Efficacy of Pulsatile Versus Continuous Insulin Administration on Hepatic Glucose Production and Glucose Utilization in Type I Diabetic Humans

Abstract

To evaluate the role of pulsatile insulin administration, hepatic glucose production (HGP) and utilization were studied in type I diabetic patients in the fasting state and during a euglycemic insulin (1 mU · kg−1 · min−1 i.v.) clamp with continuous and pulsatile insulin administration. In the latter study, insulin was infused at twice the continuous rate with 3-min-on/7-min-off intervals, thereby reducing total insulin delivery by 40%. The restraining effect of pulsatile insulin on basal HGP (1.91 ± 0.35 mg · kg−1 · min−1) was equipotent to continuous insulin exposure (1.80 ± 0.17 mg · kg−1 min−1). During the insulin-clamp studies, HGP was equally suppressed by pulsed (0.62 ± 0.12 mg · kg−1 min−1) as by continuous insulin infusion (0.63 ± 0.12 mg · kg−1 · min−1). Insulin-stimulated glucose utilization was not significantly altered in either study (2.55 ± 0.27 vs. 2.92 ± 0.23 mg · kg−1 min−1). When in further studies the total insulin dose given during the pulsatile study was infused continuously (0.6 mU · kg−1 · min−1), HGP in the basal state and residual HGP during the insulin-clamp study were 25–30% higher than in the pulsatile experiments, whereas glucose utilization was not significantly different. In conclusion, by reducing total hormone delivery by up to 40%, but given in a pulsatile fashion, insulin is equally potent in controlling HGP as continuous insulin administration. This greater efficacy of pulsatile exposure in suppressing HGP is accompanied by an equipotent effect on glucose utilization. Application of pulsatile insulin substitution in intravenous-pump users may reduce systemic hyperinsulinemia and, in the long run, insulin resistance by reversing downregulation of insulin receptors.