COMPARISON OF SUBCUTANEOUS SOLUBLE HUMAN INSULIN AND INSULIN ANALOGS (ASPB9,GLUB27-ASPB10-ASPB28) ON MEAL-RELATED PLASMA-GLUCOSE EXCURSIONS IN TYPE-I DIABETIC SUBJECTS

Objective: To compare postprandial glucose excursions and plasma free insulin-analogue levels after subcutaneous injection of three novel human insulin analogues (Asp(B10); Asp(B9),Glu(B27); and Asp(B28)) with those after injection of soluble human insulin (Actrapid HM U-100). Research Design and Methods: Six male subjects with insulin-dependent diabetes, at least 1 wk apart and after an overnight fast and basal insulin infusion, received 72 nmol (approximately 12 U) s.c. of soluble human insulin 30 min before, or 72 nmol of each of the three analogues immediately before, a standard 500-kcal meal. Results: Mean basal glucoses were similar on the 4 study days. Compared to human insulin (6.3 +/- 0.8 mM), mean +/- SE peak incremental glucose rises were similar after analogues Asp(B10) (5.4 +/- 0.8 mM) and Asp(B9),Glu(B27) (5.4 +/- 0.7 mM) and significantly lower after analogue Asp(B28) (3.6 +/- 1.2 mM, P < 0.02). Relative to soluble human insulin (100% +/- SE21), incremental areas under the glucose curve between 0 and 240 min were 79% +/- 34 (Asp(B10), NS), 70% +/- 29 (Asp(B9),Glu(B27), NS), and 43% +/- 23 (Asp(B28), P < 0.02). Basal plasma free insulin levels were similar on the 4 study days. Plasma free insulin-analogue levels rose rapidly to peak 30 min after injection at 308 +/- 44 pM (Asp(B10)); 1231 +/- 190 pM (Asp(B9),Glu(B27)) and 414 +/- 42 pM (Asp(B28)) and were significantly higher than corresponding (i.e., 30 min postmeal) plasma free insulin levels of 157 +/- 15 pM (P < 0.02 in each case). Conclusions: Plasma profiles of the insulin analogues were more physiological than that of human insulin after subcutaneous injection. All three analogues given immediately before the meal are at least as effective as soluble human insulin given 30 min earlier. These analogues are promising potential candidates for short-acting insulins of the future.