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8 4.74% , 8 .175 GLP-1 GLP-1 GLP-1 G- GLP-1R .176,177 GLP-1 GLP-1R G- 2 cAMP .34,39,177 cAMP A (PKA) , .178,179 cAMP EPAC (cAMP ) Rap1 , .180,181,183 GLP-1 - 3-(PI3K)/ B(Akt) .184,185,186,187 Interactions with other pathways GLP-1 not only promotes the release of insulin but also enhances the response of pancreatic -cells to insulin through the PI3K/Akt pathway, thereby improving insulin signal transduction and increasing the sensitivity of peripheral tissues to insulin.1,188 GLP-1 reduces hepatic glucose production, partly by inhibiting the expression and activity of key gluconeogenic enzymes.189,190,191 Activation of GLP-1R leads to the production of cAMP (cyclic Adenosine Monophosphate), which is achieved by activating Adenylyl Cyclase (AC).191,192 Following the activation of GLP-1R, the subunits of GPCRs can directly activate Class I PI3Ks.1 These PI3Ks typically include the PI3K and PI3K isoforms, which are composed of regulatory subunits containing SH2 domains and catalytic subunits.193 These subunits can directly interact with the activated GPCR or do so via intermediary proteins such as insulin receptor substrate.194,195 The activated PI3K catalyzes the conversion of membrane phospholipid Phosphatidylinositol-4,5-bisphosphate (PIP2) into Phosphatidylinositol-3,4,5-trisphosphate (PIP3).196 The generation of PIP3 is a crucial step for the activation of Akt, as PIP3 provides a membrane docking site for Akt, facilitating its translocation to the cell membrane.197 Akt, also known as Protein Kinase B (PKB), once positioned at the membrane, can be phosphorylated by PIP3-dependent kinase 1 (PDK1) and possibly PDK2 (such as mTORC2).196,197,198 The phosphorylation of Akt is necessary for its full activation, allowing it to regulate a variety of downstream effector proteins involved in cell survival, proliferation, metabolism, and glucose transport.199 Activated Akt promotes the expression and translocation of GLUT4 (Glucose Transporter Type 4) to the cell membrane, increasing cellular glucose uptake.200,201,202 Simultaneously, Akt promotes cell survival by phosphorylating and inhibiting a series of pro-apoptotic proteins, such as Bad and the FOXO family.202,203,204 Moreover, Akt can activate mTORC1, further promoting cell growth and protein synthesis

NPY1-36 causes vasoconstriction via Y1 receptors, whereas NPY3-36 is a selective Y2-receptor agonist without effect on vascular tone (76, 77)

Improved Blood Sugar Control: While semaglutide is primarily prescribed to treat type 2 diabetes, its impact on blood sugar levels is beneficial for individuals with or without diabetes

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