cellular metabolism, responding to nutrient deprivation.
- AMPK influences immune cell function, notably by regulating T regulatory lymphocytes (Tregs) via Foxo transcription factors and FOXP3.
- The role of Tregs in Type 2 diabetes (T2D) pathogenesis and complications is an emerging area of research.
Purpose of the Study:
- To explore the immunoregulatory role of AMPK in the context of antidiabetic medications.
- To investigate the potential of Sodium-glucose co-transport 2 inhibitors (SGLT2i) and Glucagon-like peptide-1 receptor agonists (GLP-1RAs) to modulate the AMPK pathway.
- To assess the consequential effects of these drugs on Treg proliferation and immune homeostasis.
Main Methods:
- Review of current evidence on AMPK, Treg function, and antidiabetic drug mechanisms.
- Analysis of how SGLT2i and GLP-1RAs impact cellular energy balance and signaling pathways.
- Correlation of drug-induced metabolic changes with immune cell modulation.
Main Results:
- SGLT2 inhibitors activate AMPK through induced negative caloric balance.
- GLP-1 receptor agonists also upregulate AMPK, unexpectedly, via cyclic adenosine monophosphate (cAMP) accumulation.
- Both drug classes are suggested to activate the AMPK pathway, potentially leading to increased Treg proliferation.
Conclusions:
- AMPK activation by SGLT2i and GLP-1RAs suggests significant immunoregulatory functions beyond metabolic control.
- These antidiabetic agents may influence Treg homeostasis, impacting T2D pathogenesis and complications.
- Further research is warranted to fully elucidate the metabolic and immune interplay of these novel therapeutic strategies.
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