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How Tirzepatide Enhances Insulin Sensitivity Dual Action on GIP and GLP-1 Receptors Unlike other GLP-1 receptor agonists, Tirzepatide activates both GLP-1 and GIP receptors

Compared with the structure of human GLP-1(7-37), the amino acid sequence of dulaglutide contains glycine at position 8, glutamic acid at position 22, and glycine at position 36.113 It was then fused to the constant region (Fc) of modified human immunoglobulin G4 (IgG4) via a -(Gly-Gly-Gly-Gly-Ser) 3-Ala- bridge and exhibits an average biological half-life of 90 h.105 Dulaglutide is the first large-molecule GLP-1RA, and the weekly dosing frequency of dulaglutide can greatly improve patient compliance.33,78,104,114 Semaglutide Semaglutide is a long-acting GLP-1RA agent used once weekly to improve glycemic control in patients with T2DM.115 Compared with the structure of human GLP-1(7-37), the amino acid sequence of semaglutide contains diaminoisobutyric acid at position 8, arginine at position 34, and acylated lysine at position 26.31 Semaglutide has a longer aliphatic chain and increased hydrophobicity, but its hydrophilicity is greatly enhanced by PEG modification of the short chain

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By this mechanism, metformin promotes gut-liver crosstalk, which further affects the regulation of glucose levels

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Tomchik, S