The Pro12→Ala Substitution in PPAR-γ Is Associated With Resistance to Development of Diabetes in the General Population

• Published in: Diabetes (New York, N.Y.) Vol. 50; no. 4; pp. 891 - 894
• Main Authors: Mori, Hiroyuki, Ikegami, Hiroshi, Kawaguchi, Yoshihiko, Seino, Susumu, Yokoi, Norihide, Takeda, Jun, Inoue, Ituro, Seino, Yutaka, Yasuda, Koichiro, Hanafusa, Toshiaki, Yamagata, Kazuya, Awata, Takuya, Kadowaki, Takashi, Hara, Kazuo, Yamada, Nobuhiro, Gotoda, Takanari, Iwasaki, Naoko, Iwamoto, Yasuhiko, Sanke, Tokio, Nanjo, Kishio, Oka, Yoshitomo, Matsutani, Akira, Maeda, Eiichi, Kasuga, Masato
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01.04.2001
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.50.4.891

The Pro 12 →Ala Substitution in PPAR-γ 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 Hiroyuki Mori 1 , Hiroshi Ikegami 2 , Yoshihiko Kawaguchi 2 , Susumu Seino 3 , Norihide Yokoi 3 , Jun Takeda 4 , Ituro Inoue 4 , Yutaka Seino 5 , Koichiro Yasuda 5 , Toshiaki Hanafusa 6 , Kazuya Yamagata 6 , Takuya Awata 7 , Takashi Kadowaki 8 , Kazuo Hara 8 , Nobuhiro Yamada 9 , Takanari Gotoda 10 , Naoko Iwasaki 11 , Yasuhiko Iwamoto 11 , Tokio Sanke 12 , Kishio Nanjo 13 , Yoshitomo Oka 14 , Akira Matsutani 14 , Eiichi Maeda 1 and Masato Kasuga 1 1 Second Department of Internal Medicine, Kobe University School of Medicine, Kobe 2 Department of Geriatric Medicine, Osaka University Medical School, Osaka 3 Department of Molecular Medicine, Chiba University Graduate School of Medicine, Chiba 4 Laboratory of Molecular Genetics, Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 5 Department of Metabolism and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto 6 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka 7 Fourth Department of Medicine, Saitama Medical School, Saitama 8 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 9 Institute of Clinical Medicine Metabolism, Endocrinology, and Atherosclerosis, University of Tsukuba, Tsukuba, Ibaraki 10 Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo 11 Diabetes Center, Tokyo Women’s Medical University, Tokyo 12 Department of Clinical Laboratory Medicine and the 13 First Department of Medicine, Wakayama University of Medical Science, Wakayama 14 Third Department of Internal Medicine, Yamaguchi University, School of Medicine, Yamaguchi, Japan Abstract The allele frequencies for a Pro 12 →Ala substitution in peroxisome proliferator–activated receptor-γ differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes ( n = 2,201) and normal control subjects ( n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala 12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala 12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol ( P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment ( P = 0.007), and tended to possess a higher level of HbA 1c . These data suggest that the Ala 12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes. ANCOVA, analysis of covariance f-IRI, fasting plasma immunoreactive insulin FPG, fasting plasma glucose HOMA-β, homeostasis model assessment for β-cell function HOMA-IR, HOMA for insulin resistance OR, odds ratio PCR, polymerase chain reaction PPAR-γ, peroxisome proliferator–activated receptor-γ RFLP, restriction fragment–length polymorphism Footnotes Address correspondence and reprint requests to Masato Kasuga, Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: kasuga{at}med.kobe-u.ac.jp . Received for publication 10 July 2000 and accepted in revised form 4 January 2001. T.H. is currently at the First Department of Internal Medicine, Osaka Medical College, Osaka, Japan.