Dose-Dependent Delay of the Hypoglycemic Effect of Short-Acting Insulin Analogs in Obese Subjects With Type 2 Diabetes A pharmacokinetic and pharmacodynamic study

OBJECTIVE - Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects healthy or with type 1 diabetes In obese patients however daily dosages are larger and ATBF is decreased This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes RESEARCH DESIGN AND METHODS - Euglycemic clamps after subcutaneous lis pro injections were performed Six healthy control subjects received 10 units Seven obese (BMI 38 3 +/- 7 0 kg/m(2)) subjects with type 2 diabetes received 10 30 and 50 units Plasma lispro was measured by specific radioimmunoassay and ATBF by the Xe-133 washout technique RESULTS - ATBF was 64% lower in subjects with type 2 diabetes than in control subjects After 10 units injection time to lispro plasma peak (T-max) was similar (48 3 vs 55 7 mm control subjects versus type 2 diabetic subjects) although maximal concentration (C-max)/dose was 41% lower in subjects with type 2 diabetes with lower and delayed maximal glucose infusion rate (GIR(max) 9 0 vs 0 6 mg/kg/min P < 0 0001 69 vs 130 mm P < 0 0001 respectively) After 30- and 50-unit injections T-max. (88 6 and 130 0 min respectively) and time to GIRmax (175 and 245 mm) were further delayed and dose related (r(2) = 0 51 P = 0 0004 and r(2) = 0 76 P < 0 0001 respectively) CONCLUSIONS - Absorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes