BRIEF REPORT High Incidence of Type 2 Diabetes in Peroxisome Proliferator–Activated Receptor ␥2 Pro12Ala Carriers Exposed to a High Chronic Intake of Trans Fatty Acids and Saturated Fatty Acids 1 3 RAUL EDUARDO PISABARRO, MD MARIO STOLL, MD in shortening, also widely used. The 2 4 CARLOS SANGUINETTI DANIEL PRENDEZ weekly caloric expenditure for physical activity was evaluated through the Paffen- barger Physical Questionnaire (8). Waist circumference and BMI were also regis- ne of the most frequent polymor- were known diabetes, the presence of any tered. Baseline insulin was determined by phisms of peroxisome proliferator– other disease or drug that alters glucose radioimmunoassay (Diagnosis Products). O activated receptor (PPAR)␥2isthe and lipid metabolism, and having fol- The Pro12Ala polymorphism of PPAR␥2 Ala allele. Its incidence in the expression lowed a diet in the last year. Each subject was determined by PCR single-strand of obesity, insulin resistance, and type 2 answered a standardized food-frequency conformation polymorphism. diabetes is controversial (1–4). Recently questionnaire. Portion sizes were speci- The diagnosis of type 2 diabetes was it was suggested (5) that a gene-nutrient fied for each foodstuff, and subjects were performed following the new American interaction at the PPAR␥ locus exists. We asked how often their consumption of Diabetes Association criteria (9). hypothesized that when exposed to a that was in a scale ranging from “never or chronic environment of high trans fatty once a month ” to “five or more times a acid (FA) and saturated FA (SFAs) intake day.” The types of fat commonly used for RESULTS — The polymorphism was and sedentary lifestyle, 12Ala carriers ex- cooking and at the table were surveyed detected in 21.4% of the sample: 11 het- press more type 2 diabetes at lower BMI and registered. The values for the amount erozygotes and 1 homozygote (Table 1). and age than subjects without the poly- of dietary fats in food were obtained from Fifty percent of Ala carriers had abnor- morphism. This could be due to some computerized nutritional data, including malities in their glucose metabolism: five weakness in the defenses against the ec- regional data (6) as well as basic data from subjects had type 2 diabetes and one im- topic storage of triglycerides, particularly the U.S. Department of Agriculture’s Nu- paired fasting glucose. This significantly in myocytes and ␤-cells. The current tritive Value of Food (7). Nutritional infor- differed with the figure of 10.4% detected study is aimed at examining these possi- mation from manufacturers and in Pro12Pro subjects: three subjects had ble relationships. published literature was also taken into type 2 diabetes and two impaired fasting account. The intake of total fat, SFAs, and glucose. Table 1 shows that type 2 diabe- RESEARCH DESIGN AND polyunsaturated and monounsaturated tes tends to occur at younger ages in Ala METHODS — This is a pilot study. FAs was calculated in grams per day. We carriers than in Pro12Pro carriers and at We have included 56 subjects (40 women estimated the daily intake of trans FAs in lower waist circumference, BMI, and in- and 16 men), all of them Caucasian, who grams, averaging the weekly intake of sulin levels; but none of them reached sig- consecutively visited our metabolic de- margarine, pastry, cookies, cakes, packed nificance, perhaps due to the smallness of partment seeking care for overweight and white bread, shortcakes (extremely pop- the sample. The daily intake of total FAs was higher in diabetic Ala carriers than in obesity, but not all were overweight or ular in Uruguay), as well as those con- ϭ obese. It was a population with a wide age tained in fried food, sandwiches, beef, nondiabetic subjects (P 0.010). The same was true for the intake of SFAs (P ϭ range (21–62 years) and range of BMI pork, or lamb. Most of the margarine used Ͻ (22.3–58.5 kg/m2), ideal for exploring in Uruguay is stick margarine, containing 0.007) and, particularly, for trans FA (P our hypothesis. Criteria for exclusion close to 30% of trans FA and nearly 15% 0.001). ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1Department of Endocrinology and Metabolism, University of the Republic, Montevideo, Uruguay; CONCLUSIONS 2 — To our knowl- the Department of Molecular Biology, University of Science, University of the Republic, Montevideo, edge, no studies have been published ex- Uruguay; the 3Department of Clinical Genetics, University of the Republic, Montevideo, Uruguay; and the 4Department of Nutrition, University of the Republic, Montevideo, Uruguay. ploring the relationships between the Address correspondence and reprint requests to Raul Eduardo Pisabarro, MD, Domingo Cullen 693, intake of trans FAs and type 2 diabetes in Montevideo CP 11100, Uruguay. E-mail: [email protected]. Pro12Ala subjects. Luan et al. (5) re- Received for publication 30 April 2004 and accepted in revised form 31 May 2004. ported the gene-nutrient interaction at Abbreviations: FA, fatty acid; PPAR, peroxisome proliferator–activated receptor; SFA, saturated FA. ␥ A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion the PPAR locus. From the biological factors for many substances. point of view, it is plausible for trans FAs © 2004 by the American Diabetes Association. to have the same effect as SFAs in activat- DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 2251 Type 2 diabetes in PPAR␥2 Pro12Ala carriers Table 1—Comparisons between diabetic/impaired fasting glucose (IFG) and nondiabetic subjects according to PPAR␥ genotype status Non–Ala carriers Ala carriers Variable Nondiabetic Diabetic/IFGP Nondiabetic Diabetic/IFG P n 39 3/2 6 5/1 Weight (kg) 90.2 Ϯ 22.1 127.4 Ϯ 27.0 0.003 69.5 Ϯ 13.3 109.3 Ϯ 14.3 0.001 Waist circumference (cm) 100.5 Ϯ 20.0 133.8 Ϯ 12.1 0.002 78.3 Ϯ 6.1 115.8 Ϯ 19.9 0.002 BMI (kg/m2) 32.6 Ϯ 7.1 41.8 Ϯ 7.7 0.018 25.8 Ϯ 3.5 38.0 Ϯ 7.8 0.006 Age (years) 40.6 Ϯ 15.1 56.8 Ϯ 4.9 0.041 27.0 Ϯ 5.7 48.7 Ϯ 10.8 0.002 Basal insulinemia (mUI/l) 14.4 Ϯ 13.0 38.8 Ϯ 29.9 0.003 10.8 Ϯ 4.4 26.3 Ϯ 14.3 0.030 Basal glycemia (mg/dl) 92.0 Ϯ 8.6 144.8 Ϯ 38.3 Ͻ0.0001 84.7 Ϯ 10.5 163.3 Ϯ 60.4 0.010 Energy expenditure (kcal/week) 776.6 Ϯ 427.8 575.3 Ϯ 117.3 0.358 1,016.3 Ϯ 372.7 405.3 Ϯ 122.0 0.003 SFA (g/day) 39.9 Ϯ 24.8 36.8 Ϯ 18.4 0.808 26.7 Ϯ 5.4 78.4 Ϯ 36.7 0.007 Trans FA (g/day) 19.0 Ϯ 13.4 19.3 Ϯ 13.2 0.964 8.8 Ϯ 1.4 35.9 Ϯ 13.4 Ͻ0.001 Data are means Ϯ SD. ing the steatosis pathways that result in erator activated receptor gamma (PPAR References insulin resistance and early dysfunction gamma) gene and type 2 diabetes. Exp Clin ␤ 1. Altshuler D, Hirschhorn JN, Klannemark Endocrinol Diabetes 109:151–154, 2001 of the -cells. It could be possible that M, Lindgren CM, Vohl M-C, Nemesh J, 5. Luan J, Browne PO, Harding A-H, Halsall carriers who ingest these fats are more Lane CR, Schaffner SF, Bolk S, Brewer C, DJ, O’Rahilly S, Chatterjee VKK, Ware- susceptible to type 2 diabetes than non- Tuomi T, Gaudet D, Hudson TJ, Daly M, ham NJ: Evidence for gene-nutrient inter- carriers. But the reason why subjects with Groop L, Lander ES: The common PPAR- action at the PPAR␥ locus. Diabetes 50: the Pro12Ala polymorphism may exhibit gamma Pro12Ala polymorphism is asso- ciated with decreased risk of type 2 686–689, 2001 such lack of control over fat intake is still 6. Mazzei ME, Puchulo MR, Rochaix MA: ␣ ␥ diabetes. Nat Genet 26:76–80, 2000 unclear. Is it possible for PPAR and - to Tabla de Composicio´n Quı´mica de los Ali- exert a central modulation over fat intake, 2. Mancini FP, Vaccaro O, Sabatino L, Tu- fano A, Rivellese AA, Riccardi G, Colan- mentos:Centro de Endocrinologı´a Experi- acting as fatty sensors, or is it a casual tuoni V: Pro12Ala substitution in the mental Aplicada (CENEXA). Buenos Aires, finding in a small number of Ala carriers? peroxisome proliferator–activated recep- Argentina,Fundacio´n para la Promocio´n This hypothesis must be tested in future tor-␥2 is not associated with type 2 diabe- de la Educacio´n y la Investigacio´nenDi- research. tes. Diabetes 48:1466–1468, 1999 abetes y Enfermedades de la Nutricio´n In summary, we found a direct rela- 3. Hegele RA, Cao H, Harris SB, Zinman B, (FEIDEN), 1995 tionship between the intakes of trans FA Hanley AJ, Anderson CM: Peroxisome 7. U.S. Department of Agriculture: Nutritive and type 2 diabetes in Ala carriers. Con- proliferator-activated receptor-gamma2 Value of Food. Washington, DC, U.S. Govt. Printing Office, 1998 firmation of this finding will require fur- P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 85: 8. Kriska AM, Caspersen CJ: Paffembarger ther research, with larger numbers of 2014–2019, 2000 physical activity questionnaire. Med Sci subjects, and it could be very important 4. Evans D, de Heer J, Hagemann C, Wendt Sports Exerc 29:S83–S88, 1997 for our clinical practice, considering the D, Wolf A, Beisiegel U, Mann WA: Asso- 9.