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HDL kinetics, fish oils and diabetes
Atherosclerosis 159 (2001) 243– 244 www.elsevier.com/locate/atherosclerosis
Letter to the Editors HDL kinetics, fish oils and diabetes Frenais et al. [1] present a study of the effect of omega-3 fatty acids on the kinetics of HDL apoAI in a group of type 2 diabetic subjects. Such studies are to be commended as they focus on the effect of interventions on reverse cholesterol transport (RCT) in a population at high risk of atherosclerosis, and in whom kinetic assessment of RCT may be more informative than plasma HDL levels alone [2]. Plasma concentrations of HDL do not necessarily reflect the antiatherogenic potential for RCT [2]. It may, however, be premature to draw conclusions about the effect of dietary omega-3 fatty acids on apoAI metabolism in this study because of a number of experimental and analytical issues that must be addressed. This open study is an uncontrolled observation of five diabetic subjects before and after 8 weeks dietary supplementation with maxEPA capsules. The study group comprised four apparently pre-menopausal women and one male patient. The ages reported for the patients suggest that some of the women were post-menopausal, a state that may bear on the assessment of HDL metabolism. Such heterogeneity within a small sample group would suggest that this study is underpowered to adequately test the hypothesis that omega-3 fatty acids affect HDL metabolism in diabetes. Plasma HDL apoAI concentrations were not altered with omega-3 fatty acid treatment. This observation may be at variance with the known PPARa activation potential of fish oil [3]. However, the absence of an effect may be due to persistent insulin resistance in the patients on fish oil treatment [4]. Despite this, the authors observed that treatment reduced both apoAI fractional catabolic rate (FCR) and production rate. It is important to note, however, that the largest changes in apoAI FCR and production rate were seen in those subjects who lost weight or showed improved glycaemic control during the study. Weight loss and improved glycaemia by decreasing triglyceride loading of VLDL [5], would decrease the heteroexchange of neutral lipids between
lipoproteins. With respect to HDL, the particles would be larger and have a lower FCR of apoAI [6]. Hence, separating the effect of such changes from the potential effect of omega-3 fatty acid is not possible. Compartment models of HDL metabolism have identified complex metabolic pathways and kinetic heterogeneity within the HDL fraction [7]. Such models have been developed primarily using radioactive tracer data. The design of such studies, however, is key to maximising the information content of the tracer data that is generated. Short duration studies (12 –15 h), such as the one in question [1], that use primed constant infusion protocols maximise tracer recycling and reduce the information content of the kinetic data, thereby limiting modelling options for analysis of the tracer data [8]. Longer-term studies using a bolus or short-term tracer infusion followed by washout will optimally identify the kinetic heterogeneity associated with the HDL fraction. We recommend that the important issue of the effect of fish oil on HDL kinetics in diabetic and related dyslipidaemic states be examined in randomised, placebo controlled trials employing bolus infusion of isotopes and multicompartmental modelling. Future studies should also address the independent effects of the two principal fatty acids present in fish oil, eicosapentaenoic acids and docosahexaenoic acids, on HDL apoAI and apoAII kinetics.
References [1] Frenais R, Ouguerram K, Maugeais C, Mahot P, Charbonnel B, Magot T, Krempf M. Effect of dietary omega-3 fatty acids on high-density lipoprotein apolipoprotein AI kinetics in type II diabetes mellitus. Atherosclerosis 2001;157:131– 5. [2] Von Eckardstein A, Nofer J-R, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001;21:13– 27. [3] Torra IP, Chinetti G, Duval C, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice. Curr Opin Lipidol 2001;12:245– 54. [4] Duvillard L, Pont F, Florentin E, Gambert P, Verges B. Inefficiency of insulin therapy to correct apolipoprotein A-I metabolic
0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 1 ) 0 0 6 9 0 - 6
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Letter to the Editors
abnormalities in non-insulin-dependent diabetes mellitus. Atherosclerosis 2000;152:229 –37. [5] Taskinen MR, Beltz WF, Harper I, Fields RM, Schonfeld G, Grundy SM, Howard BV. Effects of NIDDM on very-low-density lipoprotein triglyceride and apolipoprotein B metabolism. Studies before and after sulfonylurea therapy. Diabetes 1986;35:1268 – 77. [6] Brinton EA, Eisenberg S, Breslow JL. Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution. Arterioscler Thromb 1994;14:707 – 20. [7] Fisher WR, Venkatakrishnan V, Zech LA, Hall CM, Kilgore LL, Stacpoole PW, Diffenderfer MR, Friday KE, Sumner AE, Marsh JB. Kinetic evidence for both a fast and a slow secretory pathway for apolipoprotein A-I in humans. J Lipid Res 1995;36:1618 – 28.
[8] Barrett PHR, Foster DM. Design and analysis of lipid tracer kinetic studies. Curr Opin Lipidol 1996;7:143 – 8.
P. Hugh R. Barrett*, Gerald F. Watts Department of Medicine Uni6ersity of Western Australia West Australian Heart Research Institute, Royal Perth Hospital, GPO Box X2213 Perth, WA 6847, Australia E-mail: [email protected] 4 July 2001
Letter to the Editors HDL kinetics, fish oils and diabetes Frenais et al. [1] present a study of the effect of omega-3 fatty acids on the kinetics of HDL apoAI in a group of type 2 diabetic subjects. Such studies are to be commended as they focus on the effect of interventions on reverse cholesterol transport (RCT) in a population at high risk of atherosclerosis, and in whom kinetic assessment of RCT may be more informative than plasma HDL levels alone [2]. Plasma concentrations of HDL do not necessarily reflect the antiatherogenic potential for RCT [2]. It may, however, be premature to draw conclusions about the effect of dietary omega-3 fatty acids on apoAI metabolism in this study because of a number of experimental and analytical issues that must be addressed. This open study is an uncontrolled observation of five diabetic subjects before and after 8 weeks dietary supplementation with maxEPA capsules. The study group comprised four apparently pre-menopausal women and one male patient. The ages reported for the patients suggest that some of the women were post-menopausal, a state that may bear on the assessment of HDL metabolism. Such heterogeneity within a small sample group would suggest that this study is underpowered to adequately test the hypothesis that omega-3 fatty acids affect HDL metabolism in diabetes. Plasma HDL apoAI concentrations were not altered with omega-3 fatty acid treatment. This observation may be at variance with the known PPARa activation potential of fish oil [3]. However, the absence of an effect may be due to persistent insulin resistance in the patients on fish oil treatment [4]. Despite this, the authors observed that treatment reduced both apoAI fractional catabolic rate (FCR) and production rate. It is important to note, however, that the largest changes in apoAI FCR and production rate were seen in those subjects who lost weight or showed improved glycaemic control during the study. Weight loss and improved glycaemia by decreasing triglyceride loading of VLDL [5], would decrease the heteroexchange of neutral lipids between
lipoproteins. With respect to HDL, the particles would be larger and have a lower FCR of apoAI [6]. Hence, separating the effect of such changes from the potential effect of omega-3 fatty acid is not possible. Compartment models of HDL metabolism have identified complex metabolic pathways and kinetic heterogeneity within the HDL fraction [7]. Such models have been developed primarily using radioactive tracer data. The design of such studies, however, is key to maximising the information content of the tracer data that is generated. Short duration studies (12 –15 h), such as the one in question [1], that use primed constant infusion protocols maximise tracer recycling and reduce the information content of the kinetic data, thereby limiting modelling options for analysis of the tracer data [8]. Longer-term studies using a bolus or short-term tracer infusion followed by washout will optimally identify the kinetic heterogeneity associated with the HDL fraction. We recommend that the important issue of the effect of fish oil on HDL kinetics in diabetic and related dyslipidaemic states be examined in randomised, placebo controlled trials employing bolus infusion of isotopes and multicompartmental modelling. Future studies should also address the independent effects of the two principal fatty acids present in fish oil, eicosapentaenoic acids and docosahexaenoic acids, on HDL apoAI and apoAII kinetics.
References [1] Frenais R, Ouguerram K, Maugeais C, Mahot P, Charbonnel B, Magot T, Krempf M. Effect of dietary omega-3 fatty acids on high-density lipoprotein apolipoprotein AI kinetics in type II diabetes mellitus. Atherosclerosis 2001;157:131– 5. [2] Von Eckardstein A, Nofer J-R, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001;21:13– 27. [3] Torra IP, Chinetti G, Duval C, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice. Curr Opin Lipidol 2001;12:245– 54. [4] Duvillard L, Pont F, Florentin E, Gambert P, Verges B. Inefficiency of insulin therapy to correct apolipoprotein A-I metabolic
0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 1 ) 0 0 6 9 0 - 6
244
Letter to the Editors
abnormalities in non-insulin-dependent diabetes mellitus. Atherosclerosis 2000;152:229 –37. [5] Taskinen MR, Beltz WF, Harper I, Fields RM, Schonfeld G, Grundy SM, Howard BV. Effects of NIDDM on very-low-density lipoprotein triglyceride and apolipoprotein B metabolism. Studies before and after sulfonylurea therapy. Diabetes 1986;35:1268 – 77. [6] Brinton EA, Eisenberg S, Breslow JL. Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution. Arterioscler Thromb 1994;14:707 – 20. [7] Fisher WR, Venkatakrishnan V, Zech LA, Hall CM, Kilgore LL, Stacpoole PW, Diffenderfer MR, Friday KE, Sumner AE, Marsh JB. Kinetic evidence for both a fast and a slow secretory pathway for apolipoprotein A-I in humans. J Lipid Res 1995;36:1618 – 28.
[8] Barrett PHR, Foster DM. Design and analysis of lipid tracer kinetic studies. Curr Opin Lipidol 1996;7:143 – 8.
P. Hugh R. Barrett*, Gerald F. Watts Department of Medicine Uni6ersity of Western Australia West Australian Heart Research Institute, Royal Perth Hospital, GPO Box X2213 Perth, WA 6847, Australia E-mail: [email protected] 4 July 2001