Grant-in-Aid for international Scientific Research
|Allocation Type||Single-year Grants|
|Research Institution||KYOTO UNIVERSITY|
SEINO Yutaka Graduate School of Medicine, Kyoto Univ., 医学研究科, 教授 (40030986)
NEWGARD Chri テキサス大学, 医学部, 准教授
JOHNSON John H The University of Texas Southwestern Medical Center, 医学部, 准教授
FUJIMOTO Wilfred Y University of Washington School of Medicine, 医学部, 教授
ISHIDA Hitoshi Graduate School of Medicine, Kyoto Univ., 医学研究科, 助教授 (80212893)
YAMADA Yuichiro Graduate School of Medicine, Kyoto Univ., 医学研究科, 助手 (60283610)
NEWGARD Christopher B The University of Texas Southwestern Medical Center
津田 謹輔 京都大学, 総合人間学部, 教授 (10180001)
|Project Period (FY)
1995 – 1996
Completed(Fiscal Year 1996)
|Budget Amount *help
¥11,500,000 (Direct Cost : ¥11,500,000)
Fiscal Year 1996 : ¥5,700,000 (Direct Cost : ¥5,700,000)
Fiscal Year 1995 : ¥5,800,000 (Direct Cost : ¥5,800,000)
|Keywords||Diabetes Mellitus / Gene / Mutation / Pancreatic beta cell / Glucose Transporter / Voltage-dependent Calcium Channel / GIP Receptor / PCR-SSCP / 転写調節|
Genetic factors play important roles in pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) as well as environmental factors. Recent studies showed that single gene mutation might have a causative effect in pathogenesis of diabetes mellitus. In Japanese patients with NIDDM,the insulin secretion induced by glucose is impaired in early stage of pathogenesis. Here, we report the mutations of candidate genes for glucose sensor in NIDDM subjects.
First, we examined the mutations of the GLUT2 gene and found a nucleotide substitution Phe^<479> (TTT->TTC). Although it was a silent mutaion, homozygote of this allele was found only in NIDDM subjects, and allelic frequency of this allele was significantly higher in NIDDM subjects than in controls.
Second, the mutations of voltage-dependent calcium channel gene (CACNL1A2) was studied. The PCR-SSCP procedure of exon 1 revealed a change from 7 to 8 ATG trinucleotide repeats in a patient with NIDDM,resulting in an addition of methionine at the amino-terminus. This change was not found in normal controls.
Third, we investigated the entire coding region of the gastric inhibitory poltpeptide receptor (GIPR) gene by PCR-SSCP.We identified two missence mutations, Gly^<198>->Cys (Gly198Cys) in exon 7 and Glu^<354>->Gln (Glu354Gln) in exon 12. Functional analysis of the GIPR with either of these mutations revealed that half-maximal stimulation value of GIP-induced cAMP response in Chinese hamster ovary cells expressing the GIPR with Gly198Cys was considerably higher than that of the wild type, whereas that of the GIPR with Glu354Gln was not significantly different from that of wild type. While allelic frequency of Glu354Gln in NIDDM subjects was not different from that in normal control, homozygotes of the Gly198Cys was detected only in NIDDM subjects.
Mutations described here might be part of mechanisms which contribute to the pathogenesis of NIDDM,and further studies will reveal the rest.