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Lipids and Atherosclerosis Research Unit, Hospital Universitario Reina Sofía, Córdoba, Spain and * UMR 476-INSERM/1260-INRA, University and Central Analytical Laboratory, Ste Marguerite University Hospital, Marseille, France
2To whom correspondence should be addressed. E-mail: md1lomij{at}uco.es.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • apoE gene promoter (–219G/T) polymorphism • dietary intervention • insulin sensitivity • genetics
Insulin resistance has been associated with type 2 diabetes mellitus (T2DM),3 obesity, hypertension, coronary heart disease (CHD), and a dyslipidemic profile characterized by high plasma triacylglycerol (TG) and LDL cholesterol (LDL-C) concentrations and a low HDL cholesterol (HDL-C) (1). The genetic background of T2DM and insulin resistance is complex and heterogeneous and is related not only to genes linked to glucose and insulin metabolism, but also to genes seemingly unrelated to carbohydrate metabolism (2,3).
Apolipoprotein E (apoE) plays an important role in lipid metabolism, both promoting efficient uptake of triacylglycerol-rich lipoproteins (TRL) from the circulation and taking part in the cellular cholesterol efflux and reverse cholesterol transport (4). It has been suggested that the effect of apoE on LDL-C concentration may require cofactors to activate the receptor-mediated uptake of this lipoprotein because apoE is not a structural part of LDL (5). One of these cofactors could be insulin. Thus, previous data suggest that the uptake of apoE-enriched lipoproteins is doubled or tripled when rat isolated adipocytes are exposed to physiological concentrations of insulin (6), and there is evidence suggesting that the apoE genotypes may modify the effect of insulin on CHD or some CHD risk factors, including BMI, plasma TG, and total and LDL-C plasma concentration (7–11). Studies assessing associations between insulin resistance and apoE genotypes have had contradictory results. Some studies found that fasting and 2-h postload insulin and glucose concentration were higher in apoE4 subjects, whereas others did not report this relation (7–12), suggesting that other genetic or environmental factors may be involved in the link between apoE gene and insulin resistance.
In accordance with this hypothesis, a polymorphism in the proximal promoter region of the apoE gene was described at position –219 G/T (13,14). The –219T allele was associated with decreased transcriptional activity (13) and plasma apoE concentration (15,16), prolonged and enhanced postprandial lipemic response (16), increased concentration of glucose 2 h after an oral glucose tolerance test (17), increased LDL-C concentrations and susceptibility to oxidation in response to a diet rich in saturated fat (18), and increased risk of myocardial infarction (15) and premature CHD (17).
Insulin sensitivity (IS) is determined by the interaction between genetic and environmental factors, including diet (19). Thus, our goal was to study whether the presence of the apoE gene promoter (–219G/T) polymorphism determines insulin sensitivity in response to changes in the quantity and quality of dietary fat in healthy young adults with the apoE3/E3 genotype.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Diets. The study design included an initial 28-d period during which all subjects consumed a saturated fat (SFA)-enriched diet, with 15% protein (% of energy in the total diet), 47% carbohydrate (CHO) and 38% fat [20% SFA (% of energy in the total diet), 12% monounsaturated fatty acid (MUFA) and 6% polyunsaturated fatty acid (PUFA)]. After this period, volunteers were randomly assigned to 1 of 2 diet sequences. Subjects (n = 22) consumed a MUFA-rich diet containing 15% protein, 47% CHO, and 38% fat (<10% SFA, 6% PUFA, 22% MUFA) for 28 d. This diet was followed for 28 d by consumption of a CHO-rich diet containing 15% protein, 55% CHO and <30% fat (<10% SFA, 6% PUFA, 12% MUFA). The other 21 subjects consumed the CHO diet before the MUFA diet. The cholesterol intake was constant (<300 mg/d) during the 3 periods. During the MUFA diet period, 80% of the MUFA content was provided by virgin olive oil, which was used for cooking, salad dressing, and as a spread. Carbohydrate intake for the CHO diet period was based on the consumption of biscuits, jam, and bread. Butter and palm oil were used during the SFA dietary period.
The composition of the experimental diets was calculated using the USDA (23) food tables and Spanish food composition tables for local foodstuffs (24). All meals were prepared in the hospital kitchen and were supervised by a dietitian. Lunch and dinner were eaten in the hospital dining room, and breakfast and an afternoon snack were eaten in the medical school cafeteria. Menus (n = 14) were prepared with regular solid foods and rotated during the experimental period. Duplicate samples from each menu were collected, homogenized, and stored at –70°C. Protein, fat, and carbohydrate contents of the diet were analyzed by standard methods (25). Dietary compliance was verified by analyzing the fatty acids in plasma LDL-C esters at the end of each dietary period (26). The study took place from January through March to minimize seasonal effects and academic stress.
Lipids analysis and biochemical determinations. Venous blood samples for insulin, glucose, lipid, and apolipoprotein analysis were collected into EDTA-containing (1 g/L) tubes from all subjects after a 12-h overnight fast at the beginning of the study and at the end of each dietary period. Plasma was obtained by low speed centrifugation (1500 x g) for 15 min at 4°C within 1 h of venipuncture. To reduce interassay variation, plasma was stored at –80°C and analyzed at the end of the study. Plasma total cholesterol (TC) and TG concentrations were measured using enzymatic techniques (27,28). HDL-C was measured after precipitation with phosphotungstic acid (29). ApoA-I and apoB were determined by immunoturbidimetry (30). The plasma apoE concentration was measured using an immunonephelometric method on a BN ProSpec System with commercial kits (Dade Behring). LDL-C concentration was calculated using the Friedewald formula (31). NEFA concentrations were analyzed by an enzymatic colorimetric assay (Boehringer Mannheim) (32).
Glucose suppression test. A modified insulin suppression test was carried out on all of the subjects at the end of each dietary period (33,34). The technique used in the present study to quantify insulin sensitivity was the insulin suppression test, a simple and cost-effective test for the measurement of insulin resistance, which has been used increasingly in recent years. The study began at 0800 h, after subjects had fasted for 12 h. A continuous infusion of somatostatin (214 nmol/h), insulin [180 pmol/(m2 · min)] and glucose [13.2mmol/(m2 · min)] were infused in the same vein. Somatostatin was used to inhibit endogenous insulin secretion. Blood was sampled every 30 min for the first 2.5 h, by which time steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations were achieved. Blood was then sampled at 10-min intervals for the last 30 min (at min 150, 160, 170, and 180) for measurement of plasma glucose and insulin concentrations. We considered the mean of these 4 values to determine the SSPG and SSPI concentrations. Because SSPI concentrations were similar in all subjects, SSPG concentrations provided a measure of the ability of insulin to promote the disposal of infused glucose. Subjects with high SSPG are relatively more insulin resistant than those with lower SSPG (33).
DNA amplification and genotyping. Genomic DNA extraction and apoE E2/E3/E4 and –219G/T genotypes were determined as previously described (16,18). Digested DNA was separated by electrophoresis on an 8% nondenaturing polyacrylamide gel at 150 V for 2 h. Bands were visualized by silver staining. Samples containing the T allele of –219G/T polymorphism were amplified a second time to verify the genotype.
Statistical methods. We used ANOVA for repeated measures to test the effects of the apoE gene promoter (–219G/T) polymorphism on plasma SSPG, NEFA, fasting glucose, fasting insulin, TC, LDL-C, HDL-C, TG, apoE, apoA-I, and apoB concentrations at the end of each dietary period. ANOVA was used to test the effect of the replacement of a SFA-rich diet by a MUFA- or CHO-rich diet within a genotype or a gender group. When the F-test was significant, Tukey’s post-hoc test was used to identify between-group differences. To determine whether plasma NEFA concentration was correlated with plasma SSPG concentration, we used the Pearson correlation test. Independent sample t test was made between the 2 groups that consumed the MUFA then CHO vs. CHO then MUFA diet to test whether the MUFA-CHO differences depended on whether MUFA or CHO was first (order effects). Plasma TG and apoE concentrations were log-transformed before statistical analyses. Differences were considered significant at P < 0.05. Statistical analyses were conducted using the SPSS statistical software, version 9.0.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Experimental animal models showed that insulin action may be modulated by replacing not only the amount of total fat, but also the type of fat. Studies in humans have had different results, probably due to the small number of subjects involved in those studies (35). A recent multicenter trial including a large healthy population showed that a change from an SFA-rich diet to one rich in MUFA improved IS (36). In agreement with these results, our group showed that shifting from an SFA-rich diet to a MUFA olive oil–rich diet also improved IS in young subjects (22). Both studies were performed under strictly controlled conditions using natural foods, thus increasing the generalization of the findings.
Although evidence exists suggesting that the apoE genotypes modulate the effect of insulin on CHD or some CHD risk factors, including BMI, plasma TG, and TC and LDL-C plasma concentrations (7–11), studies assessing associations between apoE gene polymorphism and insulin resistance have had contradictory results. Some studies found that fasting and 2-h postload insulin and glucose concentrations were higher in apoE4 subjects, whereas others did not report this relation (7–12), suggesting that other genetic or environmental factors may be involved in the link between apoE gene and insulin resistance.
In accordance with this hypothesis, a polymorphism in the proximal promoter region of the apoE gene was described recently at position –219 G/T; this polymorphism produces variations in the transcriptional activity of the gene (13,14) and is associated with an increased risk of myocardial infarction (15) and premature CHD (17). However, the mechanisms by which the –219T allele enhances atherothrombosis are yet to be elucidated. In a previous study (15), the –219G/T polymorphism did not modify baseline plasma lipid or lipoprotein concentrations, as in our study. The authors speculated that the –219TT genotype could increase the risk of myocardial infarction at a local level by modifying the macrophage apoE expression, but there are no experimental data to corroborate this hypothesis. In a previous study, the –219T allele was associated with lower postprandial apoE concentration and a higher postprandial response in large and small TRL (16). It is possible that the enlarged pool of circulating TRL could also increase plasma fatty acid concentrations by saturating peripheral removal mechanisms, thus contributing to establishing an insulin-resistant state (37). This fact could explain our results because carriers of the –219T allele had a lower IS. Furthermore, our results agree with a previous study in which the –219T allele was associated with a higher concentration of glucose 2 h after an oral glucose tolerance test (17).
Our study clearly shows that gender interacts with genotype and diet to determine apoE concentration. In the liver, apoE expression is regulated by diet (38,39), and hormones such as the thyroid hormone, insulin, growth hormones, and estrogens (40). Many of the effects of estrogens arise at the genomic level via the classical molecular mechanism of estrogens binding to nuclear estrogens receptors, ESR1 and ESR2. This is followed by binding of estrogens receptors to consensus estrogens response elements (ERE) in the target gene and leads to altered transactivation of gene expression (41). A recent study reported an allelic-dependent regulation of apoE gene expression in response to estrogens by the –219G/T polymorphism (42). This phenomenon is related to a differential ESR1 binding to ERE-like sequences in the promoter region. Thus, estrogens diminish the differences in activity between the T and G forms, most likely enhancing the transcriptional activity of the –219T allele. This phenomenon would explain why we did not find differences in the plasma apoE concentration in women. Unlike in women, our results showed that diet interacts with the –219G/T polymorphism to determine apoE concentration in men. Thus, male carriers of the –219T allele had lower plasma apoE concentrations than men homozygous for the G allele after consumption of the SFA diet. However, the mechanism by which apoE expression is regulated by SFA in male carriers of the –219T allele is not known. Bohnet et al. (43) demonstrated that apoE concentrations in VLDL help to determine VLDL affinity for the apoE-binding receptors, and likely subsequent variations in plasma LDL-C concentration. It is probable that the lower plasma apoE concentration observed in male carriers of the T allele after consumption of the SFA-rich diet are also associated with lower apoE-VLDL concentration, thus decreasing clearance by hepatic receptors. This phenomenon could explain the higher LDL-C and apoB plasma concentrations observed in these subjects after consuming a SFA-rich diet (18).
The current study is the first to examine the associations between apoE gene promoter (–219G/T) polymorphism and IS with dietary fat. We observed a significant diet x genotype interaction effect for SSPG and for plasma NEFA and fasting insulin concentrations. Thus, the replacement of an SFA-rich diet by a CHO- or a MUFA-rich diet increased IS in GG and GT, but not in TT subjects. Inappropriate release of NEFA into the circulation is a hallmark of the metabolic syndrome and it is likely to both reduce the sensitivity of glucose metabolism to insulin and enhance postprandial lipemia. In our study, plasma NEFA concentrations also were higher after the SFA-rich diet than in the other 2 diets in carriers of the –219G allele, which could inhibit glucose utilization by peripheral cells (44) and increase gluconeogenesis in the liver (45). Both of these circumstances reduce the effect of peripheral insulin. Currently, the mechanism for the association between the apoE gene promoter (–219G/T) polymorphism and diet to determine IS is not known.
In conclusion, our findings show that carriers of the –219T allele have lower IS than GG individuals, independently of the diet consumed. Furthermore, only carriers of the –219G allele have an improvement in IS when a MUFA- or a CHO-rich diet is consumed instead of a SFA-rich diet. The present findings in a Spanish population need to be replicated in independent studies to determine whether the presence of the –219G/T polymorphism determines IS and is truly implicated in insulin resistance in individuals at risk. We cannot exclude the possibility that the –219G/T polymorphism is not itself responsible for the observed association with diet in determining IS. Rather, it could be in linkage disequilibrium with an unknown causative variant in a distal regulatory site or with an unidentified causative polymorphism in a gene different from, but close to the apoE gene.
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; C, cholesterol; CHD, coronary heart disease, CHO, carbohydrate; ERE, estrogen response element; ESR, estrogen receptor; MUFA, monounsaturated fatty acid; NEFA, nonesterified FFA; SSPG, steady-state plasma glucose; SSPI, steady-state plasma insulin; TC, total cholesterol; T2DM, type 2 diabetes mellitus; TG, triacylglycerol; TRL, triacylglycerol-rich lipoprotein.
Manuscript received 2 December 2004. Initial review completed 11 February 2005. Revision accepted 10 August 2005.
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