Reduced Insulin Clearance in Normal Subjects Due to Extreme Hyperinsulinemia

• Published in: The American journal of the medical sciences 1988-01, Vol.295 (1), p.15-22
• Main Authors: Nestler, John E., Clore, John N., Blackard, William G.
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Endocrine pancreas; Female; Fundamental and applied biological sciences. Psychology; Half-Life; Hormones. Régulation; Humans; Hyperinsulinism - metabolism; Infusions, Intravenous; Insulin; Insulin - pharmacokinetics; Insulin Receptor; Male; Metabolic Clearance Rate; Receptor, Insulin - metabolism; Time Factors; Vertebrates: endocrinology
• ISSN: 0002-9629; 1538-2990
• DOI: 10.1097/00000441-198801000-00005

Insulin clearance was assessed in five normal subjects infused with insulin at a rate of 10 mU·kg−1min−1 for 12-16 hours, which produced insulin levels of 1500-2000 μU/ml (~10−8 M). This level approximates the Kd of low affinity insulin binding sites, whereas previous clearance studies had been performed at insulin concentrations of 10−9 M or less, approximating the Kd of the high affinity insulin receptor. The metabolic clearance rate for insulin during the infusion averaged 214 ± 29 ml·min−1·m−2, which is half of that reported previously when lower insulin levels were achieved. Upon termination of the insulin infusion, the disappearance of insulin was markedly prolonged with an average “half-life” of 62 minutes. The rapidity with which hyperinsulinemia altered clearance suggested that down-regulation of insulin receptors was probably not the explanation for the reduced clearance. To elucidate the cause for the observed decrease in insulin clearance, five additional subjects were studied. If insulin was infused for 3.0-4.5 hours, the half-life of insulin disappearance was intermediate between that for an insulin bolus dose and that for a 12-16-hour insulin infusion. Administration of an insulin bolus dose at the end of a 12-hour infusion, while the insulin concentration was still ~10−8 M, or 140 min later, when the insulin concentration was 10−9 M, was followed by rapid disappearance with half-lives of 1.5 and 6-8 minutes, respectively. The extraordinarily short half-life of the insulin bolus dose administered at a steady-state insulin concentration of 10−8 M is compatible with a greater volume of distribution for insulin at that concentration. The prolonged rate of insulin disappearance following termination of a 12-16-hour insulin infusion suggests that clearance may have been altered as a result of reentry of insulin from a low affinity, high capacity System into the vascular compartment, since the disappearance rate was prolonged even at an insulin concentration of 10−9 M when a simultaneously administered insulin bolus dose was cleared normally. These observations suggest that low affinity binding sites served as a high capacity “reservoir” in which insulin could accumulate and from which insulin could subsequently recycle into the circulation, thereby decreasing apparent clearance rates.