In healthy people, postprandial GIP levels are approximately 4-fold higher than GLP-1 levels.55 The predicted quantity of GIPR occupied by tirzepatide is also more than that of GLP-1R (6.3-fold at 5mg, 4.6-fold at 10mg and 4.1-fold at 15mg).56 This may be the secret of the extraordinary efficacy of tirzepatide, but it is still possible that the best ratio of GLP-1 and GIP activity in a dual agonist has not been discovered
Regulating histone acetyltransferases and deacetylases
After LPL hydrolyzes TRLs, sortilin, a member of the vacuolar protein sorting 10 (or VPS10) family, facilitates the uptake of secreted LPL and transfers it to endosomes in parenchymal cells, and LPL ends up in lysosomes for degradation [50,84]
This system even has a name: the colonic brake
The weight regain observed after the discontinuation of currently approved GLP-1 and GIP/GLP-1 receptor agonists represents an unmet need for anti-obesity regimens with sustained efficacy
So, in this case, the water retention can be an indirect side effect of the peptide's primary effect on appetite
