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Because the cleavage activity of DPP-4 is depending on the presence of a penultimate Pro or Ala at the N-terminus, analogs of GLP-1 with substitutions at this position should be protected, and analogs with Ser, Val, or alpha-aminobutyric acid remained biologically active (104), so this problem could easily be solved, but the substitutions only increased the half-life from 1.5 to 45 min (104), the reason being a rapid extraction of GLP-1 in the kidneys (105), and probably also other enzymatic attacks (106)

These effects are often more common during dose increases

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Serra FE, Cohen RV

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