Variability of Directly Measured First-Pass Hepatic Insulin Extraction and Its Association With Insulin Sensitivity and Plasma Insulin

Abstract

Although the β-cells secrete insulin, the liver, with its first-pass insulin extraction (FPE), regulates the amount of insulin allowed into circulation for action on target tissues. The metabolic clearance rate of insulin, of which FPE is the dominant component, is a major determinant of insulin sensitivity (SI). We studied the intricate relationship among FPE, SI, and fasting insulin. We used a direct method of measuring FPE, the paired portal/peripheral infusion protocol, where insulin is infused stepwise through either the portal vein or a peripheral vein in healthy young dogs ( = 12). FPE is calculated as the difference in clearance rates (slope of infusion rate vs. steady insulin plot) between the paired experiments. Significant correlations were found between FPE and clamp-assessed SI ( = 0.74), FPE and fasting insulin ( = -0.64), and SI and fasting insulin ( = -0.67). We also found a wide variance in FPE (22.4-77.2%; mean ± SD 50.4 ± 19.1) that is reflected in the variability of plasma insulin (48.1 ± 30.9 pmol/L) and SI (9.4 ± 5.8 × 10 dL · kg · min · [pmol/L]). FPE could be the nexus of regulation of both plasma insulin and SI.

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes

“…The predominant cellular mechanism is receptor-mediated uptake and therefore a correlation is typically seen between insulin sensitivity and insulin clearance. 49,50 Our data in WE men are in line with these expected relationships. In Americans, which reported lower IDE activity in African Americans.…”

Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes

“…Our experiments showed first that insulin clearance is highly variable in a normal population and second that environmental factors, such as diet, can change clearance in a predictable fashion. We have also shown that fasting insulin levels and insulin sensitivity correlate strongly with first-pass hepatic extraction (33). Thus, hyperinsulinemia in a prediabetes population (cf.…”

“…Slope of portal infusion Slope of systemic infusion Using this direct measurement, we were surprised to discover that even in a population of normal animals, there was a remarkable variance in first-pass hepatic insulin extraction, varying over a 3.5-fold range: from 22% to 77%, with a 20% coefficient of variation among individuals (33). Statistical analysis and repeated measurements support the reproducibility of this measurement in a single individual, with a measurement coefficient of variation of 3-12% (33). Thus, direct measures of insulin clearance revealed that this parameter is highly variable, even in a normal population.…”

Hepatic Insulin Clearance in Regulation of Systemic Insulin Concentrations—Role of Carbohydrate and Energy Availability

“…Thus, early changes in hepatic insulin clearance act to regulate systemic insulin availability and thereby affect the response of the peripheral tissues. In this context, it is of interest that 40 h of moderate hyperinsulinemia induces peripheral insulin resistance in healthy lean subjects (85) and that a low first-pass hepatic insulin extraction seems to determine peripheral insulin resistance in dogs (12).…”

“…Splanchnic extraction of peripherally administered insulin is 50-70% when directly measured by the hepatic venous catheter technique, and this represents almost exclusively hepatic clearance (8)(9)(10). For endogenous insulin, hepatic extraction is of even greater importance due to the direct delivery to the portal vein (11,12). The kidneys are the main site of extrasplanchnic insulin clearance, with additional contributions resulting from uptake and degradation by peripheral insulinsensitive tissues, i.e., skeletal muscle and adipose tissue (10).…”