Research progress on oral glucagon-like peptide-1 receptor agonists in the treatment of diabetes mellitus type 2

Abstract

Objective: In view of the high incidence of type 2 diabetes mellitus (T2DM) and the high prevalence of multi-organ complications, as well as the issues that traditional hypoglycemic drugs are prone to causing weight gain and the molecular targets and signaling pathways of classic drugs such as metformin have not been systematically clarified, this study aims to systematically analyze the mechanism of action and clinical value of glucagon-like peptide-1 receptor agonists (GLP-1RAs), and It further clarifies key signaling pathways including adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt), cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA), and interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) cytokine pathways, prkviding theoretical support for precision interventions in T2DM. Methods: The latest domestic and international multi-omics research data, cell/animal functional experiment results, and clinical evidence were systematically integrated to analyze the structural modification strategies and glucose concentration-dependent mechanism of action of GLP-1RAs. Emphasis was placed on dissecting their regulatory pathways for insulin/glucagon secretion, as well as key receptor-related networks. Result: Glucagon-like peptide-1 receptor agonist (GIP-1RA), when modified at specific amino acid positions, becomes resistant to dipeptidyl peptidase 4 (DPP-4) degradation. It activates the Gs/cAMP/PKA/exchange protein activated by cAMP (EPAC) signaling axis to promote insulin release in a glucose concentration-dependent manner, while suppressing glucagon secretion through Gi/cAMP downregulation and insulin synergistic effects. Additionally, it induces transient IL-6 release in monocytes, enhancing adipose tissue brownification and thermogenesis via the IL-6/STAT3 pathway. This mechanism protects pancreatic β-cells by preventing apoptosis and promoting proliferation, while improving insulin resistance in adipose, hepatic, and skeletal muscle tissues. The compound also exhibits dual effects of weight loss and hepatoprotective (miRNA-regulated lipid metabolism) and nephroprotective (sodium excretion and anti-inflammatory) actions. Key regulatory targets include AMPK, PI3K-Akt, cAMP-PKA, and IL-6/STAT3. Conclusion: GLP-1RAs overcome the limitations of endogenous GLP-1 and traditional hypoglycemic drugs, providing a new strategy for the comprehensive treatment of T2DM featuring “hypoglycemia-organ protection-weight loss”. The mechanisms and pathway networks analyzed in this study lay a foundation for the precise intervention of T2DM and rational clinical drug use.