Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: Effects of fat composition and gender

K J Newens, A K Thompson, K G Jackson, C M Williams, K J Newens, A K Thompson, K G Jackson, C M Williams

Abstract

Background and aims: We have reported that adverse effects on flow-mediated dilation of an acute elevation of non-esterified fatty acids rich in saturated fat (SFA) are reversed following addition of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA), and hypothesised that these effects may be mediated through alterations in insulin signalling pathways. In a subgroup, we explored the effects of raised NEFA enriched with SFA, with or without LC n-3 PUFA, on whole body insulin sensitivity (SI) and responsiveness of the endothelium to insulin infusion.

Methods and results: Thirty adults (mean age 27.8 y, BMI 23.2 kg/m(2)) consumed oral fat loads on separate occasions with continuous heparin infusion to elevate NEFA between 60 and 390 min. For the final 150 min, a hyperinsulinaemic-euglycaemic clamp was performed, whilst FMD and circulating markers of endothelial function were measured at baseline, pre-clamp (240 min) and post-clamp (390 min). NEFA elevation during the SFA-rich drinks was associated with impaired FMD (P = 0.027) whilst SFA + LC n-3 PUFA improved FMD at 240 min (P = 0.003). In males, insulin infusion attenuated the increase in FMD with SFA + LC n-3 PUFA (P = 0.049), with SI 10% greater with SFA + LC n-3 PUFA than SFA (P = 0.041).

Conclusion: This study provides evidence that NEFA composition during acute elevation influences both FMD and SI, with some indication of a difference by gender. However our findings are not consistent with the hypothesis that the effects of fatty acids on endothelial function and SI operate through a common pathway. This trial was registered at clinical trials.gov as NCT01351324 on 6th May 2011.

Keywords: Fatty acids; Flow-mediated dilatation; Hyperinsulinaemic-euglycaemic clamp; Insulin signalling; Nitric oxide.

Copyright © 2015 Elsevier B.V. All rights reserved.

Figures

Figure 1
Figure 1
Change in a) FMD, b) Serum NOx and c) Plasma ET-1 after insulin infusion (240 min–390 min) in females (n ≥ 13) and males (n ≥ 13) following consumption of SFA (white bars) and SFA + LC n-3 PUFA (grey bars). Data are presented as mean ± SEM. There was no difference in any measure between fat loads, significant differences within a gender group is denoted by † (P < 0.05).
Figure 2
Figure 2
Plasma a) NEFA and b) TG following consumption of SFA () or SFA + LC n-3 PUFA (), solid lines represent the females (n = 15) and broken lines the males (n = 14). Data are presented as mean ± SEM. For both analytes, there was a significant effect of time (P < 0.001).

References

    1. Kim J.A., Montagnani M., Koh K.K., Quon M.J. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006;113(15):1888–1904.
    1. Muniyappa R., Montagnani M., Koh K.K., Quon M.J. Cardiovascular actions of insulin. Endocr Rev. 2007;28(5):463–491.
    1. Itani S.I., Ruderman N.B., Schmieder F., Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes. 2002;51(7):2005–2011.
    1. Belfort R., Mandarino L., Kashyap S., Wirfel K., Pratipanawatr T., Berria R., et al. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes. 2005;54(6):1640–1648.
    1. Lind L., Fugmann A., Branth S., Vessby B., Millgard J., Berne C., et al. The impairment in endothelial function induced by non-esterified fatty acids can be reversed by insulin. Clin Sci (Lond) 2000;99(3):169–174.
    1. Galgani J.E., Uauy R.D., Aguirre C.A., Diaz E.O. Effect of the dietary fat quality on insulin sensitivity. Br J Nutr. 2008;100(3):471–479.
    1. Jackson K.G., Armah C.K., Minihane A.M. Meal fatty acids and postprandial vascular reactivity. Biochem Soc Trans. 2007;35(Pt 3):451–453.
    1. Wang X.L., Zhang L., Youker K., Zhang M.X., Wang J., LeMaire S.A., et al. Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes. 2006;55(8):2301–2310.
    1. Xiao-Yun X., Zhuo-Xiong C., Min-Xiang L., Xingxuan H., Schuchman E.H., Feng L., et al. Ceramide mediates inhibition of the AKT/eNOS signaling pathway by palmitate in human vascular endothelial cells. Med Sci Monit. 2009;15(9) BR254-61.
    1. Kim F., Tysseling K.A., Rice J., Pharm M., Haji L., Gallis B.M., et al. Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta. Arterioscler Thromb Vasc Biol. 2005;25(5):989–994.
    1. Khan F., Elherik K., Bolton-Smith C., Barr R., Hill A., Murrie I., et al. The effects of dietary fatty acid supplementation on endothelial function and vascular tone in healthy subjects. Cardiovasc Res. 2003;59(4):955–962.
    1. Tagawa H., Shimokawa H., Tagawa T., Kuroiwa-Matsumoto M., Hirooka Y., Takeshita A. Long-term treatment with eicosapentaenoic acid augments both nitric oxide-mediated and non-nitric oxide-mediated endothelium-dependent forearm vasodilatation in patients with coronary artery disease. J Cardiovasc Pharmacol. 1999;33(4):633–640.
    1. Goodfellow J., Bellamy M.F., Ramsey M.W., Jones C.J., Lewis M.J. Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. J Am Coll Cardiol. 2000;35(2):265–270.
    1. Newens K.J., Thompson A.K., Jackson K.G., Wright J., Williams C.M. DHA-rich fish oil reverses the detrimental effects of saturated fatty acids on postprandial vascular reactivity. Am J Clin Nutr. 2011;94(3):742–748.
    1. Thompson A.K., Newens K.J., Jackson K.G., Wright J., Williams C.M. Glu298Asp polymorphism influences the beneficial effects of fish oil fatty acids on postprandial vascular function. J Lipid Res. 2012;53(10):2205–2213.
    1. Thompson A.K., Przemska A., Vasilopoulou D., Newens K.J., Williams C.M. Combined oral contraceptive pills containing desogestrel or drospirenone enhance large vessel and microvasculature vasodilation in healthy premenopausal women. Microcirculation. 2011;18(5):339–346.
    1. DeFronzo R.A., Tobin J.D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214–E223.
    1. Beysen C., Belcher A.K., Karpe F., Fielding B.A., Herrera E., Frayn K.N. Novel experimental protocol to increase specific plasma nonesterified fatty acids in humans. Am J Physiol Endocrinol Metab. 2003;284(1):E18–E24.
    1. Pyke K.E., Tschakovsky M.E. The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol. 2005;568(Pt 2):357–369.
    1. Wang R.X., Chai Q., Lu T., Lee H.C. Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity. Cardiovasc Res. 2011;90(2):344–352.
    1. Huang A., Sun D., Wu Z., Yan C., Carroll M.A., Jiang H., et al. Estrogen elicits cytochrome P450–mediated flow-induced dilation of arterioles in NO deficiency: role of PI3K-Akt phosphorylation in genomic regulation. Circ Res. 2004;94(2):245–252.
    1. Kruszynska Y.T., Worrall D.S., Ofrecio J., Frias J.P., Macaraeg G., Olefsky J.M. Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. J Clin Endocrinol Metab. 2002;87(1):226–234.
    1. Jensen C.B., Storgaard H., Holst J.J., Dela F., Madsbad S., Vaag A.A. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men. J Clin Endocrinol Metab. 2003;88(6):2775–2783.
    1. Storgaard H., Jensen C.B., Bjornholm M., Song X.M., Madsbad S., Zierath J.R., et al. Dissociation between fat-induced in vivo insulin resistance and proximal insulin signaling in skeletal muscle in men at risk for type 2 diabetes. J Clin Endocrinol Metab. 2004;89(3):1301–1311.
    1. Stefan N., Wahl H.G., Fritsche A., Haring H., Stumvoll M. Effect of the pattern of elevated free fatty acids on insulin sensitivity and insulin secretion in healthy humans. Horm Metab Res. 2001;33(7):432–438.
    1. Mostad I.L., Bjerve K.S., Basu S., Sutton P., Frayn K.N., Grill V. Addition of n-3 fatty acids to a 4-hour lipid infusion does not affect insulin sensitivity, insulin secretion, or markers of oxidative stress in subjects with type 2 diabetes mellitus. Metabolism. 2009;58(12):1753–1761.
    1. Morris A.D., Ueda S., Petrie J.R., Connell J.M., Elliott H.L., Donnelly R. The euglycaemic hyperinsulinaemic clamp: an evaluation of current methodology. Clin Exp Pharmacol Physiol. 1997 Jul;24(7):513–518.
    1. Nauck M.A., Blietz R.W., Qualmann C. Comparison of hyperinsulinaemic clamp experiments using venous, 'arterialized' venous or capillary euglycaemia. Clin Physiol. 1996 Nov;16(6):589–602.
    1. Morgantini C., Stea F., Boldrini B., Duranti E., Ghiadoni L., Natali A. Effect of mild hyperinsulinaemia on conduit vessel endothelial function: role of noradrenergic activation. J Hypertens. 2012;30(4):720–724.

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