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1996 Fiscal Year Final Research Report Summary

A study on the beta-Cell glucose sensors in insulin secretion : The relationship between dysfunction of glucose sensors and development of diabetes mellitus

Research Project

Project/Area Number 07044256
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SEINO Yutaka  Graduate School of Medicine, Kyoto Univ., 医学研究科, 教授 (40030986)

Co-Investigator(Kenkyū-buntansha) 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
Project Period (FY) 1995 – 1996
KeywordsDiabetes Mellitus / Gene / Mutation / Pancreatic beta cell / Glucose Transporter / Voltage-dependent Calcium Channel / GIP Receptor / PCR-SSCP
Research Abstract

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.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Y.Ihara,et al.: "Molecular diversity and functional characterization of votage-dependent calcium channels(CACN4)expressed in pancreatic β-cells." Mol.Endocrinol. 9. 121-130 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] N.Inagaki,et al.: "Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues,including pancreatic islets,pituitary,skeletal muscle and heart." J.Biol.Chem.270. 5691-5694 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Kato,et al.: "Alterations in basal and glucose-stimulated voltage-dependent Ca2+ channel activities in pancreatic β cells of non-insulin-dependent diabetes mellitus GK rats." J.Clin.Invest.97. 2417-2425 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Yamada,et al.: "The Structures of the human Calcium Channel α 1 Subunit(CACNL1A2)and β Subunit(CACNLB3)Genes" GENOMICS. 27. 312-319 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y,Yamada,et al.: "Human Gastric Inhibitory Polypeptide Receptor:Cloning of the Gene(GIPR)and cDNA" GENOMICS. 29. 773-776 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A.Kubota,et al: "Identification of Two Missense Mutations in the GIP Receptor Gene:A Functional Study and Association Analysis with NIDDM" DIABETES. 45. 1701-1705 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Ihara, et al.: "Molecular diversity and functional characterization of votage-dependent calcium channels (CACN4) expressed in pancreatic beta-cells." Mol.Endocrinol.9. 121-130 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] N.Inagaki, et al.: "Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart." J.Biol.Chem.270. 5691-5694 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Kato, et al.: "Alterations in basal and glucose-stimulated voltage-dependent Ca2+ channel activities in pancreatic beta cells of non-insulin-dependent diabetes mellitus GK rats." J.Clin.Invest.97. 2417-2425 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y.Yamada, et al.: "The Structures of the human Calcium Channel alpha 1 Subunit (CACNL1A2) and beta Subunit (CACNLB3) Genes" GENOMICS. 27. 312-319 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y.Yamada, et al.: "Human Gastric Inhibitory Polypeptide Receptor : Cloning of the Gene (GIPR) and cDNA" GENOMICS. 29. 773-776 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A.Kubota, et al.: "Identification of Two Missense Mutations in the GIP Receptor Gene : A Functional Study and Association Analysis with NIDDM" DIABETES. 45. 1701-1705 (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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