Augmented effect of short-term pulsatile versus continuous insulin delivery on lipid metabolism but similar effect on whole-body glucose metabolism in obese subjects

Abstract

The present study was designed to examine the effect of pulsatile versus continuous insulin delivery on glucose and lipid metabolism in insulin-resistant subjects. Six obese women (body mass index, 40.0 ± 2.8 kg/m 2) underwent a euglycemic glucose clamp (plasma glucose, 90 mg/dL) twice. In random order, insulin was infused intravenously for 375 minutes either at a constant rate (0.4 mU/kg/min) or in a pulsatile manner (2.4 mU/kg/min for 2 minutes followed by an off interval of 10 minutes). Endogenous insulin release was suppressed by infusion of somatostatin (250 μg/h). Mean circulating insulin concentrations were similar during the two protocols (pulsatile v continuous infusion, 60 ± 10 v 56 ± 9 mU/L), but pulsatile infusion was accompanied by oscillations with an amplitude of 120 mU/L. After 6 hours of pulsatile versus continuous insulin, isotopically determined total glucose disposal (3- 3H-glucose) and hepatic glucose production (HGP) were comparable (pulsatile v continuous, 2.80 ± 0.56 v 2.82 ± 0.51 and 0.37 ± 0.14 v 0.32 ± 0.17 mg/kg/min). However, the rate of glucose oxidation (indirect calorimetry) was augmented ( P < .05), whereas lipid oxidation tended to be diminished (.10 > P > .05) following pulsatile infusion. In addition, blood glycerol was more suppressed with pulsatile (31 ± 9 nmol/L) than with continuous infusion (36 ± 10 nmol/L, P < .05), whereas blood lactate, alanine, and 3-hydroxybutyrate were similar in the two infusion protocols. Lipoprotein lipase (LPL) activity in abdominal adipose tissue (taken at 375 minutes) was significantly increased following pulsatile insulin delivery (pulsatile v continuous infusion, 707 ± 120 v 474 ± 87 nmol/nonesterified fatty acids [NEFA]/h/g, P < .05). Thus, in obese individuals pulsatile insulin exposure for approximately 6 hours has a greater impact on lipid metabolism than an equimolar amount of insulin infused at a constant rate. Both a greater suppression of lipolysis and activation of LPL occurred, implying presumably an increased rate of reesterification of NEFA. In contrast, whole-body insulin-stimulated glucose disposal and suppression of HGP were similar with pulsatile and constant insulin administration.