Comparison of the priming effects of pulsatile and continuous insulin delivery on insulin action in man

Abstract

Insulin is normally secreted in man in regular pulses every 5 to 15 minutes. Disordered pulsation has been demonstrated in several insulin-resistant states and it is unclear whether this represents a primary beta-cell defect contributing to impairment of peripheral insulin action or rather is a consequence of insulin resistance. Basal or near basal insulin administration by pulsatile infusion augments hypoglycemic effect and improves insulin-mediated glucose uptake compared with insulin by continuous infusion. To date no study has examined whether normal basal insulin pulsatility is required to preserve subsequent insulin sensitivity during hyperinsulinemia. We studied the effect of overnight pulsatile versus continuous basal insulin on a subsequent hyperinsulinemic euglycemic clamp. Nineteen normal volunteers (male:female ratio, 17:2; mean age ± SEM, 26.1 ± 2.3 years) were studied on 2 occasions each. Endogenous insulin secretion was inhibited by octreotide (0.43 μg kg −1 · h −1) and replaced overnight at 5.4 mU kg −1 · h −1 either by continuous infusion or in 2-minute pulses every 13 minutes (n = 10) or every 7 minutes (n = 9). Glucagon was replaced at physiological concentration by continuous infusion (30 ng · kg −1 · h −1). Venous plasma glucose overnight was not significantly different between the pulsatile and continuous protocols. After discontinuing the overnight insulin infusion, insulin action was assessed during a hyperinsulinemic euglycemic clamp (1 mU kg −1 · h −1). Glucose infusion rates at steady-state during the hyperinsulinemic clamp were similar between continuous and both frequencies of pulsatile infusion (continuous 44.6 ± 4.3 μmol · kg −1 · min −1 v 13-minute pulsatile 41.7 ± 5.9 μmol · kg −1 · min −1, P = .27; continuous 34.6 ± 2.5 μmol · kg −1 min −1 v 7-minute pulsatile 41.4 ± 3.2 μmol · kg −1 · min −1, P = .08). We conclude that overnight pulsatile compared with continuous insulin administration has no different effect on subsequent peripheral insulin-mediated glucose uptake. A priming effect cannot therefore explain the previously demonstrated association between endogenous insulin pulse frequency and peripheral insulin action.