This Article Abstract Full Text (PDF) All Versions of this Article: 90/4/2297    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pérez-Martínez, P. Articles by López-Miranda, J. Search for Related Content PubMed PubMed Citation Articles by Pérez-Martínez, P. Articles by López-Miranda, J. Pubmed/NCBI databases Gene OMIM Substance via MeSH Hazardous Substances DB OLIVE OIL VEGETABLE OIL Related Collections Diabetes and Insulin Metabolism

A Polymorphism Exon 1 Variant at the Locus of the Scavenger Receptor Class B Type I (SCARB1) Gene Is Associated with Differences in Insulin Sensitivity in Healthy People during the Consumption of an Olive Oil-Rich Diet

Unit of Lipids and Atherosclerosis (P.P.-M., F.P.-J., C.B., J.A.M., C.M., P.G., J.D.-L., F.F., J.-L.M.), Hospital Universitario Reina Sofía, 14004 Cordoba, Spain; and Nutrition and Genomics Laboratory (J.M.O.), United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111-1524

Address all correspondence and requests for reprints to: Prof. José López-Miranda, Unidad de Lipidos y Arteriosclerosis, Hospital Universitario Reina Sofía, Avenida Menéndez Pidal, sin número 14004 Cordoba, Spain. E-mail: jlopezmir{at}uco.es.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Scavenger receptor class B type I (SCARB1) was described as the first high-density lipoprotein receptor. Increasing evidence indicates that SCARB1 plays additional roles particularly in type 2 diabetes mellitus. Our aim was to determine whether the presence of an exon 1 (GA) polymorphism at the SCARB1 gene modifies the insulin sensitivity to dietary fat.

Methods: We studied 59 healthy volunteers (30 men and 29 women, 42 G/G homozygous and 17 G/A heterozygous). Subjects consumed three diets for 4 wk each: a saturated fatty acid (SFA)-rich diet (38% fat, 20% SFA), followed by a carbohydrate (CHO)-rich diet (30% fat, 55% CHO) or a monounsaturated fatty acid (MUFA)-rich diet (38% fat, 22% MUFA) after a randomized crossover design. For each diet, we investigated peripheral insulin sensitivity with the insulin suppression test.

Results: Steady-state plasma glucose after the MUFA diet was lower in G/A compared with G/G subjects (P = 0.030). This effect was not observed after CHO and SFA diets (P = 0.177 and 0.957, respectively). Plasma nonesterified free fatty acid values were lower in subjects carrying the A allele for all the diet periods.

Conclusions: Our findings show that carriers of the G/A genotype have significant increases in insulin sensitivity after a MUFA-rich diet compared with G/G individuals.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
INSULIN RESISTANCE IS considered to be the major pathogenetic factor in the development of type 2 diabetes mellitus (T2DM) and subsequent increase in coronary heart disease risk. Insulin resistance usually precedes the diagnosis of T2DM by decades, and it has been suggested that the clinical expression of the disease could be prevented by dietary and lifestyle modification (1). Epidemiological evidence and intervention studies clearly indicate that the quality of dietary fat influences insulin resistance in humans; in particular, saturated fat worsens it, whereas monounsaturated and polyunsaturated fats improve it (2, 3).

One of the most common lipid abnormalities observed in T2DM is low serum concentrations of high-density lipoprotein cholesterol (HDL-C). The regulation of HDL-C levels is very complex. However, the recent characterization of two key components, the scavenger receptor class B type I (SCARB1) and the ABCA1 transporter, has greatly advanced our knowledge about the metabolism of these particles. Specifically, the SCARB1 was described as the first functionally active HDL receptor capable of facilitating the selective uptake of HDL-C, and it is expressed primarily in liver and steroidogenic tissues (4, 5). Several recent in vivo studies suggest that this cell surface glycoprotein receptor may also process low-density lipoprotein (LDL) and other apo B-containing particles (6). Previous population studies have shown associations between body mass index (BMI) and serum concentrations of LDL-C, HDL-C, and triacylglycerols (TAGs) in relation to the SCARB1 gene variants (7, 8). Furthermore, we have shown in dietary intervention studies that carriers of the less common allele at the SCARB1 exon 1 polymorphism are more susceptible to the presence of saturated fatty acid (SFA) in the diet, responding with a greater increase in plasma LDL-C (9). These findings are consistent with the fact that the SCARB1 may have a role in the metabolism of LDL-C. It is possible that the receptor contributes to the clearance of the fraction of LDL not removed by the LDL receptor pathway or removes some cholesteryl ester from particles in VLDL-LDL cascade. This hypothesis may explain, in part, our finding of a lower postprandial response of small TAG-rich lipoprotein (TRL) TAGs in G/A genotype individuals than in those homozygous for the G allele (G/G) (10). In addition, we have shown that diabetic subjects carrying the less common A allele at the SCARB1 exon 1 gene have significantly lower LDL-C and HDL-C concentrations (11).

Based on this previous evidence, our goal was to study whether the presence of the exon 1 polymorphism at the SCARB1 gene is related with significantly different insulin sensitivity in response to changes in the quality of dietary fat.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Fifty-nine healthy subjects (30 men and 29 women) were recruited from among 250 students at the University of Cordoba. The selected subjects had a mean age (±SD) of 23.1 ± 1.8 yr. Of these, 42 were homozygous for the most common G allele (G/G), and 17 were carriers of the A allele (G/A). There were no homozygotes for the A allele (A/A). The distribution of genotypes was as expected from the Hardy-Weinberg equilibrium. These subjects had participated in a previous study (3). The SCARB1 exon 1 allele frequencies were similar to those previously reported. Informed consent was obtained from all participants. Subjects showed no evidence of any chronic disease (hepatic, renal, thyroid, or cardiac dysfunction), obesity, or unusually high levels of physical activity (e.g. sports training). None of the subjects had a family history of premature coronary artery disease or had taken medications or vitamin supplements in the 6 months before the study. Physical activity and diet, including alcohol consumption, were recorded in a personal log for 1 wk, and the data were used to calculate individual energy requirements. Mean BMI was 22.8 ± 2.4 kg/m² (mean ± SD) at the onset of the study and remained constant throughout the experimental period. Subjects were encouraged to maintain their regular physical activity and lifestyle and were asked to record in a diary any event that could affect the outcome of the study, such as stress, change in smoking habits and alcohol consumption, or intake of foods not included in the experiment design. All studies were carried out in the Research Unit at the Reina Sofia University Hospital, and the experimental procedure was approved by the hospital’s Human Investigation Review Committee.

Diets

The study design included an initial 28-d period during which all subjects consumed a SFA-enriched diet, with 15% protein, 47% carbohydrate (CHO), and 38% fat [20% SFA, 12% monounsaturated fatty acid (MUFA), and 6% polyunsaturated fatty acid (PUFA)]. After this period, 30 subjects received a MUFA-enriched diet for 28 d in a randomized, crossover design. The diet contained 15% protein, 47% CHOs, and 38% fat (<10% SFA, 6% PUFA, and 22% MUFA). The MUFA-enriched diet was followed by a high-CHO diet for 28 d containing 15% protein, 55% CHOs, and less than 30% fat (<10% SFA, 6% PUFA, and 12% MUFA). The other 29 subjects received the CHO diet before the MUFA diet. Volunteers were randomly assigned to this sequence of diets. Cholesterol content remained constant (under 300 mg/d) during the three periods. Of the MUFA diet, 80% was provided by virgin olive oil, which was used for cooking, salad dressing, and as a spread. CHO intake in the CHO diet 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 United States Department of Agriculture (12) food tables and Spanish food composition tables for local foodstuffs (13). All meals were prepared in the hospital kitchen and were supervised by a dietitian. Lunch and dinner were eaten in the hospital dining room, whereas breakfast and an afternoon snack were eaten in the medical school cafeteria. Fourteen menus were prepared with regular solid foods and were rotated during the experimental period. Duplicate samples from each menu were collected, homogenized, and stored at –70 C. The protein, fat, and CHO contents of the diet were analyzed by standard methods (14). Dietary compliance was verified by analyzing the fatty acids in LDL-C esters at the end of each dietary period (15). The study took place during January and March to minimize seasonal effects and academic stress.

Lipid analysis and biochemical determinations

Venous blood samples for glucose, lipid, and lipoprotein analysis were collected into EDTA-containing (1 g/liter) 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 for 15 min at 4 C within 1 h of venipuncture. Plasma cholesterol and TAG levels were determined by enzymatic techniques (16, 17). HDL-C was determined after precipitation with fosfowolframic acid (18). Apo A-I and B were determined by immunoturbidimetry (19). LDL-C concentration was calculated using the Friedewald formula (20). Nonesterified free fatty acid (NEFA) concentrations were analyzed by an enzymatic colorimetric assay (Roche Molecular Biochemicals, Mannheim, Germany) (21). To reduce interassay variation, plasma was stored at –80 C and analyzed at the end of the study.

Insulin suppression test

A modified insulin suppression test was carried out on all the subjects at the end of the dietary period (22, 23). The study began at 0800 h, after 12 h of fasting. A continuous infusion of somatostatin (214 nmol/h), insulin (180 pmol·^m–2·min^–1) and glucose (13.2 mmol·^m–2·min^–1) 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. These four values determined 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 others with lower SSPG.

DNA amplification and genotyping

Genotyping of the SCARB1 exon 1 (GA and GlySer change at amino acid position 2, rs 4238001) was carried out as previously described (24). Each probe consisted of an oligonucleotide with a 5' reporter dye and 3' quencher dye. The reporter dyes used were 6 carboxy-fluorescein (FAM) and VIC, and 6 carboxy-tetramethyl-rhodamine (TAMRA) was used as the quencher dye. The primer and probe sequences used were as follows: forward primer, 5'-GTCCCCGTCTCCTGCCA-3'; reverse primer, 5'-CCCAGCACAGCGCACAGTA-3'; G allele probe, 5'-FAM-AGACATGGGCTGCTCCGCCA-TAMRA-3'; and A allele probe, 5'-VIC-CAGACATGAGCTGCTCCGCCA-TAMRA-3'. The bases in bold type represent point mutations. PCR was performed in a 10-µl final volume for each individual single-nucleotide polymorphism. The reaction mixture contained 5 µl TaqMan 2x Universal PCR Master Mix (Applied Biosystems, Foster City, CA); 200 nmol/liter FAM-labeled probe, 150 nmol/liter VIC-labeled probe, 900 nmol/liter reverse primer, and 900 nmol/liter forward primer (all from Epoch Biosciences, Bothell, WA); and 2–20 ng genomic DNA. The thermal cycler program included one cycle at 50 C for 2 min to active uracil-N-glycosylase (Trevigen Inc., Gaithersburg, MD), which was added to prevent carryover contamination; one cycle at 95 C for 10 min to activate the AmpliTaq Gold Polymerase (Applied Biosystems); and then 40 cycles at 95 C for 15 sec for denaturing and at 62 C for 60 sec for annealing/extending. Allelic discrimination was performed on the post-PCR product. Fluorescence data were collected by 7700 Sequence Detection System (SDS) (Applied Biosystems) on the samples for 5 sec and analyzed with the use of SDS software, version 6.0 (PerkinElmer/Applied Biosystems), which could be visualized in graph form (24).

Statistical methods

SPSS 9.0 was used for the statistical comparisons. ANOVA for repeated measures was used to analyze the differences between SSPG and SSPI concentrations among several study groups. When statistically significant effects were demonstrated, Tukey’s post hoc test was used to identify differences between groups. The Kolmogorov-Smirnov one-sample test was used to test the normality of the distribution. P < 0.05 were considered significant. All data presented in text and tables are expressed as means ± SD values.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Age, BMI, and serum lipids and glucose concentration at baseline for the participating subjects are shown in Table 1. No significant differences for any of the variables examined were observed between genotype groups or gender. Insulin values during the three SSPI periods (mean ± SD at min 150, 160, 170, and 180 of the insulin suppression test) were similar in subjects who were homozygous for the G allele (G/G) and in subjects carrying the A allele (G/A) at the SCARB1 exon 1. Mean values ± SD were 9.55 ± 2.15 and 9.27 ± 2.04 mIU/ml, respectively, during the MUFA diet; 9.45 ± 2.11 and 9.43 ± 2.64 mIU/ml during the CHO diet; and 9.52 ± 2.52 and 9.08 ± 2.56 mIU/ml during the SFA diet for the G/G and the G/A subjects, respectively. SSPG values were lower in G/A than in G/G subjects after the MUFA diet (Fig. 1; 4.41 ± 1.59 and 6.16 ± 2.78 mmol/liter, respectively, P = 0.030 by ANOVA). Such a trend is observed for CHO diet group, although it is not statistically significant (Fig. 1, P = 0.177). This effect was not observed after the SFA diet (Fig. 1, P = 0.957). These data indicate that the presence of the allele A in the exon 1 at the SCARB1 locus was associated with significantly increased insulin sensitivity after a MUFA-rich diet. Similar results were found for men and women (data not shown). Furthermore, fasting NEFA concentrations were lower during the MUFA, CHO, and SFA diets in G/A compared with G/G subjects (P = 0.03; Fig. 2). Additionally, the NEFA plasma values were correlated positively with SSPG (r = 0.26; P = 0.002).

View larger version (9K): [in this window] [in a new window]   FIG. 1. Mean glucose in SSPG during the insulin suppression test according to the exon 1 variant at the SCARB1 gene locus after the SFA, CHO-rich, and MUFA diets. *, Significantly different from G/G, P < 0.05 (Tukey’s test).

View larger version (9K): [in this window] [in a new window]   FIG. 2. NEFA during the insulin suppression test, according to the exon 1 variant at the SCARB1 gene locus after the SFA, CHO-rich, and MUFA diets. *, Significantly different from G/G, P < 0.05 (Tukey’s test).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Experimental animal models have shown that insulin action may be modulated by changing not only the amount of total fat but also the type of fat. Studies in humans have shown different results, probably due to the small number of subjects involved in those studies (25). A recent multicenter trial (Kuopio, Aarhus, Naples, Wollongong, and Upsala; the KANWU study), including a large healthy population, has shown that a change from a SFA-rich diet to one rich in MUFA improved insulin sensitivity (26). In agreement with these results, our group has shown that shifting from a SFA-rich diet to a MUFA olive oil-rich diet also improved insulin sensitivity in young subjects (3). Both studies were performed under strictly controlled conditions using natural foods, thus increasing the generalization of the findings.

A series of population studies examining the association of polymorphisms in the SCARB1 gene with different lipoprotein parameters has suggested that SCARB1 genetic variability plays a significant role in lipoprotein metabolism in humans (7, 8, 9, 10, 11, 27). In addition, we have demonstrated that healthy male carriers of the A allele at the SCARB1 exon 1 polymorphism have a lower postprandial response for small TRLs as compared with G/G subjects (10). It has been suggested that higher concentrations of serum TAGs could lead to insulin resistance (28). The enlarged pool of circulating TRLs could also increase plasma fatty acid concentrations by saturating peripheral removal mechanism and thus contribute to establishing an insulin-resistant state. Moreover, the SCARB1 gene is located in 12q24, a chromosomal region that has been repeatedly linked with diabetes in several genome scan studies, and several candidate genes have localized to that region. The current study is the first to examine the association between SCARB1 gene variants and insulin sensitivity in response to dietary intervention. Our data indicate that subjects carrying the A allele in the exon 1 at the SCARB1 gene locus were associated with relevant increase in insulin sensitivity after the MUFA diet. Such a trend is also observed for CHO diet group, although it is not statistically significant. One might argue that if enough subjects are examined, a statistically significant difference might emerge. However, our study was only powered to detect a difference of 30%, and a difference of more than 30% was not detected. This effect was not observed during the SSPG after SFA-rich diet. Furthermore, G/G subjects present increasing plasma concentrations of NEFA, which could inhibit glucose use by peripheral cells and reduce the effect of peripheral insulin. If the polymorphism acts by increasing levels of NEFA independently of diet, it is likely that it would have an effect on insulin resistance regardless of dietary intervention.

One of the limitations to genetic association studies is the difficulty in corroborating the findings observed in populations with different characteristics. In addition, our P value is only nominal, and the previous association studies at this level of statistical significance have seldom been reproduced; therefore replication of our finding is essential (29). Currently, the mechanism by which this genetic variation can influence glucose metabolism is not known.

In conclusion, allele variability in the SCARB1 gene could partly explain the interindividual differences in insulin sensitivity response after the MUFA olive oil-rich diet in healthy people. New studies are needed, however, to elucidate whether it is a specific effect of the polymorphism or whether, instead, it is a consequence of an association in disequilibrium with other polymorphisms.

	Acknowledgments

 
We appreciate the cooperation of Beatriz Pérez in the translation of the manuscript.

	Footnotes

 
This work was supported by the Plan Nacional de Investigación (Ministerio de Educación y Ciencia) (Grants SAF 01/2466-C05 04 to F.P.-J. and SAF 01/0366 to J.L.-M.); by the Spanish Ministry of Health (Grant FIS 01/0449); by the Fundación Hospital Reina Sofía-Cajasur (to P.G.); by the Consejería de Salud, Servicio Andaluz de Salud (Grants 00/212, 00/39, 01/239, 01/243, 02/64, 02/65, and 02/78); by the Consejería de Educación, Plan Andaluz de Investigación, Universidad de Córdoba; and by National Institutes of Health/National Heart, Lung, and Blood Institute Grant HL54776, and Contracts 53-K06-5-10 and 58-1950-9-001 from the United States Department of Agriculture Research Service.

First Published Online January 25, 2005

Abbreviations: BMI, Body mass index; CHO, carbohydrate; FAM, 6 carboxy-fluorescein; HDL-C, high-density lipoprotein-cholesterol; LDL, low-density lipoprotein; MUFA, monounsaturated fatty acid; NEFA, nonesterified free fatty acid; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; SSPG, steady-state plasma glucose; SSPI, steady-state plasma insulin; TAG, triacylglycerol; TAMRA, 6 carboxy-tetramethyl-rhodamine; T2DM, type 2 diabetes mellitus; TRL, TAG-rich lipoprotein.

Received July 28, 2004.

Accepted January 14, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Lovejoy JC 2002 The influence of dietary fat on insulin resistance. Curr Diab Rep 2:435–440[Medline]
2. Rivellese AA, Lilli S 2003 Quality of dietary fatty acids, insulin sensitivity and type 2 diabetes. Biomed Pharmacother 57:84–87[CrossRef][Medline]
3. Perez-Jimenez F, Lopez-Miranda J, Pinillos MD, Gomez P, Paz-Rojas E, Montilla P, Marin C, Velasco MJ, Blanco-Molina A, Jimenez Pereperez JA, Ordovas JM 2001 A Mediterranean and a high-carbohydrate diet improve glucose metabolism in healthy young persons. Diabetologia 44:2038–2043[CrossRef][Medline]
4. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M 1996 Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271:518–520[Abstract]
5. Trigatti B, Rigotti A, Krieger M 2000 The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism. Curr Opin Lipidol 11:123–131[CrossRef][Medline]
6. Swarnakar S, Temel RE, Connelly MA, Azhar S, Williams DL 1999 Scavenger receptor class B, type I, mediates selective uptake of low density lipoprotein cholesteryl ester. J Biol Chem 274:29733–29739[Abstract/Free Full Text]
7. Acton S, Osgood D, Donoghue M, Corella D, Pocovi M, Cenarro A, Mozas P, Keilty J, Squazzo S, Woolf EA, Ordovas JM 1999 Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population. Arterioscler Thromb Vasc Biol 19:1734–1743[Abstract/Free Full Text]
8. Hsu LA, Ko YL, Wu S, Teng MS, Peng TY, Chen CF, Chen CF, Lee YS 2003 Association between a novel 11-base pair deletion mutation in the promoter region of the scavenger receptor class B type I gene and plasma HDL cholesterol levels in Taiwanese Chinese. Arterioscler Thromb Vasc Biol 23:1869–1874[Abstract/Free Full Text]
9. Perez-Martinez P, Ordovas JM, Lopez-Miranda J, Gomez P, Marin C, Moreno J, Fuentes F, Fernandez de la Puebla RA, Perez-Jimenez F 2003 Polymorphism exon 1 variant at the locus of the scavenger receptor class B type I gene: influence on plasma LDL cholesterol in healthy subjects during the consumption of diets with different fat contents. Am J Clin Nutr 77:809–813[Abstract/Free Full Text]
10. Perez-Martinez P, Lopez-Miranda J, Ordovas JM, Bellido C, Marin C, Gomez P, Paniagua JA, Moreno JA, Fuentes F, Perez-Jimenez F 2004 Postprandial lipemia is modified by the presence of the polymorphism present in the exon 1 variant at the SR-BI gene locus. J Mol Endocrinol 32:237–245[Abstract]
11. Osgood D, Corella D, Demissie S, Cupples LA, Wilson PW, Meigs JB, Schaefer EJ, Coltell O, Ordovas JM 2003 Genetic variation at the scavenger receptor class B type I gene locus determines plasma lipoprotein concentrations and particle size and interacts with type 2 diabetes: the Framingham study. J Clin Endocrinol Metab 88:2869–2879[Abstract/Free Full Text]
12. Human Nutrition Information Service, Department of Agriculture Composition of Foods 1987 Agriculture handbook no. 8. Washington, DC: U.S. Government Printing Office
13. Varela G 1980 Food composition tables (tablas de composición de alimentos). Madrid: Instituto de Nutrición CSIC
14. 1990 Official methods of analysis. 15th ed. Arlington, VA: Association of Official Analytical Chemists
15. Ruiz-Gutierrez V, Prada JL, Perez-Jimenez F 1993 Determination of fatty acid and triacylglycerol composition of human very-low-density lipoproteins. J Chromatogr 622:117–124[Medline]
16. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC 1974 Enzymatic determination of total serum cholesterol. Clin Chem 20:470–475[Abstract]
17. Bucolo G, David H 1973 Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 19:476–482[Abstract]
18. Assmann G, Schierwer H, Schmitz G, Hägele E 1983 Quantification of high density lipoprotein cholesterol by precipitation with phosphotungstic acid-MgCl₂. Clin Chem 9:2026–2030
19. Riepponem P, Marniemi J, Rautaoja T 1987 Immunoturbidimetric determination of apolipoproteins A-I and B in serum. Scand J Clin Lab Invest 47:739–744[Medline]
20. Friedewald WT, Levy RI, Fredrickson DS 1972 Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of a preparative ultracentrifuge. Clin Chem 18:499–502[Abstract]
21. Shimizu S, Inoue K, Tani Y, Yamada H 1979 Enzymatic microdetermination of serum free fatty acids. Anal Biochem 98:341–345[CrossRef][Medline]
22. Harano Y, Ohgaku S, Hidaka H, Haneda K, Kikkawa R, Shigeta Y, Abe H 1977 Glucose, insulin and somatostatin infusion for the determination of insulin sensitivity. J Clin Endocrinol Metab 45:1124–1127.[Abstract]
23. Laws A, Jeppesen JL, Maheux PC, Schaaf P, Chen YD, Reaven GM 1994 Resistance to insulin-stimulated glucose uptake and dyslipidemia in Asian Indians. Arterioscler Thromb 14:917–922[Abstract/Free Full Text]
24. Osgood-McWeeney D, Galluzzi J, Ordovas JM 2000 Allelic discrimination for single nucleotide polymorphisms in the human scavenger receptor class B type 1 gene locus using fluorescent probes. Clin Chem 46:118–119[Free Full Text]
25. Rivellese AA, De Natale C, Lilli S 2002 Type of dietary fat and insulin resistance. Ann NY Acad Sci 967:329–335[Abstract/Free Full Text]
26. Vessby B, Unsitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nalsen C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, Gustafsson IB, Storlien LH; KANWU Study 2001 Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia 44:312–319[CrossRef][Medline]
27. Fox CS, Heard-Costa NL, Wilson PW, Levy D, D’Agostino Sr RB, Atwood LD 2004 Genome-wide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. Am J Hum Genet 74:253–261[CrossRef][Medline]
28. Steiner G 1991 Altering triglyceride concentrations changes insulin-glucose relationships in hypertriglyceridemic patients. Double-blind study with gemfibrozil with implications for atherosclerosis. Diabetes Care 14:1077–1081[Abstract]
29. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN 2003 Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182[CrossRef][Medline]

This article has been cited by other articles:

				J. Delgado-Lista, F. Perez-Jimenez, T. Tanaka, P. Perez-Martinez, Y. Jimenez-Gomez, C. Marin, J. Ruano, L. Parnell, J. M. Ordovas, and J. Lopez-Miranda An Apolipoprotein A-II Polymorphism (-265T/C, rs5082) Regulates Postprandial Response to a Saturated Fat Overload in Healthy Men J. Nutr., September 1, 2007; 137(9): 2024 - 2028. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 90/4/2297    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pérez-Martínez, P. Articles by López-Miranda, J. Search for Related Content PubMed PubMed Citation Articles by Pérez-Martínez, P. Articles by López-Miranda, J. Pubmed/NCBI databases Gene OMIM Substance via MeSH Hazardous Substances DB OLIVE OIL VEGETABLE OIL Related Collections Diabetes and Insulin Metabolism