Objective: To analyze the relationship between the peroxisome proliferator-activated receptor-γ (PPARγ2) Pro12Ala variant and type-2 diabetes mellitus and its correlation with some cytokine determinants of insulin resistance such as tumor necrosis factor (TNF)-α and leptin. Methods: The PPARγ2 Pro12Ala genetic polymorphism was studied in 167 type-2 diabetic patients and 63 healthy controls. Serum leptin and plasma-soluble TNF-R2 were measured. Results: Women carriers of the Pro12Ala mutation exhibited higher leptin levels than women non-carriers (median 31.4 vs. 17.5 ng/ml; p < 0.005). sTNF-R2 levels did not show differences between the two genotypes. Analysis by the multiple linear regression model of leptin-body mass index controlled by the PPARγ2 genotype showed that leptin levels were determined by the Pro12Ala mutation in type-2 diabetic women but not in men. Conclusions: PPARγ2 seems to be implicated in leptin homeostasis in type-2 diabetic women.

Keywords:
Peroxisome proliferator-activated receptor-=γ, Leptin, Diabetes mellitus type-2
1.
Auwerx J: PPARγ, the ultimate thrifty gene. Diabetologia 1999;42:1033–1049.
2.
Tontonoz P, Graves RA, Budavari AB, Erdjument-Bromage H, Lui M, Hu E, Tempst P, Spiegelman BM: Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPARγ2 and RXRα. Nucleic Acids Res 1999;22:5628–5634.
3.
Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-Puig A, Flier JS: Ligand-independent activation domain in the N terminus of peroxisome roliferator-activated receptor γ (PPARγ). J Biol Chem 1997;272:20230–20235.
4.
Yen CJ, 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-gamma gene in diabetic Caucasians: Identification of a Pro12Ala PPARgamma 2 missense mutation. Biochem Biophys Res Commun 1997;241:270–274.
5.
Deeb S, Fajas L, Nemoto M, Laakso M, Fujimoto W, Auwerx J: A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998;20:284–287.
6.
Beamer BA, Yen CJ, 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-γ2 gene with obesity in two Caucasian populations. Diabetes 1998;47:1806–1808.
7.
Mancini FP, Vaccaro O, Sabatino L, Tufano A, Rivellese AA, Riccardi G, Colantuoni V: Pro12Ala substitution in the peroxisome proliferator-activated receptor-γ2 is not associated with type 2 diabetes. Diabetes 1999;48:1466–1468.
8.
Oh EY, Min KM, Chung JH, Min JK, Lee MS, Kim KW, Lee MK: Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-γ2 in Korean diabetic and obese subjects. J Clin Endocrinol Metab 2000;85:1801–1804.
9.
Hollenberg AN, Susulic VS, Madura JP, Zhang B, Moller DE, Tonotonoz P, Sarraf P, Spiegelman BM, Lowell BB: Functional antagonism between CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ on the leptin promoter. J Biol Chem 1997;272:5283–5290.
10.
Xing H, Northrop JP, Grove JR, Kilpatrick KE, Su JL, Ringold GM: TNF-α-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARγ without effects on Pref-1 expression. Endocrinology 1997;138:2776–2783.
11.
Peraldi P, Xu M, Spiegelman BM: Thiazolidinediones block tumor necrosis factor-α-induced inhibition of insulin signalling. J Clin Invest 1997;100:1863–1869.
12.
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 Disord 2000;24:391–393.
13.
Ringel J, Engeli S, Distler A, Sharma AM: Pro12Ala missense mutation of the peroxisome proliferator activated receptor γ and diabetes mellitus. Biochem Biophys Res Commun 1999;54:450–453.
14.
Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Auwerx J, Deeb S, Amouyel P: Impact of the peroxisome proliferator activated receptor γ2 Pro12Ala polymorphism on adiposity, lipids and non-insulin-dependent diabetes mellitus. Int J Obes Relat Metab Disord 2000;24:195–199.
15.
Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Groop L, Lander ES: The common PPAR gamma Pro12Ala polimorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.
16.
Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki H, Hagura R, Akamuna Y, Kimura S, Ito C, Kadowaki T: The Pro12Ala polimorphism in PPARgamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun 2000;271:212–216.
17.
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 PPARgamma 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. Diabetes 2001;50:891–894.
18.
Hara K, Kubota N, Tobe K, Terauchi Y, Miki H, Komeda K, Tamemoto H, Yamauchi T, Hagura R, Ito C, Akanuma Y, Kadowaki T: The role of PPARgamma as a thrifty gene both in mice and humans. Br J Nutr 2000;84(suppl 2):S235–S239.
19.
Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJG, Anderson CM: Peroxisome proliferator-activated receptor-γ2 P12A and type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 2000;85:2014–2019.
20.
World Health Organization: Diabetes mellitus. Report of a WHO Study Group. World Health Organ Tech Rep Ser 1985;727:1–113.
21.
Muls E, Blaton V, Rosseneu M, Lesaffre E, Lamberigts G, De Moor P: Serum lipids and apolipoproteins A-I, A-II, and B in hyperthyroidism before and after treatment. J Clin Endocrinol Metab 1982;55:459–464.
22.
Douglas JA, Erdos MR, Watanabe RM, Braun A, Johnston CL, Oeth P, Mohlke KL, Valle TM, Ehnholm C, Buchanan TA, Bergman RN, Collins FS, Boehnke M, Tuomilehto J: The peroxisome proliferator-activated receptor-gamma2 Pro12Ala variant. Association with diabetes type 2 and trait differences. Diabetes 2001;50:886–890.
23.
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 γ2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men. Biochem Biophys Res Commun 1998;251:195–198.
24.
Ek J, Urhammer SA, Sorensen FIA, Anderson T, Auwerx J, Pedersen O: Homozygosity of the Pro12Ala variant of the peroxisome proliferator activated receptor Y2 (PPARγ2): Divergent modulating effects on body mass index in obese and lean men of Caucasian origin. Diabetologia 1999;42:892–895.
25.
Fernández-Real JM, Broch M, Ricart W, Casamitjana R, Gutiérrez C, Vendrell J, Richart C: Plasma levels of the soluble fraction of tumor necrosis factor receptor 2 and insulin resistance. Diabetes 1998;47:1757–1762.
26.
Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan Q, Garwey WT: The metabolic significance of leptin in humans: Gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. J Clin Endocrinol Metab 1997;82:1293–1300.
27.
Cole SA, Mitchell BD, Hsueh WC, Pineda P, Beamer BA, Shuldiner AR, Comuzzie AG, Blangero J, Hixson JE: The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with measures of obesity in Mexican Americans. Int J Obes Relat Metab Disord 2000;24:522–524.
28.
Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y: Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: Evidence for sex and site-related specificities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor gamma 2. Endocrinology 2000;141:649–656.
29.
Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose tissue expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 1993;259:87–91.
30.
Cohen B, Novick D, Rubinstein M: Modulation of insulin activities by leptin. Science 1996;274:1185–1188.
31.
Spiegelman BM: PPAR-γ: Adipogenic regulator and thiazolidinedione receptor. Diabetes 1998;47:507–514.
32.
Souza SC, Yamamoto MT, Franciosa MD, Lien P, Greenberg AS: BRL 49653 blocks lipolytic actions of tumor necrosis factor-alpha: A potential new insulin-sensitizing mechanism for thiazolidinediones. Diabetes 1998;47:691–695.
33.
Cases JA, Gabriely I, Hui Ma X, Yang XM, Miachaeli T, Fleischer N, Rossetti L, Barzilai N: Physiological increase in plasma leptin markedly inhibits insulin secretion in vivo. Diabetes 2001;50:348–352.
34.
Stefan N, Fritsche A, Häring H, Stumvoli M: Effect of experimental elevation of free fatty acids on insulin secretion and insulin sensitivity in healthy carriers of Pro12Ala polimorphism of the peroxisome proliferator-activated receptor-gamma2 gene. Diabetes 2001;50:143–148.
35.
Krempler F, Breban D, Oberkofler H, Esterbauer H, Hell E, Paulweber B, Patsch W: Leptin, peroxisome proliferator-activated receptor-gamma, and CCAAT/enhancer binding protein-alpha mRNA expression in adipose tissue of humans and their relation to cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2000;20:443–449.
36.
Elberg G, Gimble JM, Tsai SY: Modulation of the murine peroxisome proliferator-activated receptor gamma 2 promoter activity by CCAAT/enhancerr binding proteins. J Biol Chem 2000;275:27815–27822.
37.
Soderberg S, Ahren B, Jansson JH, Johnson O, Hallmans G, Asplund K, Olsson T: Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999;246:409–418.
© 2002 S. Karger AG, Basel
2002
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