Dose-Response Effect of a Single Administration of Oral Hexyl-Insulin Monoconjugate 2 in Healthy Nondiabetic Subjects

Dose-Response Effect of a Single Administration of Oral Hexyl-Insulin Monoconjugate 2 in Healthy Nondiabetic Subjects Estela Wajcberg , MD 1 2 , Yoshinori Miyazaki , MD, PHD 2 , Curtis Triplitt , PHARMD 1 2 , Eugenio Cersosimo , MD 1 2 and Ralph A. DeFronzo , MD 1 2 1 Department of Medicine, Diabetes Division, University of Texas Health Science Center, San Antonio, Texas 2 Texas Diabetes Institute, San Antonio, Texas Address correspondence and reprint requests to Ralph A. DeFronzo, MD, University of Texas Health Science Center, Diabetes Division, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. E-mail: albarado{at}uthscsa.edu Abstract OBJECTIVE — 1 ) To evaluate the effect of a single oral dose of hexyl-insulin monoconjugate 2 (HIM2) on the rate of whole-body glucose disposal ( R d ) and endogenous glucose production (EGP) in healthy nondiabetic subjects, 2 ) to examine the reproducibility of HIM2 on glucose metabolism, and 3 ) to compare the results obtained with HIM2 with those using a bioequivalent dose of subcutaneous lispro insulin. RESEARCH DESIGN AND METHODS —Six healthy subjects ([means ± SE] aged 31 ± 5 years and BMI 23.1 ± 3.9 kg/m 2 ) participated in four studies performed in random order on separate days. Subjects ingested a single dose of HIM2 (0.125, 0.5, and 0.75 mg/kg) or received subcutaneous lispro insulin (0.1 units/kg). Studies were performed with [3- 3 H]glucose, and plasma glucose concentration was maintained at basal levels for 4 h with the euglycemic clamp technique. After 6 weeks, subjects participated in two repeat studies to examine the reproducibility of HIM2 (0.5 mg/kg) and lispro insulin (0.1 units/kg). RESULTS —Fasting plasma insulin (7 μU/ml) increased to a maximum of 102, 321, and 561 μU/ml at 60 min after all three HIM2 doses (0.125, 0.5, and 0.75 mg/kg, respectively). A dose-related decrease in basal EGP was observed as the HIM2 dosage was increased from 0 to 0.125 to 0.5 mg/kg ( P < 0.05 vs. each preceding dose). Suppression of EGP was similar with the 0.5- and 0.75-mg/kg HIM2 doses. A dose-related stimulation of basal R d was observed as the HIM2 dosage was increased from 0 to 0.125 to 0.5 ( P < 0.05 vs. each preceding dose) to 0.75 mg/kg ( P < 0.10 vs. preceding dose). R d (0–240 min) was increased by 0.5 mg/kg oral HIM2 to a value similar to 0.1 units/kg lispro insulin. The 0.125-mg/kg HIM2 dose reduced EGP (0–240 min) to a value that was similar to 0.1 units/kg lispro insulin. The variability in the effect of HIM2 an