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Ile 12 Using cryo-electron microscopy, Zhang et al found that a cluster of neighboring serines (Ser 14 , Ser 17 , and Ser 18 of GLP-1) form polar interactions with Thr 298 , the backbone oxygen of Trp 297 , and the nitrogen of Arg 299 in GLP-1R.12 However, Ala mutations at any of these positions hardly affected activity.25,29 In contrast, if GLP-1R Thr 298 was mutated into Ala, it increased affinity to the ligand.30 Keliher et al ran a series of modifications of Lys 12 in exenatide, indicating that this position is not important for interactions with GLP-1R and that it is, to some extent, tolerant of bigger groups.31 The mutation of GIP Ile 12 to Ala caused a notable decrease in its insulinotropic effect.27 Hence, using Ile 12 in tirzepatide seems not to weaken its GLP-1 activity and to strengthen its GIP activity
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Why is it important to address obesity
It provided a dedicated pathway for patients to access tirzepatide specifically for weight loss rather than relying on a diabetes diagnosis
