Sex-Specific Differences in Lipid Metabolism and Insulin Resistance: Protective Mechanisms in Females

Objectives: Males and females show differences in lipid metabolism, but the mechanisms and their effects on insulin sensitivity need further study. This research examines how lipid infusion affects metabolism differently in males and females, highlighting protective mechanisms in females against insulin resistance.

Methods: Ten metabolically healthy, lean participants (6 males, 4 females) with normal glucose tolerance (NGT) underwent randomized glycerol (CON) and lipid infusions (LIP) followed by a euglycemic-hyperinsulinemic clamp. Female participants were studied in the luteal phase to account for hormonal influences. Blood samples were collected at baseline, during glycerol/lipid infusion and during the clamp, allowing for comprehensive metabolic profiling. Systemic insulin sensitivity (M-value, M/I ratio), adipose-IR, triglycerides (TG), and free fatty acids (FFA), were assessed. Metabolic flexibility was evaluated as ΔRQ (change from baseline to the end of the clamp). Additional biomarkers, including adiponectin and leptin, were analysed to investigate potential sex-specific regulatory mechanisms. Statistical analyses included paired t-tests and two-way ANOVA to compare responses between infusion types and sexes.

Results: A 73% increase in FFA led to a>20% reduction of whole-body insulin sensitivity in 4/6 males, while all females remained below this threshold of clinically relevant changes. After 4 hours, TG levels were 77% higher in males (344±103 vs. 194±48 mg/dL; p=0.02) despite similar lipid infusion rates and peak TG values, suggesting differences in lipid clearance. ΔRQ did not differ (-0.12±0.07 vs. -0.06±0.102; p=0.76), but males showed a significant RQ drop (0.66±0.08 to 0.55±0.02; p=0.002), indicating greater lipid oxidation. FFA suppression during hyperinsulinemic clamp was greater in females (71.80±8.10 vs. 54.40±10.50%; p=0.02). Adipo-IR increased by 75% in males (p<0.0001), with no significant change in females, who had higher adiponectin levels (p<0.05), supporting higher adipose tissue insulin sensitivity and enhanced lipid storage capacity in females.

Conclusion: These findings reveal that males develop greater systemic IR during increased lipid availability compared to females. This difference is likely due to male’s lower adipose tissue lipid storage capacity despite more pronounced lipid oxidation presumably in skeletal muscle. Females demonstrate adaptive advantages, such as enhanced free fatty acid suppression and higher adiponectin levels, which protect against lipid-induced IR. These findings highlight the importance of adipose tissue function in sex-specific metabolic adaptations providing valuable insights for targeted, sex-specific strategies to improve insulin sensitivity and reduce metabolic disease risk.

Publication History

Article published online:
28 May 2025