A novel minimal model to describe NEFA kinetics following an intravenous glucose challenge

Abstract

Dynamics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification if we are to understand the etiology of such diseases as type 1 and 2 diabetes, as well as metabolic syndrome and obesity, or if we are to elucidate the mechanism of action of various interventions. We present a new compartmental model that employs the pattern of plasma glucose concentrations in healthy young adults to predict dynamic changes that occur in plasma NEFA concentrations during either a glucose-only intravenous glucose tolerance test, or an insulin-modified intravenous tolerance test, or a modified protocol during which variable-rate glucose infusions were administered to prevent plasma glucose from declining below 100 mg/dl. The model described all of the major features of NEFA response to an intravenous glucose tolerance test, including an initial latency phase, a phase during which plasma NEFA concentrations plummet to a nadir, and a rebound phase during which plasma NEFA concentrations may rise to a plateau concentration, which may be substantially higher than the initial basal NEFA concentration. This model is consistent with physiological processes and provides seven adjustable parameters that can be used to quantify NEFA production (lipolysis) and utilization (oxidation). When tested on data from the scientific literature, the range in estimated rate of lipolysis was 24-36 micromol.l(-1).min(-1) and for NEFA oxidation rate was 25-54 micromol.l(-1).min(-1). All model parameters were well identified and had coefficients of variation < 15% of their estimated values. It is concluded that this model is suitable to describe NEFA kinetics in human subjects.

NEFA minimal model parameters estimated from the oral glucose tolerance test and the meal tolerance test

“…Considering just the period between 0 and 1,000 min, the overall adjusted R 2 was 0.85 for the HIGH-GLUC treatment and 0.61 for the HIGH-FRUC treatment. These R 2 values are substantially less than the R 2 values obtained previously with IVGTT data (9) and less than the R 2 values obtained with the OGTT data from studies 1 and 2. We speculate that because the meal study tests were of such long duration, a number of uncontrolled and unmodeled factors may have been responsible for the discrepancies between data and model fits.…”

“…The NEFA model was implemented using WinSAAM (36) (available from http://www.winsaam.org), and the model was fitted to the NEFA and glucose data, as described previously (9, 10). Our original intention was to focus on the Complete Boston model of NEFA kinetics (9), which was developed using intensively sampled data from the IVGTT in humans. We wanted to determine whether it could be employed to model NEFA data apropos of the OGTT and the MTT.…”

“…Recently, a novel model has been presented to describe plasma nonesterified fatty acid (NEFA) kinetics in humans apropos of the intravenous glucose tolerance test (IVGTT) (9). This model (henceforth called the Boston Complete NEFA model) is novel in that it utilizes plasma glucose concentrations as the principal driver that influences NEFA kinetics.…”

The influence of placental metabolism on fatty acid transfer to the fetus

“…The 13 C-fatty acid amount used in the experiments were much lower than the metabolic K m . Thus, equations 10 and 11 can be simplified: (31,32) at their reference values (either best-fit estimates or as given in Table 1) to evaluate the impact on the uptake and delivery for 13 C-fatty acid and the maternal and fetal recovery for endogenous fatty acids. An analysis of the controlling effects of the parameters and mechanisms affecting uptake and transfer in the system was carried out in which the MVM maximum rate v MVM was varied over three orders of magnitude.…”

Mixed Meal Model in Type 1 Diabetes

“…Representative models of fatty acid dynamics include Boston model [6] and others with detailed consideration of counter-regulatory hormones [7], whereas mixed meal models that include gut transit and the ultimate impact on BG levels are, to our knowledge, limited to that of Roy and colleagues [8]. Its physiological representation, nonetheless, includes two 'remote' compartments with unknown physiological conceptualization and a questionable direct incorporation of fatty acid into the glucose compartment to represent insulin resistance.…”