Trafficking of nonesterified fatty acids in insulin resistance and relationship to dysglycemia

Abstract

In adipose, insulin functions to suppress intracellular lipolysis and secretion of nonesterified fatty acid (NEFA) into plasma. We applied glucose and NEFA minimal models (MM) following a frequently sampled intravenous glucose tolerance test (FSIVGTT) to assess glucose-specific and NEFA-specific insulin resistance. We used total NEFA and individual fatty acids in the NEFA MM, comparing the model parameters in metabolic syndrome (MetSyn) subjects (n = 52) with optimally healthy controls (OptHC; n = 14). Results are reported as mean difference (95% confidence interval). Using the glucose MM, MetSyn subjects had lower [-73% (-82, -57)] sensitivity to insulin (S_i) and higher [138% (44, 293)] acute insulin response to glucose (AIR_g). Using the NEFA MM, MetSyn subjects had lower [-24% (-35, -13)] percent suppression, higher [32% (15, 52)] threshold glucose (g_s), and a higher [81% (12, 192)] affinity constant altering NEFA secretion (ϕ). Comparing fatty acids, percent suppression was lower in myristic acid (MA) than in all other fatty acids, and the stearic acid (SA) response was so unique that it did not fit the NEFA MM. MA and SA percent of total were increased at 50 min after glucose injection, whereas oleic acid (OA) and palmitic acid (PA) were decreased (P < 0.05). We conclude that the NEFA MM, as well as the response of individual NEFA fatty acids after a FSIVGTT, differ between OptHC and MetSyn subjects and that the NEFA MM parameters differ between individual fatty acids.

Keywords: adipose; compartmental modeling; fatty acids; insulin resistance.

Fig. 1.

Application of the minimal model of glucose and insulin dynamics following a frequently sampled intravenous glucose tolerance test (FSIVGTT) using the MinMod Millennium software (9). A: compartmental model for insulin and glucose kinetics. B: geometric mean data (symbols) and model predicted curves for plasma insulin (dotted lines) and glucose (solid lines) concentrations vs. time for 14 optimally healthy control (OptHC; blue) and 52 metabolic syndrome (MetSyn; red) subjects. A glucose challenge was injected at time 0, and starting at 20 min, insulin was infused for 5 min. Goodness of fit of model predictions to observed data was strong for both groups, with an R² of 99%. C: model-simulated insulin in the functional compartment vs. time for the OptHC (blue) and MetSyn (red) groups. D: insulin-attributable glucose disposal (IAGD) calculated as a function of time. IAGD starts higher in MetSyn, but OptHC subjects spike at a higher level following the insulin infusion at 20 min. AIR_g, acute insulin response to glucose; DI, disposition index; G₀, plasma glucose concentration immediately following glucose challenge; G_b, baseline plasma glucose concentration; GEZI, glucose effectiveness with zero insulin; HOMA, homeostatic model assessment; I_b, basal insulin; P(2), rate of insulin removal from the functional compartment; P(3), insulin removal from the functional compartment; S_g, glucose effectiveness; S_i, insulin sensitivity.

Fig. 2.

Application of the minimal model of nonesterified fatty acid (NEFA) dynamics following a frequently sampled intravenous glucose tolerance test (FSIVGTT). A: NEFA minimal models (MM) (6) for glucose and NEFA kinetics. B: geometric mean data (red and blue diamonds) and model predicted curves for plasma glucose (dotted lines) and NEFA (solid lines) concentrations vs. time for 14 optimally healthy control (OptHC; blue) and 52 metabolic syndrome (MetSyn; red) subjects. A glucose challenge was injected at time 0, and starting at 20 min, insulin was infused for 5 min. A fractional standard deviation (FSD) of 0.02–0.08 was used as a weighting factor on the NEFA data. Parameter identifiability was assessed and a FSD of < 0.5 was considered well-identified. Goodness of fit was evaluated by comparing the model predictions with the observed values; R² was calculated using linear regression analysis. Model results were then used to calculate the rates of lipolysis (LIP₀) and clearance at time 0 (CL₀) and as a function of time. NEFA %suppression was calculated from initial NEFA concentration (NEFA₀) and NEFA concentration at the nadir. C: model simulated glucose action in the functional compartment vs. time for the OptHC (blue) and MetSyn (red) groups. D: lipolysis and clearance rates were calculated as a function of time. Both lipolysis and clearance rates are generally lower and are suppressed less after insulin infusion in MetSyn subjects. g_s, threshold glucose concentration; k_c, rate of %transfer of glucose into the functional compartment from the plasma compartment; K_NEFA, NEFA %clearance rate; Φ, Michaelis-Menton affinity constant; S_NEFA, initial rate of NEFA secretion; τ, delay time before NEFA suppression begins.

Fig. 3.

Best-fit models for each individual fatty acid. Using the nonesterified fatty acid (NEFA) minimal models (MM), data for each individual fatty acid were normalized to baseline and are reported as fraction of baseline. Calculated stearic acid (SA) values from the NEFA MM are shown here, although acceptable model convergence could not be achieved. Values shown are visually representative of the SA data. A: for optimally healthy control (OptHC) subjects, the best-fit model was different from the total for all fatty acids. Suppression of palmitic acid (PA) and oleic acid (OA) was greater, and suppression of SA and myristic acid (MA) was lower compared with total NEFA. B: in metabolic syndrome (MetSyn) subjects, individual fatty acid response was closer to the total NEFA response. Data represented here are geometric mean data from MetSyn and OptHC groups (MetSyn n = 7; OptHC n = 8).

Fig. 4.

Fatty acid composition of nonesterified fatty acid (NEFA) fraction changes with time following glucose challenge. A: %suppression of each fatty acid was reduced in in metabolic syndrome (MetSyn); suppression of myristic acid (MA; blue) was lower than all other fatty acids using Tukey post hoc analysis. H, optimally healthy; M, metabolic syndrome. ^A,BGroups with different letters are statistically different from each other. B: changes in fatty acid %total are most pronounced in optimally healthy control (OptHC) subjects at 50–60 min and then return to baseline. Stearic acid (SA; green) increases as %total, whereas oleic acid (OA; orange) and palmitic acid (PA; brown) decrease. C: MA and SA increase and PA and OA decrease as %total NEFA at 50 min following glucose challenge in OptHC subjects. However, MA and PA do not change in MetSyn subjects. Differences were tested by repeated-measures ANOVA, adjusted for age and sex and considered significant at P < 0.05. *%Suppression was significantly different in optimally healthy (OH) compared with metabolic syndrome (MS) subjects.