An anomaly of insulin removal in perfused livers of obese-hyperglycemic (ob/ob) mice.

A B S T R A C T Oral glucose (25 g) fed to seven healthy, conscious dogs resulted in an increase in peripheral plasma glucose from 109±3 to 178±10 mg/dl. Concurrently serum insulin increased in the portal vein to levels approximately threefold greater than those in the periphery. Hepatic insulin delivery rose from 10.8±0.7 to 59.0±19.9 mU/min at 60 min, coincident with an increased hepatic insulin extraction from 3.3 to 41.4 mU/min (corresponding to an increase in hepatic extraction from 31±4 to 59±7%), both returning to basal at 3 h. In each animal there was a positive correlation between hepatic insulin delivery and extraction (r = 0.80, P < 0.001 for the seven experiments combined). These changes in hepatic insulin delivery and extraction after glucose feeding were correlated with changes in hepatic glucose metabolism associated with insulin action. As hepatic insulin extraction increased, hepatic glucose output declined, both parameters returning to basal levels by 3 h, indicating a negative correlation between hepatic insulin extraction and hepatic glucose output (r = 0.63, P < 0.001; n = 7).The factors that mediate this marked and rapidly occurring increase in hepatic insulin extraction after oral glucose are unknown, and may include hepatic insulin delivery, glucose levels in the blood supplying the liver, factors related to increased hepatic blood flow, and gut factors released by oral glucose intake. The association of changes in hepatic insulin extraction in vivo with an insulin effect on the liver as measured

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Glucose ingestion in dogs alters the hepatic extraction of insulin. In vivo evidence for a relationship between biologic action and extraction of insulin.

Jaspan¹,

Polonsky²

1982

“…The number of insulin receptors on the membrane may be an important determining factor in the rate of insulin degradation by intact tissues. Indeed, in states of hyperinsulinism, where a decreased number of receptors is found, insulin degradation by the liver is decreased despite an increase in total degrading activity found intracellularly (38). The situation in vivo, however, is more complex.…”

Section: Discussionmentioning

confidence: 99%

Increased Clearance and Degradation of [3H]Insulin in Streptozotocin Diabetic Rats

Philippe¹,

Halban²,

Gjinovci³

et al. 1981

A B S T R A C T The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance.

“…Fluctuations in receptor concentration or receptor affinity, as has been demonstrated under numerous circumstances in vivo, will have a great effect on how closely the areas under the curves reflect secretion. For example, Karakash et al (50) found that in the obese-hyperglycemic mouse (where presumably receptor concentrations are reduced to 1/3 of normal) the uptake of insulin across the liver was reduced substantially, presumably reflecting the decreasedl binding to receptor. Thus, identical curves of plasma hormone versus time will indicate identical secretory rates only when receptor concentration and receptor affinity are unchanged.…”

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

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.