Measuring and estimating insulin resistance in clinical and research settings

Abstract

The article discusses how to measure insulin resistance in muscle, liver, and adipose tissue in human participants. The most frequently used methodologies to evaluate insulin resistance are described in detail starting from the gold standard, that is, the euglycemic hyperinsulinemic clamp, to the intravenous glucose tolerance test, surrogate indices based on fasting measurements, or dynamic tests (such as oral glucose or mixed meal tolerance tests). The accuracy, precision, and reproducibility of the tests as well as cutoff values are reported.

FIGURE 1

Insulin is secreted by the pancreas in the portal vein and then passes through the liver, which degrades 60% to 70% of secreted insulin, so only 30% to 40% reaches peripheral tissues. Insulin acts at the level of the liver by suppressing endogenous glucose production (EGP), at the level of the muscle by promoting glucose disposal (Rd), and at the level of the adipose tissue by suppressing lipolysis and free fatty acid (FFA) release.

FIGURE 2

The principle behind the euglycemic hyperinsulinemic clamp: insulin infusion will suppress endogenous glucose production (mainly hepatic) and promote glucose disposal (mainly muscular). Insulin sensitivity is measured as the M value as described in the formula. GIR is the glucose infusion rate expressed in mg/kg min, G is the glucose concentration measured at 90 and 120 minutes of the clamp and expressed in mg/dL, V is the glucose volume of distribution that is usually considered 2.5 dL/kg of body weight, and UC is the correction factor for urinary loss of glucose

FIGURE 3

Left panel: Endogenous glucose production (EGP) measured by tracer infusion during fasting conditions (basal) and at different rates of insulin infusions during the euglycemic hyperinsulinemic clamp in groups with different degrees of insulin resistance (i.e., participants without diabetes (ND) or obesity [blue], ND participants with obesity [red], and participants with diabetes [green]). Right panel: The hyperbolic relationship between insulin concentrations and EGP values (same colors used in left panel) (redrawn from Groop et al. [4] and Bonadonna et al. [5])

FIGURE 4

Left panel: examples of data obtained from a 40 mU/min kg euglycemic hyperinsulinemic clamp (EHC), i.e., glucose and insulin concentrations, glucose infusion rates used to measure M value, and tracer enrichment in case a tracer is infused for better estimate of glucose disposal. Right panel: schematic diagram of the devices needed to perform the EHC. TTR, tracer to tracee ratio

FIGURE 5

The standard protocol of the intravenous glucose tolerance test (STANDARD‐IVGTT) consists of a single injection of glucose (0.3 g/kg) and frequent blood sampling during the first minutes after the injection until glucose returns to fasting concentration. Because the decay in glucose concentration might be slow because of insulin resistance or reduced insulin secretion (i.e., in study participants with diabetes), a modified test (MODIFIED‐IVGTT) was designed, and either tolbutamide or insulin is administered at 20 minutes to allow a rapid decay of glucose concentration