ABSORPTION KINETICS AND ACTION PROFILES OF SUBCUTANEOUSLY ADMINISTERED INSULIN ANALOGS (ASP(B9)GLU(B27),ASP(B10),ASP(B28)) IN HEALTHY-SUBJECTS

Objective: The subcutaneous absorption and resulting changes in plasma insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations after subcutaneous bolus injection of three soluble human insulin analogues (Asp(B9) Glu(B27), monomeric; Asp(B28), mixture of monomers and dimers; and Asp(B10), dimeric) and soluble human insulin were evaluated. Research Design and Methods: Fasting healthy male volunteers (n = 7) were studied on five occasions 1 wk apart randomly receiving 0.6 nmol . kg-1 s.c. I-125-labeled Asp(B10) or soluble human insulin (Novolin R, Novo, Copenhagen); lst study and 0.6 nmol . kg-1 s.c. I-125-labeled Asp(B28), Asp(B9) Glu(B27) or soluble human insulin (2nd study). Residual radioactivity at the injection site was measured over 8 h with frequent venous sampling for plasma immunoreactive insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations. Results: The three analogues were absorbed 2-3 times faster than human insulin. The mean +/- SE time to 50% residual radioactivity was 94 +/- 6 min for Asp(B10) compared with 184 +/- 10 min for human insulin (P < 0.001), 83 +/- 8 min for Asp(B28) (P < 0.005), and 63 +/- 9 min for Asp(B9) Glu(B27) (P < 0.001) compared with 182 +/- 21 min for human insulin. DELTA-Peak plasma insulin analogue levels were significantly higher after each analogue than after human insulin (P < 0.005). With all three analogues, the mean hypoglycemic nadir occurred earlier at 61-65 min postinjection compared with 201-210 min for the reference human insulins (P < 0.005). The magnitude of the hypoglycemic nadir was greater after Asp(B9) Glu(B27) (P < 0.05) and Asp(B28) (P < 0.001) compared with human insulin. There was a significantly faster onset and offset of responses in C-peptide and intermediary metabolite levels after the analogues than after human insulin (P < 0.05). Conclusions: The rapid absorption and biological actions of these analogues offer potential therapeutic advantages over the current short-acting neutral soluble insulins.