Insulin activation of plasma nonesterified fatty acid uptake in metabolic syndrome

Abstract

Objective: Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. The goal of the present study was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics.

Methods and results: Fatty acid kinetics were measured during a meal tolerance test and insulin sensitivity assessed by intravenous glucose tolerance test in overweight human subjects (n=15; body mass index, 35.8 ± 7.1 kg/m(2)). Non-steady state tracer kinetic models were formulated and tested using ProcessDB software. Suppression of adipose fatty acid release, by itself, could not account for postprandial nonesterified fatty acid concentration changes, but adipose suppression combined with insulin activation of fatty acid uptake was consistent with the measured data. The observed insulin K(m) for nonesterified fatty acid uptake was inversely correlated with both insulin sensitivity of glucose uptake (intravenous glucose tolerance test insulin sensitivity; r=-0.626; P=0.01) and whole body fat oxidation after the meal (r=-0.538; P=0.05).

Conclusions: These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states.

Trial registration: ClinicalTrials.gov NCT01371396.

Conflict of interest statement

DISCLOSURE

R.D. Phair and S.A. Lapidot are employed by Integrative Bioinformatics, Inc, developer of the ProcessDB© modeling software used in this study. The authors had no conflicts of interest except for R.D. Phair, who is Chief Science Officer of Integrative Bioinformatics, Inc.

Figures

FIGURE 1. Concentrations of glucose and insulin, and RaNEFA before and after a standardized meal. Concentrations of NEFA with model fits

Mean plasma concentrations of (A) glucose and (B) insulin, and (C) mean total fatty acid delivery to the plasma (RaNEFA) in subjects with metabolic syndrome (n = 15) fed a standardized meal at t=0 (12 noon). For details of meal, see Methods. The lines on graphs A–C represent simple linear interpolations between data points. By contrast, the lines on graph D are model solutions. The dotted line represents the model with constant plasma NEFA FCR and is incapable of accounting for the experimental data (filled triangles) representing the mean plasma NEFA concentration time course after the test meal. This model was constrained using the directly measured total RaNEFA as the only input to plasma NEFA and the value of the constant FCR was optimized during the fitting process. The solid line, by contrast, is the model solution that includes insulin-sensitive fatty acid uptake. Parameter values for this fit for the Puptake rate law (see text) are DelayFacUptake = 11 min; kmaxFacUptake = 0.063 min−1; KmFacUptake = 14 pmol/kgBW and hFacUptake = 4.2; kdiff = 0.112 min−1.

FIGURE 2. NEFA model fits to the measured meal-induced plasma NEFA concentrations and RaNEFA fluxes and IVGTT-induced plasma NEFA transients in 3 representative subjects

Symbols represent measured data; the lines represent the model fits. Panels A and B are derived from the MTT while panel C represents data for the IVGTT. Note differing y-axes between the three subjects within each row. NEFA data were collected for 6h after the MTT and for 3h after the IVGTT. For all 15 subjects, mean parameter values are listed in table 1. Individual fits for each of the 15 subjects’ data can be found in supplementary figures I, II, and III.

FIGURE 3. INEFA model diagram

The INEFA model of insulin-regulated plasma NEFA dynamics including two insulin-regulated processes: 1) fatty acid release from adipocytes and 2) fatty acid uptake by peripheral tissues (adipose, heart, skeletal muscle). Model state variables are molecules (indicated by molecule names in rectangles) in particular physiological places (adipose, blood plasma, and peripheral tissues) indicated by the labeled “swim lanes.” Dotted arrows represent the physiological distribution and intracellular signaling delays associated with the two insulin-mediated regulatory control systems.

FIGURE 4. Concentrations of glucose, insulin and NEFA during the IVGTT

Data are mean ± SE for 15 subjects.

FIGURE 5. Relationships between INEFA model parameters, body fat, and metabolic variables

The figures demonstrate the relationships between parameters obtained from the INEFA model (KiInsulin for insulin suppression of fatty acid release and KmFacUptake for insulin stimulation of fatty acid uptake), those obtained during the IVGTT (SI), and during the MTT (RaNEFA, body composition, and plasma concentrations of NEFA and long-chain acylcarnitines, LCAC). Abbreviations: MTT, meal-tolerance test; FatOx, whole-body fat oxidation assessed by indirect calorimetry, and LCAC represent the saturated, mono-, and poly-unsaturated acylcarnitines with chain lengths from 12–18.