[LYS(B28), PRO(B29)]-HUMAN INSULIN - A RAPIDLY ABSORBED ANALOG OF HUMAN INSULIN

[Lys(B28), Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 a nd 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clini cal studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans. We wanted to evaluate the eff ect of adding zinc to LYSPRO on its pharmacokinetics and pharmacodynam ics. In addition, we compared the pharmacokinetics and pharmacodynamic s of LYSPRO and human Regular insulin after subcutaneous injection to those of human Regular insulin given intravenously. Thus, we compared four treatments: solutions of zinc-free LYSPRO given subcutaneously (A ), zinc-containing LYSPRO given subcutaneously (B), human Regular insu lin given subcutaneously (C), and human Regular insulin given intraven ously (D). We gave a 10-U dose of each treatment to 10 healthy (nondia betic) men during glucose clamps. Serum insulin concentrations peaked more than two times higher (maximum serum insulin level [C-max], 698 v s. 308 pM, A vs. C) and in less than half the time (time to C-max [T-m ax], 42 vs. 101 min, A vs. C) after subcutaneous injection of zinc-fre e LYSPRO. At the same time, the glucose infusion rate peaked in about half the time (time to maximum glucose infusion rate [TR(max)], 99 vs. 179 min, A vs. C) and was slightly but not significantly higher (maxi mum glucose infusion rate [R(max)], 3.1 vs. 2.2 mmol/min, A vs. C) tha n that of human Regular insulin. Although the addition of zinc retarde d the absorption of LYSPRO slightly (C-max, 550 vs. 698 pM, B vs. A), zinc-containing LYSPRO retained its distinct profile (T-max, 53 vs. 42 min, B vs. A). LYSPRO displays faster pharmacodynamic action than hum an Regular insulin when injected subcutaneously.