Hepatic Removal of Insulin in Normal Man: Dose Response to Endogenous Insulin Secretion*

Abstract

The hepatic extraction of insulin in normal man was evaluated by kinetic analysis of peripheral insulin behavior in the plasma following stimulation of endogenous insulin secretion. Prehepatic insulin production was determined by deconvolution of plasma connecting peptide behavior (C-peptide) and hepatic extraction of the secreted insulin determined with a three-compartment model for hepatic, vascular, and extravascular plasma spaces. Three dosages of oral glucose (10, 25, and 100 g) administered to normal volunteers resulted in 1.8 +/- 0.5, 2.7 +/- 1.1, and 7.2 +/- 1.6 U endogenous insulin secretion, respectively. Total hepatic exposure to insulin exceeded the endogenous secretion due to recycling to the liver from the systemic circulation. Decreasing insulin extraction by the liver (67-53-42%) in the presence of increasing insulin exposure (2.6-4.4-13.2 U) was observed during the dose-response to glucose. The rates of hepatic insulin extraction observed with arginine (58 +/- 9% with 3.2 U), and a normal meal (50 +/- 9% with 7.6 U) were intermediate between the extremes seen with the 10- and 100-g glucose challenge. These results quantitate hepatic exposure of insulin in man during differing stimuli of endogenous insulin secretion, and demonstrate reduced fractional hepatic extraction with increasing insulin exposure.

Pulsatile Insulin Secretion Dictates Systemic Insulin Delivery by Regulating Hepatic Insulin Extraction In Humans

“…The minute-to-minute adaptive changes in insulin clearance by the liver reported here in vivo reflect greater extraction of the insulin within than between insulin secretory bursts. The fact that absolute insulin clearance increases with insulin concentration (6,31) agrees with the present observations that the liver clears larger insulin secretory bursts to a greater extent than smaller insulin pulses, given that at least 70% of insulin secretion is pulsatile. In addition, analyses based on direct portal-vein catheterization established an ϳ100-fold higher amplitude of insulin concentration oscillations in the portal vein than in the peripheral circulation in humans (18).…”

“…The calculated fractional hepatic insulin extraction reported in the present study is higher than the estimated ϳ50% in the dog (2,4) but consistent with values reported in most human studies (5)(6)(7)44). In particular, based on a similar hepatic-vein sampling technique, hepatic first-pass extraction of insulin has been estimated as 70 -85% by different groups (7,45,46).…”

“…Thus, when insulin secretion is relatively low, and insulin pulses are small, an adaptive decrease in the rate of transhepatic insulin clearance would tend to sustain basal insulin levels in the systemic circulation. As a consequence of the liver's capacity to rapidly modify insulin clearance, the secretion and the hepatic extraction of insulin are closely linked (6,31). In fact, the present data demonstrate that changes in insulin clearance accompany the changes in prehepatic insulin secretion with a lag period of Ͻ1 min.…”

“…Five nondiabetic subjects (two men and three women, mean age 32 years [range 25 F ollowing insulin secretion, the first organ of impact is the liver, where a proportion of secreted insulin is cleared through a receptormediated process (1)(2)(3). The proportion of insulin cleared has been estimated as ϳ50% in dogs (2,4) and ϳ40 -80% in humans (5)(6)(7)(8). Insulin is secreted in discrete secretory bursts occurring approximately every 4 min (9,10).…”

Metabolic and hormonal studies of Type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation

“…Normal glucose metabolism is achieved at the expense of basal and stimulated hyperinsulinaemia. The higher insulin levels are mainly due to the systemic rather than the physiological portal venous drainage of islet cell secretory products (Diem et al 1990a) with reduced first pass hepatic extraction of insulin (Eaton et al 1983). However, as discussed by Diem et al (1990a), basal elevated insulin and C-peptide levels in pancreas recipients may be a physiological response by the graft to increased glucose output from the liver.…”