Insulin delivery rate into plasma in normal and diabetic subjects

Abstract

A B S T R A C T Removal of insulin-1'3I from plasma was studied in normal and diabetic subjects with both single injection and continuous infusion of isotope techniques. Patients were studied either in the fasting state or during steady-state hyperglycemia produced by a continuous intravenous glucose infusion. Steady-state plasma insulin concentration during these studies ranged from 10 to 264 JuU/ml. Labeled insulin specific activity time curves consisted of more than one exponential, indicating that a multicompartmental system for insulin metabolism exists. A mathematical technique which is applicable to non-first order processes was used to calculate the rate at which insulin was lost irreversibly from the plasma insulin pool. A direct, linear relationship was found between insulin irreversible loss rate and plasma insulin concentration over the range of concentrations studied. This linearity implies lack of saturability of the insulin removal mechanism. Since the plasma insulin pool was in a steady state during these studies, insulin irreversible loss rate was equal to the rate at which newly secreted insulin was being delivered to the general circulation. Therefore, these results indicate that changes in plasma insulin concentration result from parallel INTRODUCTIONDevelopment of a precise immunoassay for the measurement of plasma insulin concentration (1) has greatly facilitated study of carbohydrate and insulin metabolism. Interpretation of plasma insulin measurements has generally rested on the belief that changes in concentration are direct reflections of parallel changes in pancreatic insulin secretion rate. However, there is little experimental evidence in support of this assumption. Because insulin is secreted into the portal vein, and not into the systemic circulation, determination of pancreatic insulin secretion rate in intact subjects presents formidable difficulties. In contrast, plasma insulin removal rate, which in the steady state is equal to the rate of delivery of insulin into the systemic circulation, can be determined by standard isotopic techniques, and many such studies have been published (2-8). Unfortunately these studies suffer from a variety of defects. In some cases (3-7) disappearance of nonspecific proteinprecipitable radioactivity has been followed despite the fact that Berson, Yalow, Bauman, Rothschild, and Newerly (2), and subsequently others (9,10) In three patients (G.B., W.K., and E.D.), continuous infusions of insulin-'I were given by means of a constant infusion pump. In each of these studies, the continuous infusion of isotope was preceded by a primer dose. The infusion rates were: G.B., 170,686 cpm/min; W.K., 135,240 cpm/min; and E.D., 71,439 cpm/min.Primer doses were in each instance equal to 10 times the per minute infusion rate. Venous blood samples were obtained at i hr intervals for 4 hr. Only those samples obtained after isotopic steady state had been achieved were used in the subsequent calculations.Technical procedures. Blood was drawn into tubes containing e...

Derivation of a three compartment model describing disappearance of plasma insulin-131I in man

“…Discriminant analysis, as seen in Table VI, suggested that insulin in patients with maturity-onset diabetes exchanges at a more rapid rate between pools 2 (plasma) and 3 (interstitial fluid) than it does in subjects with normal glucose tolerance. Our previous work indicated that patients with modest hyperglycemia deliver a greater load of insulin to the tissue, and that this greater load of insulin is degraded at the same rate as observed in normal patients (1). Thus, the greater fractional rate of exchange noted in the current studies may be a reflection of the fact that patients with mild maturity-onset diabetes deliver more insulin to tissue sites of utilization and degradation.…”

“…In a recent paper we demonstrated that disappearance of insulin-w'I from plasma of man clearly reflected a non-first order process (1). The potential errors resulting from the use of first order concepts to analyze such situations were pointed out, and alternative meth ods were described which did permit estimation of the rate at which insulin was being delivered into the general circulation.…”

Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism

“…An antecubital IV catheter was kept patent with 0.154 mol/1 saline and blood was sampled for measurement of insulin disappearance at 3,5,10,15,20,30,40,50 and 60 min after the insulin infusion. Insulin (pork, Actrapid, Novo) was infused IV within 5 s at a dose of approximately 0.04 U/kg body weight in the hyperthyroid patients and 0.06 U/kg in the control subjects.…”

“…It has been reported that the absolute degradation rate of insulin is proportional to the plasma insulin concentration, i.e. the fractional rate is constant [15]. Although several authors have shown that the irreversible loss rate of insulin is not linearly related to plasma concentration [13][14][15], the difference is not very large, and it is reasonable to assume that the fractional rate of loss of unlabelled insulin is relatively constant regardless of the plasma concentrations.…”

“…the fractional rate is constant [15]. Although several authors have shown that the irreversible loss rate of insulin is not linearly related to plasma concentration [13][14][15], the difference is not very large, and it is reasonable to assume that the fractional rate of loss of unlabelled insulin is relatively constant regardless of the plasma concentrations. Therefore, it is reasonable to assume that the calculated rate of insulin removal, following a single dose of insulin, can be applied to the delivery of various amounts of insulin following glucose or arginine infusion.…”