Associations of plasma phospholipid cis-vaccenic acid with insulin resistance markers in non-diabetic men with hyperlipidemia

Fatty acids (FAs) are crucial for cell membrane function and signaling, influencing various metabolic processes. Dysregulation of FA metabolism is implicated in insulin resistance (IR), a hallmark of metabolic syndrome and type 2 diabetes mellitus (T2DM). The roles of different FA classes in IR are complex and not fully understood. While saturated fatty acids (SFAs), particularly palmitic acid, are often associated with IR, the roles of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) are less clear. Some studies suggest that cis-vaccenic acid (cVA), a MUFA, may be associated with improved insulin sensitivity and cardiovascular health. However, findings are inconsistent. This study aimed to investigate the association between the proportion of cVA in plasma phospholipids (PL) and markers of IR in non-diabetic men with hyperlipidemia, a condition characterized by high cardiovascular risk and often associated with IR.

Existing literature presents conflicting findings on the relationship between fatty acids and insulin resistance. While high levels of saturated fatty acids, especially palmitic acid, are generally associated with insulin resistance, the roles of PUFAs and MUFAs are more nuanced. Studies on linoleic acid (LA, 18:2n-6) have shown both positive and negative associations with T2DM risk. Similarly, the impact of palmitoleic acid (POA), a MUFA, on cardiometabolic health remains controversial. Some studies have linked POA to beneficial effects on glucose and lipid homeostasis, while others show it is associated with abdominal obesity and hyperglycemia. The elongation of POA produces cVA (18:1n-7), and studies on cVA have yielded mixed results. Some studies suggest a beneficial effect on cardiometabolic health, demonstrating an inverse relationship between erythrocyte membrane cVA and heart failure risk and inverse association of plasma phospholipid cVA with incident T2DM risk. However, other studies have not found these associations. This discrepancy highlights the need for further research, especially considering potential sex and ethnic differences in FA metabolism.

This was a cross-sectional study involving 231 men (median age 50) with newly diagnosed hyperlipidemia and a control group of 50 healthy men. Patients were referred to a lipid clinic and met inclusion criteria including LDL-C >3.0 mmol/L or triacylglycerols >1.70 mmol/L, while excluding those with lipid-lowering medication, excessive alcohol use, hormonal therapy, or specific medical conditions. Six weeks prior, they were advised to follow the AHA Step One diet. Basic clinical parameters, anthropometric measurements (BMI, waist circumference, waist-hip ratio), blood pressure, and body fat mass (using bioelectrical impedance) were recorded. Blood samples were collected to assess various biochemical parameters: fasting glucose, insulin, HOMA-IR (homeostasis model assessment of insulin resistance), NEFA (non-esterified fatty acids), apolipoprotein A-I and B, lipid profiles, hs-CRP (high sensitivity C-reactive protein), and uric acid. Plasma phospholipid FA composition was analyzed using gas chromatography-flame ionization detection (GC-FID). Dietary habits were assessed via a 3-day dietary questionnaire. The main group was stratified into quartiles based on cVA content in plasma PL, and the upper (Q4) and lower (Q1) quartiles were compared. Statistical analysis included independent t-tests, Wilcoxon tests (for non-normal data), and multivariate linear regression with backward stepwise analysis, with Benjamini-Hochberg correction for multiple comparisons.

Compared to the Q1 group (low cVA), the Q4 group (high cVA) demonstrated significantly lower plasma insulin (p<0.05), HOMA-IR (p<0.01), and apolipoprotein B (p<0.001), and significantly higher total plasma NEFA (p<0.01). Other parameters (age, BMI, waist circumference, blood pressure, lipid profiles excluding apolipoprotein B, fasting glucose, hs-CRP) showed no significant differences between groups. Fatty acid profile analysis revealed that the Q4 group had a higher molar percentage of total MUFAs (due to increased oleic acid, palmitoleic acid, and cis-vaccenic acid) and a lower proportion of n-6 PUFAs (primarily γ-linolenic acid and dihomo-γ-linolenic acid). Estimated activities of desaturases and elongases showed increased delta-9-desaturase (D9D) activity for both stearic and palmitic acids, and increased ELOVL5 activity in the Q4 group. D6D activity was significantly lower in Q4. Correlations within the entire study group showed that cVA negatively correlated with insulin, HOMA-IR, and apolipoprotein B. Stepwise regression analysis confirmed the independent association of 18:1n-7c (cVA) with insulin and HOMA-IR. The Q4 group also had significantly lower levels of conjugated dienes in LDL particles (CD-LDL), a marker of oxidative stress.

This study's findings support the hypothesis that higher plasma PL cVA is associated with improved insulin sensitivity in hyperlipidemic men. The lower insulin, HOMA-IR, and apolipoprotein B levels, alongside the elevated NEFA in the Q4 group, suggest a potential beneficial metabolic effect of cVA. The observed differences in fatty acid profiles, particularly the higher MUFAs and lower n-6 PUFAs in Q4, align with previous research suggesting the importance of MUFA in improving insulin sensitivity and reducing cardiovascular risk. The lower CD-LDL in Q4 points to a potential reduction in oxidative stress, further contributing to improved metabolic health. However, the increased NEFA in Q4 might seem contradictory, although this could be linked to effects on ectopic fat deposition and the action of cVA on PPARγ in adipose tissue. This study is limited by its cross-sectional design; hence causal relationships cannot be firmly established. Further research is needed to elucidate the mechanisms linking cVA to insulin sensitivity and to confirm findings in other populations and using longitudinal studies.

This study demonstrates a significant association between higher plasma phospholipid cis-vaccenic acid and improved insulin sensitivity markers in hyperlipidemic men. The findings highlight the complex roles of individual fatty acids in metabolic health and suggest a potential beneficial role for cVA. Further research is necessary to investigate the underlying mechanisms and replicate these findings in larger, more diverse populations, including women and individuals with T2DM. Longitudinal studies are also warranted to confirm the causal relationship.

This study's cross-sectional design limits the ability to establish causality. The sample comprises only men, and results may not be generalizable to women. The dietary assessment used a 3-day questionnaire, which may not capture dietary intake accurately. Information on physical activity levels was unavailable, a factor known to influence metabolic health. Finally, the study did not analyze the profile of individual NEFAs and dietary levels of specific MUFAs and PUFAs.