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 (n = 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 (r_s = 0.74), FPE and fasting insulin (r_s = -0.64), and SI and fasting insulin (r_s = -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 × 10⁴ dL · kg^-1 · min^-1 · [pmol/L]^-1). FPE could be the nexus of regulation of both plasma insulin and SI.

Figure 1

PPII method for measuring FPE. A: Insulin profile during the PPII experiments. Insulin 1, 3.0 and 1.5 pmol/kg/min intraportal and peripheral infusions, respectively. Insulin 2, 6.0 and 3.0 pmol/kg/min intraportal and peripheral infusions, respectively. Insulin 3, 9.0 and 4.5 pmol/kg/min intraportal and peripheral infusions, respectively. B: Infusion rate versus steady-state plasma insulin with slope m. For portal and peripheral infusion, respectively, r_s = 0.98 and 0.99. Slope of the portal infusion plot (m_po) was 25.8 kg * min/mL and that of the peripheral infusion (m_pe) was 52.0 kg * min/mL for n = 12. FPE (%) = [1 − (m_po/m_pe)] * 100 = 50.4%; for derivation of equation refer to calculations in research design and methods.

Figure 2

A: Correlation between FPE and SI. B: Correlation between FPE and fasting insulin. C: Correlation between SI and fasting insulin.

Figure 3

A: Correlation between FPE and SiP. B: Correlation between FPE and SiHGO.

Figure 4

A: Correlation between FPE and INSR. B: Correlation between FPE and CEACAM1. C: Correlation between FPE and IDE.

Figure 5

A: Correlation between fasting HGO and INSR. B: Correlation between fasting HGO and FPE.

Figure 6

Distribution of FPE of 18 dogs. The mean of 53.4% is indicated by the dashed line (SD 19.5). Previously published baseline data of six dogs (3) were included to increase the sample size in the assessment of the FPE distribution.