Effects of Dietary n-3 Fatty Acids on Hepatic and Peripheral Insulin Sensitivity in Insulin-Resistant Humans

Abstract

Objective: Dietary n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), prevent insulin resistance and stimulate mitochondrial biogenesis in rodents, but the findings of translational studies in humans are thus far ambiguous. The aim of this study was to evaluate the influence of EPA and DHA on insulin sensitivity, insulin secretion, and muscle mitochondrial function in insulin-resistant, nondiabetic humans using a robust study design and gold-standard measurements.

Research design and methods: Thirty-one insulin-resistant adults received 3.9 g/day EPA+DHA or placebo for 6 months in a randomized double-blind study. Hyperinsulinemic-euglycemic clamp with somatostatin was used to assess hepatic and peripheral insulin sensitivity. Postprandial glucose disposal and insulin secretion were measured after a meal. Measurements were performed at baseline and after 6 months of treatment. Abdominal fat distribution was evaluated by MRI. Muscle oxidative capacity was measured in isolated mitochondria using high-resolution respirometry and noninvasively by magnetic resonance spectroscopy.

Results: Compared with placebo, EPA+DHA did not alter peripheral insulin sensitivity, postprandial glucose disposal, or insulin secretion. Hepatic insulin sensitivity, determined from the suppression of endogenous glucose production by insulin, exhibited a small but significant improvement with EPA+DHA compared with placebo. Muscle mitochondrial function was unchanged by EPA+DHA or placebo.

Conclusions: This study demonstrates that dietary EPA+DHA does not improve peripheral glucose disposal, insulin secretion, or skeletal muscle mitochondrial function in insulin-resistant nondiabetic humans. There was a modest improvement in hepatic insulin sensitivity with EPA+DHA, but this was not associated with any improvements in clinically meaningful outcomes.

Trial registration: ClinicalTrials.gov NCT01686568.

Figure 1

Hyperinsulinemic-euglycemic clamp. The glucose infusion rates (GIRs) required to maintain euglycemia in 10-min intervals during the 6-h insulin infusion in placebo (A) and n-3 (B) groups at baseline and follow-up. The average glucose infusion rate during the final 60 min of each stage of the clamp (low insulin and high insulin) in placebo (C) and n-3 (D) groups at baseline and follow-up. EGP measured in the basal fasting state and during low-dose insulin (E and F). EGP suppression was greater with n-3 (G). Data bars are means ± SEM. Data points represent individual subject responses with dotted lines linking baseline with follow-up observations. *P < 0.05 for the group × time interaction.

Figure 2

Mixed-meal tolerance test. Plasma glucose (A and B), insulin (C and D), and C-peptide (E and F) concentrations measured 6 h after ingestion of a liquid meal were similar in both groups and unchanged with either intervention. Data are means ± SEM.

Figure 3

Mitochondrial function in skeletal muscle. Mitochondrial oxygen consumption rates (J_O2) were measured under state 3 respiration conditions with carbohydrate-based mitochondrial substrates (A) and lipid substrates (B). Mitochondrial coupling was assessed from the respiratory control ratio (RCR) (C) and ADP:O ratio (D). Oxidative capacity measured in vivo by magnetic resonance spectroscopy (E). Data bars are means ± SEM. Data points represent individual subject responses with dotted lines linking baseline (●) with follow-up (○) observations.