The Pro12→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 Mori1,
- Hiroshi Ikegami2,
- Yoshihiko Kawaguchi2,
- Susumu Seino3,
- Norihide Yokoi3,
- Jun Takeda4,
- Ituro Inoue4,
- Yutaka Seino5,
- Koichiro Yasuda5,
- Toshiaki Hanafusa6,
- Kazuya Yamagata6,
- Takuya Awata7,
- Takashi Kadowaki8,
- Kazuo Hara8,
- Nobuhiro Yamada9,
- Takanari Gotoda10,
- Naoko Iwasaki11,
- Yasuhiko Iwamoto11,
- Tokio Sanke12,
- Kishio Nanjo13,
- Yoshitomo Oka14,
- Akira Matsutani14,
- Eiichi Maeda1 and
- Masato Kasuga1
- 1Second Department of Internal Medicine, Kobe University School of Medicine, Kobe
- 2Department of Geriatric Medicine, Osaka University Medical School, Osaka
- 3Department of Molecular Medicine, Chiba University Graduate School of Medicine, Chiba
- 4Laboratory of Molecular Genetics, Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma
- 5Department of Metabolism and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto
- 6Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka
- 7Fourth Department of Medicine, Saitama Medical School, Saitama
- 8Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo
- 9Institute of Clinical Medicine Metabolism, Endocrinology, and Atherosclerosis, University of Tsukuba, Tsukuba, Ibaraki
- 10Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo
- 11Diabetes Center, Tokyo Women’s Medical University, Tokyo
- 12Department of Clinical Laboratory Medicine and the
- 13First Department of Medicine, Wakayama University of Medical Science, Wakayama
- 14Third Department of Internal Medicine, Yamaguchi University, School of Medicine, Yamaguchi, Japan
Abstract
The allele frequencies for a Pro12→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 Ala12 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 Ala12 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 HbA1c. These data suggest that the Ala12 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
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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.
