Effect of Nephrectomy and Splanchnicectomy on Plasma Disappearance of Labeled Insulin in the Rabbit.

A B S T R A C T Based on studies of the interaction of' insulin with its receptors in vitro, we calculated that a receptor compartment should be measurable directly in vivo. For this purpose, rabbits were injected intravenously with a labeled insulin that has low affinity for receptors in combination with a radioiodinated insulin that has high affinity for receptors. Plasma concentrations of labeled insulins were measured at selected intervals after injection. Apparent volumes of distribution were calculated by extrapolation of plasma disappearance curves; high affinity insulins consistently distributed into spaces that were two-three times greater than those of the low affinity insulins.Injections of unlabeled pork insulin before tracer insulins decreased the distribution space of the high affinity insulin in a dose-dependent manner while having little or no effect on the distribution space of the low affinity labeled insulin. When unlabeled insulin was injected after the tracer insulins, there was an immediate rise in the plasma concentration of the high affinity insulin with only a slight change in the plasma concentration of the low affinity insulin.These results demonstrate that high affinity insulins distribute into a body compartment which has many properties of the insulin receptor previously studied in vitro. This receptor compartment: (a) recognizes insulins based on their biological potencies; (b) is saturated by elevated concentrations of insulin; and (c) instulin bound to receptors is in equilibrium with free hormone in plasma. Further, the bound to free ratios for hormone, calculated from these data, suggest that in vivo >50% of the extrapancreatic insulin is bound to receptors during normal physiological states.

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Demonstration of the insulin receptor in vivo in rabbits and its possible role as a reservoir for the plasma hormone.

Zeleznik¹,

Roth²

1978

“…Considerable evidence has accumulated since that time indicating that the kidney plays a major role in insulin degradation, and this has been the topic of a recent excellent review article (2). However, there are only a relatively few papers dealing with the quantitative effects of kidney disease on insulin degradation (22)(23)(24), and these studies seem to suffer from certain defects. In the first place, disappearance of nonspecific trichloroacetic acid (TCA)-precipitable radioactivity has been followed, despite the fact that several authors have indicated that this method does not adequately separate intact immunoprecipitable insulin from its labeled degradation products (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

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

Silvers¹,

Swenson²,

Farquhar³

et al. 1969

Veterans Administration Hospital, Palo Alto, California 94305 AB S T R A C T Insulin-LuI was administered intravenously to normal subjects, to patients with maturityonset diabetes and normal renal function, and to nondiabetic patients with renal failure. The ensuing plasma disappearance curves of immunoprecipitable radioactive insulin were determined, and these data were analyzed in a variety of ways. Firstly, fractional irreversible loss rates of insulin from plasma were calculated and found to be greatly diminished in patients with renal failure (t4 = 39 min), as compared with normal (t4 = 15 min) and diabetic subjects (ti = 12 min). Secondly, plasma insulin-2'I disappearance curves were resolved into sums of three exponentials by the method of "peeling," and values for the resultant three slopes and half-lives were determined. Patients with normal renal function had similar values for all parameters, while those patients with renal failure were differentiated on the basis of the slope of the last component, with a prolongation of its half-life to 275 min (approximately twice normal). Finally, a three pool model was formulated to describe the kinetics of plasma insulin disappearance in man. representing plasma (pool 1), interstitial fluid (pool 2), and all tissues in which insulin is utilized and degraded (pool 3). The proposed model adequately describing the disappearance curves of insulin-'I observed in all patients indicated that volumes (per cent body weight) of pool 1 (4.04) and pool 2 (10.11), calculated on the basis of the model and the experimental data, corresponded closely to estimates of plasma and interstitial fluid vol- umes obtained by independent means. It also demonstrated that patients with renal failure were characterized by a decreased removal rate of insulin from pool 3 and an increased recycling rate of insulin from pool 3 to pool 2. It is concluded that the proposed model represents a reasonable description of the kinetics of insulin distribution and degradation, and that its use provides quantitative insights into the physiology of insulin metabolism.

“…However, inspection of Fig. 1 | SAtdt=SAo(X +2X2) (6) in which Xt, is the fraction of insulin in compartment j that is transferred per minute to compartment i. The notation 1 refers to pool 1, 2 to pool 2, and 0 to the site of removal.…”

Section: Analysis Of Datamentioning

confidence: 99%

“…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)(3)(4)(5)(6)(7)(8). Unfortunately these studies suffer from a variety of defects.…”

mentioning

confidence: 99%

Insulin delivery rate into plasma in normal and diabetic subjects

Stern¹,

Farquhar²,

Silvers³

et al. 1968

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...