Influence of the PPAR-γ2 Pro12Ala and ACE I/D Polymorphisms on Insulin Sensitivity and Training Effects in Healthy Offspring of Type 2 Diabetic Subjects

Abstract

Aerobic endurance training improves insulin sensitivity, and is of great importance in the prevention and treatment of type 2 diabetes. The improvement in insulin sensitivity and cardiovascular function through exercise is highly variable among individuals, and is probably partly determined by genetic components. This study evaluated the peroxisome proliferation-activated receptor-γ2 (PPAR-γ2) Pro12Ala polymorphism and the angiotensin converting enzyme (ACE) I/D polymorphism with respect to any potential influence that these highly prevalent polymorphisms may impose on changes in insulin sensitivity and maximal aerobic capacity induced by exercise. Seventy-nine healthy first-degree relatives of type 2 diabetic patients were compared to a control group consisting of 54 subjects without any family history of type 2 diabetes. All subjects had a normal OGTT. The groups were comparable with respect to age (34 ± 7 vs. 33 ± 7 years), gender ((m/f) 43/36 vs. 30/24) and BMI (25.7 ± 2.6 vs. 25.3 ± 2.5 kg/m²); p (all) = NS. Furthermore, a subgroup of 29 offspring and 17 control subjects were engaged in a standardized training program lasting ten weeks. Insulin sensitivity (hyperinsulinemic euglycemic clamp technique) and VO₂max (exhaustive exercise test) was assessed before and after the training period. We will demonstrate the allelic frequency of the Ala-allele of the Pro12Ala polymorphism to be lower in offspring to type 2 diabetic patients (13.3 %) compared to control subjects (21.3 %); p < 0.05. In offspring only, the Pro12Ala polymorphism of the PPAR-γ2 gene appeared to enhance weight changes brought about by exercise (Δweight = - 0.3 ± 1.4 kg vs. - 1.8 ± 1.8 kg; p < 0.05; (Pro/Pro vs. Pro/Ala + Ala/Ala) - suggesting possible gene-environment or gene-gene interactions. The ACE I/D polymorphism was not of significant importance in determining the capability of responding to exercise in terms of improvement in insulin sensitivity or maximal aerobic capacity.

Key words

Polymorphism · Type 2 diabetes · Exercise · Insulin resistance

References

• 1 DeFronzo R A, Ferrannini E. .  Diabetes Care. 1991;  14 173-194
• 2 Tuomilehto J, Lindstrom J, Eriksson J G, Valle T T, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M. .  N Engl J Med. 2001;  344 1343-1350
• 3 Knowler W C, Barrett-Connor E, Fowler S E, Hamman R F, Lachin J M, Walker E A, Nathan D M. .  N Engl J Med. 2002;  346 393-403
• 4 McIntyre E A, Walker M. .  Clin Endocrinol (Oxf). 2002;  57 303-311
• 5 Bouchard C, An P, Rice T, Skinner J S, Wilmore J H, Gagnon J, Perusse L, Leon A S, Rao D C. .  J Appl Physiol. 1999;  87 1003-1008
• 6 Altshuler D, Hirschhorn J N, Klannemark M, Lindgren C M, Vohl M C, Nemesh J, Lane C R, Schaffner S F, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson T J, Daly M, Groop L, Lander E S. .  Nat Genet. 2000;  26 76-80
• 7 Kahara T, Takamura T, Hayakawa T, Nagai Y, Yamaguchi H, Katsuki T, Katsuki K, Katsuki M, Kobayashi K. .  Metabolism. 2003;  52 209-212
• 8 Lindi V I, Uusitupa M I, Lindstrom J, Louheranta A, Eriksson J G, Valle T T, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Tuomilehto J. .  Diabetes. 2002;  51 2581-2586
• 9 Katsuya T, Horiuchi M, Chen Y D, Koike G, Pratt R E, Dzau V J, Reaven G M. .  Arterioscler Thromb Vasc Biol. 1995;  15 779-782
• 10 Huang X H, Rantalaiho V, Wirta O, Pasternack A, Koivula T, Hiltunen T, Nikkari T, Lehtimaki T. .  Hum Genet. 1998;  102 372-378
• 11 Thamer C, Koch M, Haap M, Machicao F, Haring H U, Stumvoll M. .  Atherosclerosis. 2002;  160 257-258
• 12 Rankinen T, Wolfarth B, Simoneau J A, Maier-Lenz D, Rauramaa R, Rivera M A, Boulay M R, Chagnon Y C, Perusse L, Keul J, Bouchard C. .  J Appl Physiol. 2000;  88 1571-1575
• 13 Williams A G, Rayson M P, Jubb M, World M, Woods D R, Hayward M, Martin J, Humphries S E, Montgomery H E. .  Nature. 2000;  403 614
• 14 Martin B C, Warram J H, Krolewski A S, Bergman R N, Soeldner J S, Kahn C R. .  Lancet. 1992;  340 925-929
• 15 Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. .  N Engl J Med. 1989;  321 337-343
• 16 Nyholm B, Fisker S, Lund S, Moller N, Schmitz O. .  Eur J Endocrinol. 1997;  136 173-179
• 17 Aastrand I. .  Acta Physiologica Scandinavia. 1960;  49 1-92
• 18 Ek J, Urhammer S A, Sorensen T I, Andersen T, Auwerx J, Pedersen O. .  Diabetologia. 1999;  42 892-895
• 19 Saltin B, Grimby G. .  Circulation. 1968;  38 1104-1115
• 20 Baecke J A, Burema J, Frijters J E. .  Am J Clin Nutr. 1982;  36 936-942
• 21 Yen C J, Beamer B A, Negri C, Silver K, Brown K A, Yarnall D P, Burns D K, Roth J, Shuldiner A R. .  Biochem Biophys Res Commun. 1997;  241 270-274
• 22 Douglas J A, Erdos M R, Watanabe R M, Braun A, Johnston C L, Oeth P, Mohlke K L, Valle T T, Ehnholm C, Buchanan T A, Bergman R N, Collins F S, Boehnke M, Tuomilehto J. .  Diabetes. 2001;  50 886-890
• 23 Ek J, Andersen G, Urhammer S A, Hansen L, Carstensen B, Borch-Johnsen K, Drivsholm T, Berglund L, Hansen T, Lithell H, Pedersen O. .  Diabetologia. 2001;  44 1170-1176
• 24 Jacob S, Stumvoll M, Becker R, Koch M, Nielsen M, Loblein K, Maerker E, Volk A, Renn W, Balletshofer B, Machicao F, Rett K, Haring H U. .  Horm Metab Res. 2000;  32 413-416
• 25 Deeb S S, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. .  Nat Genet. 1998;  20 284-287
• 26 Stumvoll M, Haring H. .  Diabetes. 2002;  51 2341-2347
• 27 Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki H, Hagura R, Akanuma Y, Kimura S, Ito C, Kadowaki T. .  Biochem Biophys Res Commun. 2000;  271 212-216
• 28 Stumvoll M, Wahl H G, Loblein K, Becker R, Machicao F, Jacob S, Haring H. .  Diabetes. 2001;  50 876-881
• 29 Koch M, Rett K, Maerker E, Volk A, Haist K, Deninger M, Renn W, Haring H U. .  Diabetologia. 1999;  42 758-762
• 30 Luan J, Browne P O, Harding A H, Halsall D J, O'Rahilly S, Chatterjee V K, Wareham N J. .  Diabetes. 2001;  50 686-689
• 31 Nicklas B J, van Rossum E F, Berman D M, Ryan A S, Dennis K E, Shuldiner A R. .  Diabetes. 2001;  50 2172-2176
• 32 Pihlajamaki J, Vanhala M, Vanhala P, Laakso M. .  Obes Res. 2004;  12 187-190
• 33 Montgomery H, Clarkson P, Barnard M, Bell J, Brynes A, Dollery C, Hajnal J, Hemingway H, Mercer D, Jarman P, Marshall R, Prasad K, Rayson M, Saeed N, Talmud P, Thomas L, Jubb M, World M, Humphries S. .  Lancet. 1999;  353 541-545
• 34 Strazzullo P, Iacone R, Iacoviello L, Russo O, Barba G, Russo P, D'Orazio A, Barbato A, Cappuccio F P, Farinaro E, Siani A. .  Ann Intern Med. 2003;  138 17-23
• 35 Wang J G, He X, Wang G L, Li Y, Zhou H F, Zhang W Z, Zhan Y M, Zhu D L. .  J Hypertens. 2004;  22 487-491
• 36 Panahloo A, Andres C, Mohamed-Ali V, Gould M M, Talmud P, Humphries S E, Yudkin J S. .  Circulation. 1995;  92 3390-3393
• 37 Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. .  J Clin Invest. 1990;  86 1343-1346
• 38 Pollare T, Lithell H, Berne C. .  N Engl J Med. 1989;  321 868-873
• 39 Heise T, Heinemann L, Kristahn K, Berger M, Sawicki P T. .  Horm Metab Res. 1999;  31 418-423
• 40 Rankinen T, Perusse L, Gagnon J, Chagnon Y C, Leon A S, Skinner J S, Wilmore J H, Rao D C, Bouchard C. .  J Appl Physiol. 2000;  88 1029-1035
• 41 Sonna L A, Sharp M A, Knapik J J, Cullivan M, Angel K C, Patton J F, Lilly C M. .  J Appl Physiol. 2001;  91 1355-1363
• 42 Montgomery H E, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, Hayward M, Holliman D E, Jubb M, World M, Thomas E L, Brynes A E, Saeed N, Barnard M, Bell J D, Prasad K, Rayson M, Talmud P J, Humphries S E. .  Nature. 1998;  393 221-222