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Metabolism. 2016 Jan;65(1):66-72. doi: 10.1016/j.metabol.2015.10.011. Epub 2015 Oct 9.

Synergistic association of elevated serum free fatty acid and glucose levels with large arterial stiffness in a general population: The Nagahama Study.

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Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address:
Department of Health Informatics, Kyoto University School of Public Health, Kyoto, Japan.
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Kyoto, Japan.
Center for Preventive Medical Science, Chiba University, Chiba Japan.



Previous studies have reported that artificial increases in circulating free fatty acid (FFA) levels might have adverse effects on the vasculature. However, whether or not this effect can be extrapolated to physiological variations in FFA levels has not been clarified. Given that FFAs exert a lipotoxic effect on pancreatic β-cells and might directly damage the arterial endothelium, we hypothesized that these adverse effects might synergize with hyperglycemia.


A total of 9396 Japanese subjects were included in the study. Serum FFA levels were measured at baseline examination. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness.


As serum levels of FFA were markedly lower in subjects with higher insulin level, a significant association between FFA levels and baPWV was observed only in subjects with blood samples taken under fasting (≥12 h, P<0.001) or near-fasting (5-11 h, P<0.001) conditions, and not in those taken under non-fasting (<5 h, P=0.307) conditions. Although type 2 diabetes and HbA1c showed a strong association with baPWV, the association between FFA level and baPWV remained significant (β=0.052, P<0.001) after adjustment for glycemic levels. In addition to their direct relationship, FFA and glucose levels were synergistically associated with baPWV (FFA(⁎)glucose; β=0.036, P<0.001). Differences in baPWV between the lowest and highest subgroups divided by a combination of FFA and glucose reached approximately 300 cm/s.


Physiological variations in FFA concentrations might be a risk factor for large arterial stiffness. FFA and hyperglycemia exert a synergistic adverse effect on the vasculature.


Arterial stiffness; Free fatty acid; Hyperglycemia; Insulin

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