A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults

Abstract

Relative to diets enriched in palmitic acid (PA), diets rich in oleic acid (OA) are associated with reduced risk of type 2 diabetes. To gain insight into mechanisms underlying these observations, we applied comprehensive lipidomic profiling to specimens collected from healthy adults enrolled in a randomized, crossover trial comparing a high-PA diet to a low-PA/high-OA (HOA) diet. Effects on insulin sensitivity (SI) and disposition index (DI) were assessed by intravenous glucose tolerance testing. In women, but not men, SI and DI were higher during HOA. The effect of HOA on SI correlated positively with physical fitness upon enrollment. Principal components analysis of either fasted or fed-state metabolites identified one factor affected by diet and heavily weighted by the PA/OA ratio of serum and muscle lipids. In women, this factor correlated inversely with SI in the fasted and fed states. Medium-chain acylcarnitines emerged as strong negative correlates of SI, and the HOA diet was accompanied by lower serum and muscle ceramide concentrations and reductions in molecular biomarkers of inflammatory and oxidative stress. This study provides evidence that the dietary PA/OA ratio impacts diabetes risk in women.

FIG. 1.

The FA composition of the diet is reflected in a broad range of circulating and intramuscular lipids (see text for abbreviations, except where indicated). A and B: Heat maps depicting diet-induced changes in the PA/OA ratio of blood and muscle lipids according to the scale on the right (total FA [TFA]). Change scores were calculated from absolute values of log base 5 transformed PA/OA data in the fasted or fed state on the HPA versus HOA diet (HPA/HOA). Each square represents an individual subject, and black indicates a missing value. S_I reflects insulin sensitivity measured in the fasted state. Results in men and women were combined to show diet effects on serum concentrations (μmol/L) of nonesterified PA and OA (C); serum concentration (μmol/L) of total PA and OA (D); the PA/OA ratio in serum NEFA, TFA, AC, and PC (E); and the PA/OA ratio in skeletal muscle lipid metabolites (F): TAG, DAG, PC, and LCAC. *P ≤ 0.001, **P ≤ 0.01 denote diet effect.

FIG. 2.

The HOA diet improved insulin secretion and sensitivity in women. A: DI. B and C: Insulin sensitivity index (S_I) in individual women and men measured during the HOA and HPA diets. D: S_I. Relationship between diet-induced change in S_I (HOA − HPA) (S_I Change) and VO_2peak in women (E) and men (F) (*Spearman r = 0.90; P ≤ 0.001). In women, during the HOA diet, S_I correlated inversely with PCF1-Fasted (G) (***r = −0.786, P = 0.021) and PCF1-Fed (H) (**r = −0.850, P = 0.004). ***P ≤ 0.05 denotes a diet effect.

FIG. 3.

Dietary FA composition affected lipid biomarkers of insulin resistance in women. A: Serum ceramide concentrations measured in the fasting and fed states. B: Relationship between S_I and MCAC measured in the fed state during the HPA diet (**r = −0.783, P = 0.013). C: Relationship between S_I and the serum MCAC/LCAC measured in the fed state during the HPA diet (**r = −0.867, P = 0.002). D: Serum MCAC/LCAC ratio in the fed state. Muscle biopsy specimens harvested in the fasted and fed states were used to quantify intramuscular concentrations of TAG (E), DAG (F), and LCAC and MCAC (G) and total ceramides (H). **P ≤ 0.01, ***P ≤ 0.05 denote a diet effect.

FIG. 4.

Dietary FA composition affected lipid biomarkers of insulin resistance in men. A: Serum ceramide concentrations measured in the fasting and fed states. B: Relationship between S_I and MCAC measured in the fed state during the HPA diet (r = −0.33, P = 0.38). C: Relationship between S_I and the serum MCAC/LCAC measured in the fed state during the HPA diet (r = 0.05, P = 0.90). D: Serum MCAC/LCAC ratio in the fed state. Muscle biopsy specimens harvested in the fasted and fed states were used to quantify intramuscular concentrations of TAG (E), DAG (F), and LCAC and MCAC (G) and total ceramides (H). **P ≤ 0.01, ***P ≤ 0.05 denote a diet effect.

FIG. 5.

Dietary FA composition affected molecular markers of insulin resistance and oxidant stress in women. Skeletal muscle biopsies harvested in the fasted state were used to assess pJNK using the Bio-Plex phosphoprotein assay (Bio-Rad); results are shown for individual women (A) and group averages measured after each diet (B). Blood samples harvested in the fasted state were used to measure serum IL-6 (C) and serum ferritin (D). **P ≤ 0.01, ***P ≤ 0.05 denote a diet effect.

FIG. 6.

Dietary FA composition did not affect molecular markers of insulin resistance and oxidant stress in men. Skeletal muscle biopsies harvested in the fasted state were used to assess pJNK using the Bio-Plex phosphoprotein assay; results are shown for individual men (A) and group averages measured after each diet (B). Blood samples harvested in the fasted state were used to measure serum IL-6 (C) and serum ferritin (D).