Dose-Dependent Delay of the Hypoglycemic Effect of Short-Acting Insulin Analogs in Obese Subjects With Type 2 Diabetes

Abstract

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 lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 ± 7.0 kg/m2) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the 133Xe-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 (Tmax) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (Cmax)/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIRmax: 9.0 vs. 0.6 mg/kg/min, P < 0.0001, 69 vs. 130 min, P < 0.0001, respectively). After 30- and 50-unit injections, Tmax (88.6 and 130.0 min, respectively) and time to GIRmax (175 and 245 min) were further delayed and dose related (r2 = 0.51, P = 0.0004 and r2 = 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.