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Increased n–6 polyunsaturated fatty acids do not attenuate the effects of long-chain n–3 polyunsaturated fatty acids on insulin sensitivity or triacylglycerol reduction in Indian Asians^1,2,3

¹ From the School of Food Biosciences, University of Reading, Reading, United Kingdom (LMB, SSL, SVML, A-MM, CMW, and JAL), and the School of Health Related Professions, The University of Alabama at Birmingham (BAG).

² Supported by the Food Standards Agency of the United Kingdom.

³ Reprints not available. Address correspondence to JA Lovegrove, Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, PO Box 226, University of Reading, Reading, RG6 6AP United Kingdom. E-mail: j.a.lovegrove{at}reading.ac.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background: Indian Asians in Western countries have a higher rate of coronary artery disease than do the indigenous white populations, and this higher rate may be influenced by a dietary imbalance of n–6 and n–3 polyunsaturated fatty acids (PUFAs).

Objective: The objective of the study was to test the hypothesis that a high background dietary intake of n–6 PUFA attenuates the effects of fish-oil supplementation on insulin sensitivity and associated blood lipids of the metabolic syndrome.

Design: Twenty-nine Indian Asian men were recruited to participate in a 12-wk dietary intervention trial. Volunteers were randomly assigned to receive either a moderate or a high n–6 PUFA diet featuring modified oils and spreads over a 6-wk period. After this 6-wk period, both groups were supplemented with 4.0 g fish oil/d (2.5 g eicosapentaenoic acid + docosahexaenoic acid) for an additional 6 wk in combination with the dietary treatment. Volunteers participated in a postprandial study and an insulin sensitivity test after the 6-wk dietary intervention and again after the fish-oil supplementation period.

Results: There was no significant time x treatment interaction for blood lipids or insulin action after dietary intervention with the moderate or high n–6 PUFA diets in combination with fish oil. After the 6-wk period of fish oil supplementation, fasting and postprandial plasma triacylglycerol concentrations decreased significantly.

Conclusion: The background dietary n–6 PUFA concentration did not modulate the effect of fish-oil supplementation on blood lipids or measures of insulin sensitivity in this ethnic group.

Key Words: Fish oil • Indian Asians • insulin sensitivity • blood lipids • n–6 PUFAs • n–3 PUFAs • coronary artery disease • triacylglycerol

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
It has been suggested that an imbalance in dietary n–6 and n–3 polyunsaturated fatty acids (PUFAs) may be a contributory factor to the insulin resistance and related blood lipid abnormalities of the metabolic syndrome (1) that are prevalent among Indian Asians living in the United Kingdom (2, 3). Previously, a significantly higher intake of PUFAs—mainly as n–6 PUFAs from vegetable oils (4–6)—was reported in Indian Asians than in whites; the Indian Asians also had a significantly lower intake of the cardioprotective n–3 long-chain PUFAs (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than did whites (6, 7). Consistent with the dietary findings, studies reported a higher proportion of total fatty acids as the n–6 PUFAs linoleic acid (LA) and arachidonic acid (AA) and a lower proportion of the n–3 LC-PUFAs in plasma and membrane phospholipids in Indian Asians that in whites (5, 8, 9). Storlien et al (10) showed high skeletal muscle membrane n–6 PUFA to n–3 PUFA ratio in the skeletal muscle membrane to be adversely related to insulin sensitivity, which supports the hypothesis that a high n–6:n–3 dietary PUFA in Indian Asians may contribute to the high prevalence of insulin resistance observed in that ethnic group.

Although there has been much discussion of the potential benefits of n–3 LC-PUFA supplementation on insulin sensitivity, direct evidence of benefits in healthy human subjects is lacking. Animal studies reported that feeding n–3 LC-PUFAs resulted in improvements in insulin sensitivity (11, 12) whereas feeding n–6 PUFAs led to deterioration in insulin sensitivity (13). Among human studies, some report beneficial effect (14–17), and others report a lack of effect of n–3 LC-PUFAs (18, 19) on insulin sensitivity. The differences in these data indicate that clarification of the effects of n–3 LC-PUFAs on insulin sensitivity in humans is required. The Indian Asian population provides an ideal group in which to test this hypothesis because of evidence in Indian Asians of low dietary and tissue n–3 LC-PUFA status and greater susceptibility to insulin resistance (2, 7, 9).

The hypothesis that a high background intake of n–6 PUFAs could attenuate beneficial effects of n–3 LC-PUFA supplementation on blood lipids in Indian Asians was also tested. Potential mechanisms include direct action—ie, competing for transcription factors involved in the hypotriacylglycerolemic actions of n–3 LC-PUFAs—or indirect action—ie, reducing the putative effects of n–3 LC-PUFAs on insulin sensitivity (20). To address the hypothesis on the effects of background dietary intake of n–6 PUFAs with subsequent fish-oil supplementation on fasting and postprandial blood lipids, insulin resistance measured by using the homeostasis assessment model for insulin resistance (HOMA-IR) and insulin sensitivity measured using by the minimal model technique were investigated in Indian Asians.

	SUBJECTS AND METHODS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Subjects
Twenty-nine Indian Asian men aged 35–70 y were recruited from the towns of Reading and Slough and their surrounding areas in the United Kingdom through a combination of newspaper advertisements, distributed flyers, personal contact through the electoral register, and word of mouth. Subjects were recruited on the basis of a screening blood sample and completion of a medical and lifestyle questionnaire. For inclusion in the study, volunteers were required to be normolipidemic (triacylglycerol: 0.5–4 mmol/L; total cholesterol: <8 mmol/L), to have been resident in the United Kingdom for a minimum of 2 y, and to consume at least one traditional Indian Asian meal per day. Exclusion criteria included diagnosed cardiovascular disease, diabetes, liver disease, smoking, hypertension, or a body mass index (BMI; in kg/m²) > 35. In addition, those taking hypolipidemic therapy or other medication known to affect lipid metabolism and those consuming oil-based supplements were excluded. Volunteer characteristics are presented in Table 1. From the total study population, a representative subgroup of 14 was recruited to participate in an insulin sensitivity test (minimal model), as described below. Ethical approval for the study was given by the University of Reading, West Berkshire, East Berkshire, and Hounslow research ethics committees, and all volunteers gave written informed consent before participation.

Dietary intervention
To calculate the n–6 PUFA content of the cooking oils and spreads required to achieve the dietary targets, the total amount of exchangeable fat consumed in a typical Indian Asian diet (37 g; 16 g from spreads and 21 g from cooking oils) was determined from analyses of 5-d diet diaries previously collected from 22 Indian Asian men. Alteration of the n–6 PUFA content of the oils and spreads was achieved by varying the concentrations of monounsaturated fatty acids (MUFAs) and n–6 PUFAs. All other fatty acid classes were maintained constant between the 2 dietary intervention groups. The fatty acid profiles of the oils and spreads used in the 2 dietary intervention groups are presented in Table 2. The fatty acid composition of the platelet membrane phospholipids measured at the beginning and end of the fish-oil supplementation period provided a measure of the subjects’ compliance with the fish-oil supplement protocol, as well as confirmation that the supplement had the capacity to enrich membranes. In addition, a 3-d diet diary was completed by each subject at the beginning and end of the study period. Diet diaries were recorded on 2 weekdays and 1 weekend day, and nutrient intakes were analyzed by using the FOODBASE nutritional database computer program (version 2.0; Institute of Brain Chemistry and Human Nutrition, London). This database was customized by the addition of a range of recipes typically consumed among Indian Asians. Other dishes consumed by the study population but not present in the database were entered into the program for the purpose of the analysis.

Insulin sensitivity assessment
Insulin sensitivity was assessed by using the frequently sampled intravenous glucose tolerance test with minimal model analyses. This technique offers a more robust measure of insulin sensitivity than do surrogate techniques such as HOMA-IR, which derive a measure of insulin sensitivity or resistance from fasting concentrations of insulin and glucose (23). Insulin sensitivity was measured in a subgroup of volunteers (n = 8 and n = 6 volunteers from the moderate and high n–6 PUFA dietary treatment groups, respectively) within 3 d of the postprandial evaluation. Volunteers were asked to refrain from exercise and alcohol and to consume a low-fat evening meal the day before the postprandial study day and to arrive at the Nutrition Unit after a 12-h overnight fast. At the Nutrition Unit, a cannula was inserted into both forearms of each subject under local anesthetic. A bolus of 50% glucose solution (0.3 g/kg body weight; Phoenix Pharma Ltd, Gloucester, United Kingdom) and insulin (0.03 U/kg body weight; Novo Nordisk Pharmaceuticals, Ltd, Crawley, United Kingdom) were infused at 0 and 20 min, respectively, through one cannula, and blood samples were taken through the other cannula at regular intervals over a 3-h period (5 min before and 2, 4, 8, 19, 22, 30, 40, 50, 70, 100, and 180 min after the glucose injection; 24). Plasma glucose and insulin measurements at all time points were entered into the minimal model computer program (version 3.0; Richard N Bergman, University of Southern California, Los Angeles) to ascertain insulin sensitivity (S_i) and glucose effectiveness (S_g) according to mathematical modeling methods (21, 25).

Biochemical analysis
Blood samples were collected into 9-mL potassium EDTA-coated tubes on the postprandial study day and into 5-mL potassium EDTA-coated tubes and 1-mL fluoride oxalate tubes (for the determination of blood glucose) on the insulin sensitivity study day. Blood samples were centrifuged (Megafuge; Heraeus, Brentwood, United Kingdom) at 3000 rpm for 10 min at room temperature. The plasma was stored at –20°C for later measurement of plasma triacylglycerol, NEFAs, insulin, total cholesterol, CRP, and apoB48 concentrations by using plasma from the potassium EDTA-coated tubes and of glucose concentrations by using plasma from the fluoride oxalate tubes. For the analysis of HDL cholesterol, a subsample of plasma was precipitated with dextran sulfate and magnesium chloride to remove the apolipoprotein B-containing lipoproteins (26), and the supernatant was stored at –20°C. Plasma LDL-cholesterol concentrations were determined by using the formula of Friedewald and Levy (27). Plasma collected for the measurement of LDL subclass distribution was stored at 4°C and analyzed within 24 h. Plasma aliquots were stored at –80°C for the measurement of plasma -tocopherol.

Plasma triacylglycerol, glucose, total and HDL cholesterol, and CRP concentrations were measured by using test kits (Instrumentation Laboratories Ltd, Warrington, United Kingdom), and NEFA concentrations were measured by using test kits (Wako NEFA C kit; Alpha Laboratories Ltd, Eastleigh, United Kingdom) on the ILAB 600 automatic analyzer (Instrumentation Laboratories UK Ltd, Warrington, United Kingdom). Insulin was measured by using a specific commercial enzyme-linked immunosorbent assay kit (DakoCytomation, Ely, United Kingdom), -tocopherol was assessed by using HPLC (28), and apoB48 concentrations were measured by using an enzyme-linked immunosorbent assay (29). The mean intraassay and interassay CVs, respectively, for the measurements conducted were 2.1% and 4.0% for total cholesterol, 1.4% and 3.1% for triacylglycerol, 1.0% and 3.7% for glucose, 4.0% and 5.5% for insulin, 1.1% and 1.8% for NEFAs, 1.2% and 4.4% for CRP, 3.0% and 3.7% for -tocopherol, and 5.0% and 9.0% for apoB48. LDL subclasses were measured by using density gradient ultracentrifugation (30). Platelet membrane phospholipid fatty acid composition was measured by using lipid extraction with subsequent quantification of fatty acid methyl esters by gas chromatography (31).

Postprandial triacylglycerol and apoB48 responses are expressed as area under the curve (AUC) (0–480 mins) and incremental area under the curve (IAUC) (0–480 mins), which were calculated by using the trapezoidal rule. The postprandial NEFA response is represented as the percentage of NEFA suppression at 90 min after consumption of the postprandial test breakfast.

Statistical analysis
All statistical analyses were performed by using SPSS software (version 10.0; SPSS Inc, Chicago), and a P value of <0.05 was considered significant. Before statistical analysis, all data were examined for normality by using the Shapiro-Wilks test, and they were log transformed when necessary. Differences in the absolute changes in fasting plasma triacylglycerol; apoB48; NEFAs; total, HDL, and LDL cholesterol; percentage of LDL as LDL₃; CRP; -tocopherol; and postprandial triacylglycerol, apoB48, and NEFA concentrations and measures of insulin action over the 6-wk period of fish-oil supplementation in combination with the dietary treatment were determined by two-factor repeated-measures analysis of variance (ANOVA) with interaction. Changes in platelet membrane phospholipid fatty acid composition were also measured by using two-factor repeated-measures ANOVA with interaction. The main effects of time were investigated by using paired t tests with Bonferroni correction. The main effects of treatment were investigated by using independent-sample t tests. Results are presented as group means (± SEMs).

	RESULTS

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The baseline characteristics of the 29 volunteers who completed the study are presented in Table 1. There were no significant differences in the anthropometric or biochemical characteristics between the moderate and the high n–6 PUFA dietary treatment groups after randomization. Analysis of the 3-d diet diaries collected at the beginning and end of the study found no significant differences in total fat or fatty acid intake between the 2 groups at baseline (data not shown) or between the target and actual fatty acid intakes in either dietary treatment group after the dietary intervention period (Table 3). The actual fatty acid intakes of MUFAs and n–6 PUFAs were significantly lower and higher, respectively, in the high n–6 PUFA dietary treatment group than in the moderate n–6 dietary treatment group (Table 3).

Table 4

Table 5

The change in fasting NEFA concentrations and the percentage of NEFA suppression 90 min postprandially showed no significant differences between either of the dietary treatment groups over the fish-oil supplementation period. Similar findings were identified for total, LDL, and HDL cholesterol. There was no significant difference between the percentages of LDL₃ present in those consuming the moderate or the high n–6 PUFA dietary treatment during the fish-oil supplementation period (Table 5). However, over time there was a reduction (9% for both intervention groups combined) in the percentage of LDL circulating as LDL₃, which had a tendency to be greater in the high n–6 PUFA dietary treatment group than in the moderate n–6 PUFA group. In addition, no significant changes were observed in circulating CRP concentrations, which represent a marker of inflammatory function, or in -tocopherol concentrations, which were measured as a marker of antioxidant status.

Insulin sensitivity or resistance
There were no significant changes in insulin resistance (HOMA-IR) between or within the moderate and the high n–6 dietary PUFA groups during the fish-oil treatment period. In the insulin sensitivity substudy (n = 8 and n = 6 volunteers, respectively, from the moderate and high n–6 PUFA dietary treatment groups), no significant differences were observed in S_i or S_g over the 6-wk fish-oil supplementation period in those consuming either the moderate or the high n–6 PUFA background diet. Similarly, there were no significant differences between the 2 dietary treatment groups for either of the parameters measured (Table 5).

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The purpose of the present study was to determine whether the background dietary intake of n–6 PUFA modulates the effects of fish-oil supplementation on fasting and postprandial blood lipids and on insulin sensitivity (minimal model) or insulin resistance (HOMA-IR) in Indian Asians. Results from this study showed that, contrary to the hypothesis, a high dietary intake of n–6 PUFAs did not attenuate the beneficial effects of fish-oil supplementation on the plasma triacylglycerol response. In addition, n–3 LC-PUFA supplementation, whether given in combination with a high or a moderate n–6 LC-PUFA background dietary intake, had no effect on insulin resistance (HOMA-IR) or insulin sensitivity (minimal model).

It was previously suggested that the n–6:n–3 PUFAs in the Indian Asian diet may be a factor in the increased risk of coronary artery disease reported in this population (1). Investigations of the platelet membrane phospholipid fatty acid content in Indian Asians found differences in fatty acid compositions and reported a greater proportion of n–6 PUFA, linoleic acid, and arachidonic acid in combination with a reduced proportion of the n–3 LC-PUFAs, EPA, and DHA in Indian Asians than in whites (8, 9). We hypothesized that an imbalance in dietary n–6:n–3 PUFA may play a significant role in insulin sensitivity, thereby affecting insulin-sensitive values such as plasma triacylglycerol, through alterations of the membrane phospholipid characteristics, such as fluidity (32). We have tested this hypothesis by modifying the n–6 PUFA content of the diet with the use of modified oils and spreads. After the dietary intervention period, the moderate n–6 PUFA dietary treatment group showed a significant increase in the percentage of MUFAs in membrane phospholipids, whereas both dietary treatment groups showed significant increases in total n–3 PUFAs, DHA, and n–6:n–3 dietary PUFAs and a significant decrease in n–6 PUFAs.

For plasma triacylglycerol concentrations, there was no significant interaction between fish-oil supplementation and dietary treatment because fish oil lowered the plasma triacylglycerol concentrations in both treatment groups, irrespective of background dietary n–6 PUFA content. The effects of fish-oil supplementation in combination with both a high and a low n–6 PUFA diet were investigated in one study (33). Although that study did not investigate postprandial triacylglycerol responses, the authors reported significant reductions in fasting triacylglycerol concentrations in both dietary groups, which was consistent with our findings. It was noted in the current study that postprandial reductions in both plasma triacylglycerol and apoB48 concentrations had a tendency to be greater in the high n–6 PUFA treatment group than in the moderate n–6 PUFA treatment group, an effect that would be the opposite of the hypothesized effect. It is possible that a combination of high n–6 PUFAs and high n–3 PUFAs in the background diet operated to produce a more pronounced reduction in the lipemic response to standard fat-containing meals in the high n–6 PUFA group than in the low n–6 PUFA group. This possibility would certainly be consistent with previous reports showing reductions in postprandial responses to meals of various fatty acid compositions when the background diet is rich in n–6 PUFAs (34). In the current study, fish-oil supplementation did not compromise the antioxidant status of the study group: no changes in -tocopherol concentrations were observed after supplementation.

It is believed that plasma triacylglycerol concentrations directly influence the compositional characteristics of the LDL subclasses through neutral lipid exchange (35) and that a high plasma triacylglycerol concentration is associated with a preponderance of LDL₃ (36). The denser proatherogenic LDL₃, formed as a result of the hydrolysis of LDL triacylglycerol by lipases, is reported to be more prevalent in Indian Asians than in whites (36, 37), which is consistent with the generally higher plasma triacylglycerol values that are observed in Indian Asians. Although there was no significant effect of the interaction between dietary treatment and fish-oil supplementation on LDL₃ concentrations, in the current study, there was a tendency for a greater reduction in the percentage of circulating LDL₃ in the high n–6 PUFA dietary treatment group, which is consistent with the trend toward greater triacylglycerol reduction in this intervention group. However, we are cautious in making this interpretation because, before fish-oil supplementation, the high n–6 PUFA dietary treatment group had a higher percentage of circulating LDL₃ than did the moderate n–6 PUFA dietary treatment group (50% and 38%, respectively). The findings in this parallel study design may therefore reflect regression toward the mean over time.

The present study showed that n–3 LC-PUFA supplementation did not have any significant effect on insulin resistance (HOMA-IR) or insulin sensitivity (minimal model). Several animal studies have reported the beneficial effects on insulin sensitivity of feeding with n–3 LC-PUFAs (11, 12, 38) and the negative effect of supplementation with n–6 PUFAs (13, 39). Epidemiologic studies support these findings in animals and ascertained that habitual fish intake is inversely associated with the incidence of impaired glucose tolerance and type 2 diabetes (14, 15). However, although beneficial effects of n–3 LC-PUFA supplementation on insulin sensitivity were reported in diabetics and persons with impaired glucose tolerance (16, 17), positive effects have not been consistently reported in persons with normoglycemia (18) or in moderately hypertriacylglycerolemic (40), hypertensive (19), or healthy (41) volunteers. The current study did not identify any statistical associations between phospholipid fatty acid composition and insulin sensitivity (data not shown), and we conclude that moderate n–3 LC-PUFA supplementation over a 6-wk period has little or no effect on insulin sensitivity in normoglycemic Indian Asian subjects.

Elevated plasma NEFA concentrations are implicated as an important link between insulin resistance and the abnormal blood lipid profile reported in the metabolic syndrome, and they are thought to reflect impaired insulin-induced suppression of adipocyte lipolysis (42). Exaggerated delivery of NEFAs to the liver increases the output of VLDL, which increases competition with chylomicrons for triacylglycerol clearance and leads to further elevation in both fasting and postprandial triacylglycerol concentrations. In addition, NEFAs may exacerbate the hyperglycemia observed in insulin resistance through enhancing hepatic glucose output from gluconeogenesis (43). Despite the putative importance of NEFAs in the metabolic syndrome, few studies have measured the effects of fish-oil supplementation on NEFA concentrations (41, 44, 45). In the present study, no effect of fish-oil supplementation was observed on either fasting NEFA concentrations or the suppression of NEFA release at 90 min postprandially, which was measured as a percentage of suppression from baseline, in Indian Asian volunteers consuming either a moderate or a high n–6 PUFA diet.

This study has shown that the dietary intake of n–6 PUFAs does not modulate the effects of dietary fish-oil supplementation on fasting and postprandial blood lipids in Indian Asians. Contrary to the hypothesis that a high n–6 dietary intake could attenuate the beneficial effects of fish-oil supplementation on blood lipids linked with insulin resistance, we found no significant effect of dietary n–6 PUFA content on fasting triacylgycerol and observed a tendency toward a greater reduction in postprandial plasma triacylglycerol and apoB48 concentrations in the high n–6 PUFA group. No effect of n–3 LC-PUFA supplementation on insulin resistance (HOMA-IR) or insulin sensitivity (minimal model) was observed in these healthy subjects, albeit after a relatively short period of supplementation. Future studies with larger numbers of subjects are required to determine the effects of fish-oil supplementation on insulin action in healthy persons.

	ACKNOWLEDGMENTS

 
We thank John Wright, who performed cannulation and insulin infusions on volunteers for the postprandial and insulin sensitivity study days; Bruce Griffin, who analyzed the LDL₃; and Van den Bergh Oils (Crawley, United Kingdom), which donated the oils and spreads for the study. We also thank Jan Luff, William Roberts, Vanessa McConkey, and all the volunteers who devoted their time and effort to this study.

JAL, AMM, and CMW designed the study; LMB, SVML, SSL, and BAG collected and analyzed the data; and LMB, JAL, and CMW wrote the manuscript. The authors had no personal or financial conflicts of interest.

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