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Association of the Pro12Ala Polymorphism in the PPAR-2 Gene With 3-Year Incidence of Type 2 Diabetes and Body Weight Change in the Finnish Diabetes Prevention Study

¹ Department of Clinical Nutrition, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
² Department of Epidemiology and Health Promotion, Diabetes and Genetic Epidemiology Unit, National Public Health Institute, Helsinki, Finland
³ Social Insurance Institution, Research and Development Centre, Turku, Finland
⁴ Department of Medicine, University of Tampere and Finnish Diabetes Association, Tampere, Finland
⁵ Department of Public Health Science and General Practice, University of Oulu, Oulu University Hospital, and the Department of Sports Medicine, Oulu Deaconess Institute, Oulu, Finland
⁶ Department of Medicine, University of Kuopio, Kuopio, Finland
⁷ Department of Public Health, University of Helsinki, Helsinki, Finland

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 
The association of the Pro12Ala polymorphism of the PPAR-2 gene with the incidence of type 2 diabetes was investigated in 522 subjects with impaired glucose tolerance (IGT) participating in the Finnish Diabetes Prevention Study. Subjects were randomized to either an intensive diet and exercise group or a control group. By 3 years of intervention, the odds ratio of the development of type 2 diabetes for subjects with the Ala12 allele was 2.11-fold compared with that for subjects with the Pro12Pro genotype (95% CI 1.20–3.72). The risk for type 2 diabetes increased also in subjects who gained weight or belonged to the control group. In the intervention group, subjects with the Ala12Ala genotype lost more weight during the follow-up than subjects with other genotypes (Pro12Pro vs. Ala12Ala P = 0.043), and none of subjects with the Ala12Ala genotype developed type 2 diabetes in this group. In conclusion, the Ala12 allele may predispose to the development of type 2 diabetes in obese subjects with IGT. However, beneficial changes in diet, increases in physical activity, and weight loss may reverse, to some extent, the diabetogenic impact of the Ala12 allele, possibly due to an improved insulin sensitivity.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

Type 2 diabetes has also a strong genetic component (5). Peroxisome proliferator-activated receptor- (PPAR-), a nuclear receptor, is a promising candidate gene for type 2 diabetes and obesity, as it regulates adipocyte differentiation and lipid and glucose metabolism (6). In humans, four PPAR- mRNA isoforms have been identified (6,7). Several variants in the PPAR- gene have been reported, among them the Pro12Ala polymorphism in the PPAR-2 isoform-specific exon B (8,9). Recently, Altshuler et al. (10) reported that, based on cross-sectional studies of several populations, the more common Pro12 allele was associated with a 1.25-fold increased risk of type 2 diabetes. Several studies have also investigated the effect of the Pro12Ala polymorphism on body weight, but the results have been inconsistent (11–21).

The purpose of the present study was to examine whether the Pro12Ala polymorphism of the PPAR-2 gene is associated with the incidence of type 2 diabetes in subjects with IGT, who are at particularly high risk for the disease, followed prospectively in the Finnish Diabetes Prevention Study (DPS) (3,22). In addition, we studied whether the effect of lifestyle intervention on weight change was modified by the Pro12Ala polymorphism.

	RESEARCH DESIGN AND METHODS

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Study population and design.
The study population, inclusion and exclusion criteria, and power calculation have been described earlier in detail (3,22). In short, the DPS is a multicenter study with five participating centers in Finland. The diagnosis of diabetes and other categories of glucose intolerance were based on the criteria adopted by the World Health Organization in 1985 (23). IGT was defined as fasting plasma glucose <7.8 mmol/l and a 2-h plasma glucose 7.8–11.0 mmol/l (oral glucose tolerance test [OGTT] 75 g). Altogether 522 overweight subjects (BMI 31.1 ± 4.6 kg/m²) aged 40–68 years and with IGT were randomly allocated to one of the two treatment modalities, the intensive diet and exercise intervention group or the control group. The screening for the Pro12Ala polymorphism of the PPAR-2 gene was performed in 490 (161 men and 329 women) subjects.

The intervention program has been described previously (3,22). Briefly, subjects in the intervention group were given individually tailored dietary advice aimed at reducing weight and the intake of total and saturated fat and increasing the intake of dietary fiber. Furthermore, subjects in the intervention group were individually guided to increase their level of physical activity. The control group received general information on the benefits of weight reduction, physical activity, and healthy diet.

The study protocol was approved by the ethics committee of the National Public Health Institute in Helsinki, Finland. All subjects gave written informed consent.

Methods.
A medical history and a physical examination were done on a yearly basis. In this report, measurements at baseline and at the 3-year examination were used. Waist circumference was measured midway between the lowest rib and iliac crest and hip circumference over the great trochanters, with 0.5-cm precision with the subjects in a standing position. BMI was calculated as weight (kg) divided by height (m) squared (2). The relative weight change during the 3-year follow-up was calculated as follows: ([weight_{3-year follow-up} - weight_baseline]/weight_baseline) x 100. In a 2-h OGTT, samples for glucose and insulin were taken before (0 min) and 120 min after a glucose load (75 g). Plasma glucose was measured at each center by standard methods, and the measurements were standardized by the central laboratory in Helsinki (3). Serum insulin was determined with a radioimmunoassay (Pharmacia, Uppsala, Sweden). The homeostasis model assessment for insulin resistance (HOMA-IR) was calculated using the following formula: fasting plasma glucose (mol/l) x fasting serum insulin (µU/l)/22.5.

The Pro12Ala polymorphism of the PPAR-2 gene was determined by the PCR-SSCP (single-strand conformation polymorphism) method as previously reported (17).

Statistical analysis.
The significance of differences in allele frequencies was analyzed using two-tailed Fisher’s exact test in the StatXact-4 program version 4.0.1 (Cytel Software Corporation, Cambridge, MA). Otherwise, the data were analyzed using the SPSS/WIN program version 9.0 (SPSS, Chicago). ² analysis was applied to test for the significance of differences in sex distribution among genotypes. Normal distribution of variables was checked with the Kolmogorov-Smirnov (Lilliefors) test, and logarithmic transformation was used for those not normally distributed. The differences among the genotypes were evaluated by the univariate ANOVA (general linear model [GLM]) with adjustment for age, sex, and BMI, when appropriate. The differences in the 3-year weight change among genotypes were assessed by GLM with glucose tolerance status at the 3-year examination (IGT versus type 2 diabetes) as a covariate. Logistic regression analysis was used to assess whether the Ala12 allele predicted the development of type 2 diabetes. In the logistic regression analysis, genotypes were encoded as 0 = Pro12Pro and 1 = Pro12Ala or Ala12Ala and study groups were encoded as 1 = intervention group and 2 = control group. Weight change used in the logistic regression analysis was calculated as weight (kg)_{3 year} - weight (kg)_baseline. In subjects whose diabetes was diagnosed before the 3-year examination, the baseline weight was subtracted from the weight measured at the visit when the diabetes diagnosis was done. In addition, age and sex were considered in the logistic regression model together with genotype, study group, and weight change, but they were not significantly related to the risk of type 2 diabetes (data not shown), and therefore they were omitted from the final logistic regression model. A P value <0.05 was considered statistically significant. Data are presented as means ± SD, unless otherwise indicated.

	RESULTS

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In the intervention group, the Pro12Pro genotype was found in 163 subjects, the Pro12Ala genotype was found in 79 subjects, and 6 subjects were homozygous for the Ala12 allele. In the control group, 174 subjects had the Pro12Pro genotype, 61 had the Pro12Ala genotype, and 7 had the Ala12Ala genotype. Observed genotype frequencies of the polymorphism were in agreement with Hardy-Weinberg expectations. The frequency of the Ala12 allele did not differ between the intervention group and the control group (0.183 vs. 0.155, respectively, P = 0.268).

At baseline, the Pro12Ala polymorphism was not associated with body weight, BMI, waist and hip circumferences, waist-to-hip ratio, HOMA-IR, 2-h plasma glucose, or fasting and 2-h serum insulin concentrations (Table 1). However, subjects with the Ala12Ala genotype tended to have higher fasting plasma glucose concentrations than those with other genotypes.

View this table: [in this window] [in a new window]   TABLE 1 Baseline characteristics of the DPS study subjects according to the Pro12Ala polymorphism of the PPAR-2 gene

View larger version (40K): [in this window] [in a new window]   FIG. 1. A: Three-year weight change (%) in the intervention group and the control group by the Pro12Ala polymorphism of the PPAR-2 gene (mean and SE). In the intervention group, P = 0.191 for comparison among all three genotypes and P = 0.043 for difference between the Pro12Pro and the Ala12Ala genotypes. In the control group, P = 0.733 for comparison among all three genotypes. B: Three-year incidence of type 2 diabetes in the intervention group and the control group by the Pro12Ala polymorphism of the PPAR-2 gene [% (number of subjects who developed type 2 diabetes/total number of subjects)].

Next we studied whether the association of the Ala12 allele with type 2 diabetes risk was modified by the degree of obesity. Therefore, DPS study subjects were divided into the two groups according to median of the baseline BMI. The first group, a lower BMI group (LBMI, mean BMI 27.7 ± 1.6 kg/m², n = 244), consisted of subjects whose baseline BMI was below or equal to the median of the whole study group baseline BMI. The second group, a higher BMI group (HBMI, mean BMI 34.7 ± 4.0 kg/m², n = 246), consisted of subjects whose baseline BMI was over the median of the whole study group baseline BMI. The Ala12 allele was a significant predictor of the development of type 2 diabetes in the LBMI group only (Table 3).

	DISCUSSION

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The present study is the first to examine the association of the Pro12Ala polymorphism of the PPAR-2 gene with the incidence of type 2 diabetes in a high-risk IGT population in a longitudinal study design. Interestingly, we found that in the IGT subjects, the Ala12 allele may predispose to the development of type 2 diabetes. In line with our study, the Ala12 allele has been reported to associate with type 2 diabetes in Canadian Oji-Cree women (24). Similarly, Evans et al. (25) found an association between the Ala12 allele and type 2 diabetes. Hasstedt et al. (26) studied members of familial type 2 diabetic kindreds and reported that the proportion of individuals with type 2 diabetes increased with the number of Ala12 alleles, although the result was not statistically significant.

The Ala12 allele has been associated with high insulin sensitivity (12,27,28), but there are also studies in which this association has not been found (13,26,29). The PPAR- gene is also expressed in pancreatic ß-cells (30), and therefore the Ala12 allele could interfere with ß-cell function. Indeed, type 2 diabetic patients with the Ala12 allele might have a reduced capacity for insulin secretion (31). In addition, Stefan et al. (29) reported that in healthy normal weight carriers of the Ala12 allele, second-phase insulin secretion after the experimental elevation of serum free fatty acids was decreased compared with that in subjects with the Pro12Pro genotype. In the present study, the Ala12 allele was associated with the type 2 diabetes risk particularly in less obese IGT subjects, in whom the reason for IGT could be related to disturbances in the insulin secretion rather than impaired insulin action. Thus, it is tempting to speculate that the Ala12 allele may predispose to insulin deficiency in the high-risk IGT population and therefore contribute to the development of type 2 diabetes.

In the present study, the Ala12 allele was not significantly associated with the incidence of type 2 diabetes in the intervention group, but a small number of cases might explain this. It has also been proposed that PPAR-2 is one of the mediators of the gene-environment interactions (32) and, likewise, it could be possible that the beneficial changes in diet, increased physical activity, and concomitant weight loss, as well as some gene-nutrient and gene-exercise interactions, protected subjects with the Ala12 allele in the intervention group from the development of type 2 diabetes in the present study. For example, subjects in the intervention group reduced the intake of total and saturated fat and increased the level of physical activity (3), the factors known to improve insulin sensitivity (33,34). Therefore, we suggest that weight reduction together with other beneficial lifestyle changes improved insulin sensitivity and reduced the ß-cell stress and, consequently, alleviated the deleterious effect of the Ala12 allele on the development of type 2 diabetes in the intervention group. In accordance with this presumption, there is evidence from the Troglitazone in Prevention of Diabetes Study that an induced ß-cell rest may protect from the development of type 2 diabetes in high-risk individuals (35). In addition, Nicklas et al. (36) found that postmenopausal women with the Ala12 allele had a greater increase in insulin sensitivity and fasting carbohydrate oxidation after a 6-month hypocaloric diet compared with women with the Pro12Pro genotype in spite of similar amounts of weight loss. However, women with the Ala12 allele had a greater decrease in fasting lipid oxidation, and they regained more weight during 1-year follow-up compared with women with the Pro12Pro genotype (36). This may imply that although subjects with the Ala12 allele may in some circumstances lose weight more easily during active weight reduction program, they may regain the weight more easily after treatment as well.

In contrast to our results, the Ala12 allele has also been supposed to be slightly protective against type 2 diabetes (10,12, 21,27,31). The reason for the discrepancy between these studies and the present study may partly be related to differences in study designs. All earlier studies have been cross-sectional, and the frequency of the Ala12 allele has been compared between the groups of type 2 diabetic patients and subjects with normal glucose tolerance. In the present study, the incidence of type 2 diabetes was evaluated after the 3-year follow-up in an IGT study population known to be at an increased risk for type 2 diabetes. Thus, our study population does not represent the general population, and our results can be generalized only to those subjects with the IGT. Several of the studies investigating the relationship between the Pro12Ala polymorphism and type 2 diabetes have been carried out in Japanese Americans (12) or in Japanese subjects (27,31). In the Japanese population, the frequency of the Ala12 allele is over four times lower than in the Finnish population (12,17, 21), and this complicates the comparisons of the results obtained in these two populations. Moreover, as discussed above, the degree of obesity, the composition of diet, and the level of physical activity may modify the effect of the Ala12 allele on the risk of type 2 diabetes, and differences in these lifestyle factors between the present study and previous studies may also partly explain the divergent results.

Although the size of the DPS population was sufficient for the original intervention study (3), the number of subjects with the Ala12Ala genotype was only moderate for the association study described here. Thus, carriers of the Ala12Ala genotype were combined with subjects with the Pro12Ala genotype in the logistic regression analysis in the present study. In other words, the logistic regression model utilized in this study assumed dominant effect of the Ala12 allele over the Pro12 allele. However, it would be interesting to investigate the association between the Ala12 allele and the risk of type 2 diabetes in other large prospective studies using a statistical model supposing also a recessive mode of inheritance for the Ala12 allele.

In summary, in the present study, the Ala allele in codon 12 of the PPAR-2 gene was associated with the development of type 2 diabetes in the high-risk IGT population. However, among those who followed an intensive diet and exercise program, subjects with the Ala12Ala genotype lost more weight than subjects having the Pro12Pro genotype, and none of subjects with the Ala12Ala genotype developed type 2 diabetes in this group. Therefore, the weight loss, together with other beneficial lifestyle changes, might reverse to some extent the diabetogenic impact of the Ala12 allele. Because our study is the first longitudinal study investigating the association between the Ala12 allele and the risk of type 2 diabetes, there is a need to confirm the present findings in other prospective studies.

	ACKNOWLEDGMENTS

 
This study was supported by grants from the Finnish Academy (nos. 38387 and 46558 to J.T.; no. 40758 to M.U.), the EVO-fund of the Kuopio University Hospital (no. 5106 to M.U.), the Ministry of Education, the Finnish Diabetes Research Foundation, and the European Union (no. QLRT 1999-00674 to M.L.).

The authors thank Pirjo Halonen, MSc, for her expert guidance in statistical analyses and Minna Kiuttu for her skilful technical assistance.

	FOOTNOTES

 
Address correspondence and reprint requests to Virpi Lindi, M.Sc., University of Kuopio, Department of Clinical Nutrition, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: virpi.lindi{at}uku.fi.

Received for publication 2 November 2001 and accepted in revised form 26 April 2002.

DPS, Finnish Diabetes Prevention Study; HBMI, a higher BMI group; GLM, general linear model; HOMA-IR, homeostasis model assessment for insulin resistance; IGT, impaired glucose tolerance; LBMI, a lower BMI group; OGTT, oral glucose tolerance test; PPAR-, peroxisome proliferator-activated receptor-; SSCP, single-strand conformation polymorphism.

	REFERENCES

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Eriksson K-F, Lindgärde F: Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise: the 6-year Malmö feasibility study. Diabetologia34 :891 –898,1991[Medline]
2. Pan X-R, Li G-W, Hu Y-H, Wang J-X, Yang W-Y, An Z-X, Hu Z-X, Lin J, Xiao J-Z, Cao H-B, Liu P-A, Jiang X-G, Jiang Y-Y, Wang J-P, Zheng H, Zhang H, Bennett PH, Howard BV: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care20 :537 –544,1997[Abstract]
3. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, for the Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med344 :1343 –1350,2001[Abstract/Free Full Text]
4. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med346 :393 –403,2002[Abstract/Free Full Text]
5. Kahn CR, Vicent D, Doria A: Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med47 :509 –531,1996[Medline]
6. Auwerx J: PPAR, the ultimate thrifty gene. Diabetologia42 :1033 –1049,1999[Medline]
7. Sundvold H, Lien S: Identification of a novel peroxisome proliferator-activated receptor (PPAR) promoter in man and transactivation by the nuclear receptor ROR1. Biochem Biophys Res Commun287 :383 –390,2001[Medline]
8. Yen C-J, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR: Molecular scanning of the human peroxisome proliferator activated receptor (hPPAR) gene in diabetic Caucasians: identification of a Pro12Ala PPAR2 missense mutation. Biochem Biophys Res Commun241 :270 –274,1997[Medline]
9. Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay G, Lascols O, Auwerx J, Weissenbach J, Capeau J, Magré J: Human peroxisome proliferator-activated receptor-2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. Diabetes47 :490 –492,1998[Medline]
10. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl M-C, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPAR Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet26 :76 –80,2000[Medline]
11. Beamer BA, Yen C-J, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR: Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-2 gene with obesity in two Caucasian populations. Diabetes47 :1806 –1808,1998[Medline]
12. Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J: A Pro12Ala substitution in PPAR2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet20 :284 –287,1998[Medline]
13. Mori Y, Kim-Motoyama H, Katakura T, Yasuda K, Kadowaki H, Beamer BA, Shuldiner AR, Akanuma Y, Yazaki Y, Kadowaki T: Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor 2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. Biochem Biophys Res Commun251 :195 –198,1998[Medline]
14. Ek J, Urhammer SA, Sørensen TIA, Andersen T, Auwerx J, Pedersen O: Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-2 (PPAR-2): divergent modulating effects on body mass index in obese and lean Caucasian men. Diabetologia42 :892 –895,1999[Medline]
15. Mancini FP, Vaccaro O, Sabatino L, Tufano A, Rivellese AA, Riccardi G, Colantuoni V: Pro12Ala substitution in the peroxisome proliferator-activated receptor-2 is not associated with type 2 diabetes. Diabetes48 :1466 –1468,1999[Abstract]
16. Ringel J, Engeli S, Distler A, Sharma AM: Pro12Ala missense mutation of the peroxisome proliferator activated receptor and diabetes mellitus. Biochem Biophys Res Commun254 :450 –453,1999[Medline]
17. Valve R, Sivenius K, Miettinen R, Pihlajamäki J, Rissanen A, Deeb SS, Auwerx J, Uusitupa M, Laakso M: Two polymorphisms in the peroxisome proliferator-activated receptor- gene are associated with severe overweight among obese women. J Clin Endocrinol Metab84 :3708 –3712,1999[Abstract/Free Full Text]
18. Clement K, Hercberg S, Passinge B, Galan P, Varroud-Vial M, Shuldiner AR, Beamer BA, Charpentier G, Guy-Grand B, Froguel P, Vaisse C: The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes. Int J Obes Relat Metab Disord24 :391 –393,2000[Medline]
19. Cole SA, Mitchell BD, Hsueh W-C, Pineda P, Beamer BA, Shuldiner AR, Comuzzie AG, Blangero J, Hixson JE: The Pro12Ala variant of peroxisome proliferator-activated receptor-2 (PPAR-2) is associated with measures of obesity in Mexican Americans. Int J Obes Relat Metab Disord24 :522 –524,2000[Medline]
20. Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Auwerx J, Deeb SS, Amouyel P: Impact of the peroxisome proliferator activated receptor 2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab Disord24 :195 –199,2000[Medline]
21. Douglas JA, Erdos MR, Watanabe RM, Braun A, Johnston CL, Oeth P, Mohlke KL, Valle TT, Ehnholm C, Buchanan TA, Bergman RN, Collins FS, Boehnke M, Tuomilehto J: The peroxisome proliferator-activated receptor-2 Pro12Ala variant: association with type 2 diabetes and trait differences. Diabetes50 :886 –890,2001[Abstract/Free Full Text]
22. Eriksson J, Lindström J, Valle T, Aunola S, Hämäläinen H, Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Lauhkonen M, Lehto P, Lehtonen A, Louheranta A, Mannelin M, Martikkala V, Rastas M, Sundvall J, Turpeinen A, Viljanen T, Uusitupa M, Tuomilehto J, on behalf of the Finnish Diabetes Prevention Study Group: Prevention of type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland: study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia42 :793 –801,1999[Medline]
23. World Health Organization: Diabetes Mellitus: Report of a WHO Study Group. Geneva, World Health Org.,1985 (Tech. Rep. Ser., no.727:7-113)
24. Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJG, Anderson CM: Peroxisome proliferator-activated receptor-2 P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab85 :2014 –2019,2000[Abstract/Free Full Text]
25. Evans D, de Heer J, Hagemann C, Wendt D, Wolf A, Beisiegel U, Mann WA: Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor gamma (PPAR gamma) gene and type 2 diabetes. Exp Clin Endocrinol Diabetes109 :151 –154,2001[Medline]
26. Hasstedt SJ, Ren Q-F, Teng K, Elbein SC: Effect of the peroxisome proliferator-activated receptor-2 Pro12Ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. J Clin Endocrinol Metab86 :536 –541,2001[Abstract/Free Full Text]
27. Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki H, Hagura R, Akanuma Y, Kimura S, Ito C, Kadowaki T: The Pro12Ala polymorphism in PPAR 2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun271 :212 –216,2000[Medline]
28. Ek J, Andersen G, Urhammer SA, Hansen L, Carstensen B, Borch-Johnsen K, Drivsholm T, Berglund L, Hansen T, Lithell H, Pedersen O: Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-2 (PPAR-2) gene in relation to insulin sensitivity among glucose tolerant Caucasians. Diabetologia44 :1170 –1176,2001[Medline]
29. Stefan N, Fritsche A, Häring H, Stumvoll M: Effect of experimental elevation of free fatty acids on insulin secretion and insulin sensitivity in healthy carriers of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-2 gene. Diabetes50 :1143 –1148,2001[Abstract/Free Full Text]
30. Dubois M, Pattou F, Kerr-Conte J, Gmyr V, Vandewalle B, Desreumaux P, Auwerx J, Schoonjans K, Lefebvre J: Expression of peroxisome proliferator-activated receptor (PPAR) in normal human pancreatic islet cells. Diabetologia43 :1165 –1169,2000[Medline]
31. Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, Inoue I, Seino Y, Yasuda K, Hanafusa T, Yamagata K, Awata T, Kadowaki T, Hara K, Yamada N, Gotoda T, Iwasaki N, Iwamoto Y, Sanke T, Nanjo K, Oka Y, Matsutani A, Maeda E, Kasuga M: The Pro¹²Ala substitution in PPAR- is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes50 :891 –894,2001[Abstract/Free Full Text]
32. Luan J, Browne PO, Harding A-H, Halsall DJ, O’Rahilly S, Chatterjee VKK, Wareham NJ: Evidence for gene-nutrient interaction at the PPAR- locus. Diabetes50 :686 –689,2001[Abstract/Free Full Text]
33. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, Nälsén C, Berglund L, Louheranta A, Rasmussen BM, Calvert GD, Maffetone A, Pedersen E, Gustafsson I-B, Storlien LH: Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU study. Diabetologia44 :312 –319,2001[Medline]
34. Borghouts LB, Keizer HA: Exercise and insulin sensitivity: a review. Int J Sports Med21 :1 –12,2000[Medline]
35. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Azen SP: Protection from type 2 diabetes persists in the TRIPOD cohort eight months after stopping troglitazone (Abstract). Diabetes50 (Suppl. 2) :A81 ,2001
36. Nicklas BJ, van Rossum EFC, Berman DM, Ryan AS, Dennis KE, Shuldiner AR: Genetic variation in the peroxisome proliferator-activated receptor-2 gene (Pro12Ala) affects metabolic responses to weight loss and subsequent weight regain. Diabetes50 :2172 –2176,2001[Abstract/Free Full Text]

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				R. Jaziri, S. Lobbens, R. Aubert, F. Pean, S. Lahmidi, M. Vaxillaire, I. Porchay, N. Bellili, J. Tichet, B. Balkau, et al. The PPARG Pro12Ala Polymorphism Is Associated With a Decreased Risk of Developing Hyperglycemia Over 6 Years and Combines With the Effect of the APM1 G-11391A Single Nucleotide Polymorphism: The Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) Study. Diabetes, April 1, 2006; 55(4): 1157 - 1162. [Abstract] [Full Text] [PDF]

				G. Sesti, L. Perego, M. Cardellini, F. Andreozzi, C. Ricasoli, P. Vedani, V. Guzzi, M. Marchi, M. Paganelli, G. Ferla, et al. Impact of Common Polymorphisms in Candidate Genes for Insulin Resistance and Obesity on Weight Loss of Morbidly Obese Subjects after Laparoscopic Adjustable Gastric Banding and Hypocaloric Diet J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5064 - 5069. [Abstract] [Full Text] [PDF]

				T. Pischon, J. K. Pai, J. E. Manson, F. B. Hu, K. M. Rexrode, D. Hunter, and E. B. Rimm Peroxisome Proliferator-Activated Receptor-{gamma}2 P12A Polymorphism and Risk of Coronary Heart Disease in US Men and Women Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1654 - 1658. [Abstract] [Full Text] [PDF]

				M. Vanttinen, P. Nuutila, J. Pihlajamaki, K. Hallsten, K. A. Virtanen, R. Lautamaki, P. Peltoniemi, J. Kemppainen, T. Takala, A. P. M. Viljanen, et al. The Effect of the Ala12 Allele of the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene on Skeletal Muscle Glucose Uptake Depends on Obesity: A Positron Emission Tomography Study J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4249 - 4254. [Abstract] [Full Text] [PDF]

				ABDOMINAL OBESITY STUDY GROUP, F. E. VON EYBEN, J. P. KROUSTRUP, J. F. LARSEN, and J. CELIS Comparison of Gene Expression in Intra-Abdominal and Subcutaneous Fat: A Study of Men with Morbid Obesity and Nonobese Men Using Microarray and Proteomics Ann. N.Y. Acad. Sci., December 1, 2004; 1030(1): 508 - 536. [Abstract] [Full Text] [PDF]

				C. Knouff and J. Auwerx Peroxisome Proliferator-Activated Receptor-{gamma} Calls for Activation in Moderation: Lessons from Genetics and Pharmacology Endocr. Rev., December 1, 2004; 25(6): 899 - 918. [Abstract] [Full Text] [PDF]

				E. S. Tai, D. Corella, M. Deurenberg-Yap, X. Adiconis, S. K. Chew, C. E. Tan, and J. M. Ordovas Differential effects of the C1431T and Pro12Ala PPAR{gamma} gene variants on plasma lipids and diabetes risk in an Asian population J. Lipid Res., April 1, 2004; 45(4): 674 - 685. [Abstract] [Full Text] [PDF]

				E. Ferrannini, M. Nannipieri, K. Williams, C. Gonzales, S. M. Haffner, and M. P. Stern Mode of Onset of Type 2 Diabetes from Normal or Impaired Glucose Tolerance Diabetes, January 1, 2004; 53(1): 160 - 165. [Abstract] [Full Text] [PDF]

				A. Memisoglu, F. B. Hu, S. E. Hankinson, J. E. Manson, I. De Vivo, W. C. Willett, and D. J. Hunter Interaction between a peroxisome proliferator-activated receptor {gamma} gene polymorphism and dietary fat intake in relation to body mass Hum. Mol. Genet., November 15, 2003; 12(22): 2923 - 2929. [Abstract] [Full Text] [PDF]

				S Masud and S Ye Effect of the peroxisome proliferator activated receptor-{gamma} gene Pro12Ala variant on body mass index: a meta-analysis J. Med. Genet., October 1, 2003; 40(10): 773 - 780. [Full Text] [PDF]

				W.H. L. Kao, J. Coresh, A. R. Shuldiner, E. Boerwinkle, M. S. Bray, and F. L. Brancati Pro12Ala of the Peroxisome Proliferator-Activated Receptor-{gamma}2 Gene Is Associated With Lower Serum Insulin Levels in Nonobese African Americans: The Atherosclerosis Risk in Communities Study Diabetes, June 1, 2003; 52(6): 1568 - 1572. [Abstract] [Full Text] [PDF]

				O. Tschritter, A. Fritsche, F. Shirkavand, F. Machicao, H. Haring, and M. Stumvoll Assessing the Shape of the Glucose Curve During an Oral Glucose Tolerance Test Diabetes Care, April 1, 2003; 26(4): 1026 - 1033. [Abstract] [Full Text] [PDF]

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