Dose-response relationship of insulin glulisine in subjects with type 1 diabetes

Little is known about the dose-response relationships of rapid-acting insulin analogues in subjects with diabetes. This study compared the dose-exposure and dose-response relationships of insulin glulisine and regular human insulin (RHI) in subjects with type 1 diabetes. Eighteen male subjects with type 1 diabetes (mean glycosylated haemoglobin, HbA(1c), 7.7%; body mass index 24.5 kg/m(2)) received subcutaneous injections of insulin glulisine followed by RHI (both at doses of 0.075, 0.15 and 0.3 U/kg) in the same three-way crossover, randomized order in a euglycaemic glucose-clamp study. Insulin glulisine and RHI showed dose-proportional increases in exposure (INS-AUC(total)) and maximum serum concentration (INS-C-max) in the dose ranges 0.075, 0.15 and 0.3 U/kg. At all doses, within 2 h after injection, about twice as much insulin glulisine was absorbed as RHI (INS-AUC(0-2h): 3855, 6832 and 13237 vs. 2356, 3630 and 6231 mu U.min/mL; p < 0.05) and INS-C-max was reached in about half the time (INS-T-max: 47, 57 and 72 vs. 82, 104 and 119 min; p < 0.05). Corresponding glucose disposition was twice as large with insulin glulisine as with RHI (GIR-AUC(0-2h): 314, 491 and 536 vs. 127, 219 and 294 mg/kg; p < 0.05), but was similar in extent upon completion (GIR-AUC(total): 499, 1090 and 1476 vs. 416, 1076 and 1555 mg/kg; not significant). With escalating doses, a steady increase in insulin exposure was noticed for both insulins across the entire dose range, whereas glucose disposition increased in a dose-proportional manner only for the dose range 0.075-0.15 U/kg with insulin glulisine only. For both insulins, the end of euglycaemia occurred at insulin concentrations < 10 mu U/mL, with a subsequent rise in plasma glucose taking 80-90 min to reach >= 8.3 mmol/L (>= 150 mg/dL) and a difference in time of similar to 120 min between the insulins at any dose. Insulin glulisine presents rapid, dose-proportional absorption, resulting in saturable glucodynamic activity in subjects with type 1 diabetes.