The Measurement of Insulin Clearance

Abstract

Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations.

Figure 1

The insulin secretion and clearance rationale. Insulin and C-peptide are equimolarly secreted by the pancreatic β-cells. While C-peptide clearance is considered negligible, insulin undergoes hepatic (by the liver) and extrahepatic (by other tissues such as kidney or muscle) clearance.

Figure 2

PPII clamp for measuring first-pass hepatic insulin extraction. A: The insulin profile during the PPII experiments. For portal infusion protocol (white circles), insulin 1 = 3.0 pmol·kg⁻¹·min⁻¹, insulin 2 = 6.0 pmol·kg⁻¹·min⁻¹, and insulin 3 = 9.0 pmol·kg⁻¹·min⁻¹. For peripheral infusion protocol (black squares), insulin 1 = 1.5 pmol·kg⁻¹·min⁻¹, insulin 2 = 3.0 pmol·kg⁻¹·min⁻¹, and insulin 3 = 4.5 pmol·kg⁻¹·min⁻¹. One-half of the portal infusion rates were used in the peripheral protocol for matching systemic concentrations. B: The infusion rate versus steady-state plasma insulin concentrations. The correlation coefficient r for peripheral infusion versus steady-state concentrations (black squares) was 0.99, and slope, m_pe, was 53.1 kg·min⁻¹·L⁻¹. For portal infusion versus steady-state concentrations (white circles), r = 0.98 and slope, m_po, was 26.7 kg·min⁻¹·L⁻¹. First-pass hepatic insulin extraction (%) = [1 − (m_po/m_pe)]·100 = 50%. Each data point is a mean ± SE of n = 9. Adapted with permission from Asare-Bediako et al. (17).

Figure 3

The three-compartment model (hepatic, vascular, and extravascular pools) used to describe insulin kinetics. Adapted with permission from Eaton et al. (27).

Figure 4

The rationale for assessing insulin hepatic extraction from modeling insulin and C-peptide data. Adapted with permission from Campioni et al. (35). CP (pmol/L), C-peptide concentration in the accessible compartment; HE (%), hepatic insulin extraction; I (pmol/L), plasma insulin concentration, accessible to measurement; IDR (pmol/min), post-hepatic insulin delivery rate; ISR (pmol/min), insulin secretion rate.

Figure 5

A graphical representation of the mathematical model used to estimate hepatic and extrahepatic insulin clearance. Adapted with permission from Polidori et al. (2).