| Project/Area Number |
09557078
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内分泌・代謝学
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| Research Institution | University of Tokyo |
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Principal Investigator |
KADOWAKI Takashi Faculty of Medicine, University of Tokyo, Lecturer, 医学部・附属病院, 講師 (30185889)
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| Co-Investigator(Kenkyū-buntansha) |
ETO Kazuhiro Faculty of Medicine, University of Tokyo, Medical Staff, 医学部・附属病院, 医員
YASUDA Kazuki Faculty of Medicine, University of Tokyo, Medical Staff, 医学部・附属病院, 医員
TOBE Kazuyuki Faculty of Medicine, University of Tokyo, Assistant, 医学部・附属病院, 助手 (30251242)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 1999: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1998: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1997: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | type 2 diabetes / a polygenic, multifactorial disorder / affected sib-pair analysis / susceptibility loci / PPARγ / insulin resistance / high-fat diet / thrifty genes / β2 adrenergic receptor / Common NIDDM / 全ゲノムマッピング / 罹患同胞対 / 候補遺伝子アプローチ / インスリン分泌低下 / アミリン / 糖尿病 / 肥満 / 候補遺伝子 / ゲノムマッピング / 疾患感受性 |
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| Research Abstract |
It has been suggested that most of type, 2 diabetes is likely to be a polygenic, multifactorial disorder, although one or more major genes could be involved. In this study, we aimed to identify the susceptibility genes using affected sib-pair analysis, which is thought to be suitable for detecting susceptibility loci for such polygenic, multifactorial disorders. We have already, genotyped highly polmorphic markers on several chromosomes. Whole genome will be investigated and several loci would be mapped by the end of fiscal 2000.
We also tried to detect the susceptibility genes for type 2 diabetes using population association studies with candidate genes. We have generated PPARγ deficient mice to investigate the physiological role of PPARγ in adipocyte hypertrophy arid insulin resistance under a high-fat diet. Heterozygous PPARγ deficient mice were protected from fat accumulation, body weight gain and insulin resistance under a high-fat diet (Mol Cell 4: 597-609, 1999). Therefore we proposed that PPARγ is one of the important thrifty genes and associated with 'multifactorial' type 2 diabetes. To investigate whether PPARγ serves as a thrifty gene in humans, we investigated the association between Pro12Ala polymorphism in PPARγ gene and type2 diabetes. In obese subjects, Alal2 allele of PPARγ2 gene protects against insulin resistance. Allele of Alal2 was, significantly less frequent in type2 diabetic subjects than in non-diabetic, suggesting that the Alal2 polymorphism in PPARγ2 may protect against type2 diabetes (Diabetologia, in press).
We have also found that the Gln27Glu β2 adrenergic receptor variant is associated with obesity due to subcutaneous fat accumulation (Biochem Biophys Res Commun 258 : 138-140, 1999).
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