Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia

Abstract

We examined the extent to which priming the liver with a pulse of Humulin or the insulin analog hexyl-insulin monoconjugate 2 (HIM2) reduces postprandial hyperglycemia. Somatostatin (0.5 μg·kg−1·min−1) was given with basal intraportal insulin and glucagon for 4.5 h into three groups of 42-h-fasted conscious dogs. From 0–5 min, group 1 (BI, n = 6) received saline, group 2 (HI, n = 6) received a Humulin pulse (10 mU·kg−1·min−1), and group 3 (HIM2, n = 6) received a HIM2 pulse (10 mU·kg−1·min−1). Duodenal glucose was infused (5.0 mg·kg−1·min−1) from 15 to 270 min. Arterial insulin in BI remained basal (6 ± 1 μU/ml) and peaked at 52 ± 15 (HI) and 164 ± 44 μU/ml (HIM2) and returned to baseline by 30 and 60 min, respectively. Arterial plasma glucose plateaued at 265 ± 20, 214 ± 15, and 193 ± 14 mg/dl in BI, HI, and HIM2. Glucose absorption was similar in all groups. Significant net hepatic glucose uptake occurred at 85, 55, and 25 min in BI, HI, and HIM2, respectively. Nonhepatic glucose clearance at 270 min differed among groups (BI, HI, HIM2): 0.62 ± 0.11, 0.76 ± 0.26, and 1.61 ± 0.29 ml·kg−1·min−1( P < 0.05). A brief (5-min) insulin pulse improved postprandial glycemia, stimulating hepatic glucose uptake and prolonging enhancement of nonhepatic glucose clearance. HIM2 was more effective than Humulin, perhaps because its lowered clearance caused higher levels at the liver and periphery and its biological activity was not reduced proportionally to its decreased clearance.