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Mechanism of pancreatic β cell dysfunction in obese diabetes model db/db mice

Research Project

Project/Area Number 15590962
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionKawasaki Medical School, Faculty of Medicine

Principal Investigator

KAKU Kohei  Kawasaki Medical School, Department of Internal Medicine, Professor, 医学部, 教授 (10116709)

Co-Investigator(Kenkyū-buntansha) MATSUDA Masafumi  Kawasaki Medical School, Department of Internal Medicine, Lecturer, 医学部, 講師 (00199811)
SHIGETO Masato  Kawasaki Medical School, Department of Internal Medicine, Assistant, 医学部, 助手 (60368628)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordsdb / db mice / β cell function / Laser Capture Microdissection / islet gene expression / pioglitazone / 膵ラ氏島 / 糖・脂肪毒性 / 遺伝子発現プロファイリング / diazoxide / %膵ラ氏島面積 / β細胞比率 / アディポネクチン / 膵ラ島内中性脂肪含量
Research Abstract

It is well known that deranged pancreatic b cell function is an important phathophysiology in type 2 diabetes. In order to clarify the mechanism of β cell dysfunction, structural and functional analyses of the pancreatic islet of C57BL/KsJ db/db mice were carried out, and effects of pioglitazone on islet morphology and function were also examined. In addition, gene expression profiles of pancreatic islet was analyzed by using Laser Capture microdissection method and real time RT-PCR method. Pioglitazone has been demonstrated to have potency not only on peripheral tissues but also pancreatic β cells. To evaluate preventive effects of pioglitazone on pancreatic β-cell damage in db/db mice, an obese diabetic animal model, and to elucidate their mechanisms, we administered pioglitazone on db/db mice, and investigated the pancreas histologically, and compared pancreatic islets biochemically and physiologically with those obtained from untreated mice and db/+ non-diabetic mice. Twelve weeks' … More treatment (6-18 weeks of age) in db/db mice with pioglitazone (100 mg/kg or 30 mg/kg daily p.o.) induced a significant reduction in the fasting blood glucose level (260±12 vs 554±62 mg/dl in untreated control at 18 weeks of age, p<0.05). The % islet area in the pancreas was significantly larger in pioglitazone-treated mice than in the untreated control db/db mice (2.54±0.28 vs 1.16±0.06%, p<0.001). The ratio of β-cells determined by immunohistochemistry to total cells in a pancreatic islet was also greater in the pioglitazone-treated mice (80.6±12.0 vs 73.4±2.2 % in untreated control, p<0.01). After six weeks' treatment with pioglitazone (100 mg/kg daily p.o.), the plasma levels of glucose, triglyceride, and free fatty acid were significantly decreased, while the plasma adiponectin level increased significantly (65.2±18.0 vs 18.3±1.3 μg/ml in untreated control, p<0.05). Insulin tolerance tests revealed that pioglitazone increased insulin sensitivity. The triglyceride content in pancreatic islets was significantly reduced by pioglitazone (43.3±3.6 vs 65.6±7.6 ng/islet in untreated control, p<0.05). Impaired glucose-stimulated insulin secretion from pancreatic islets in the control mice was restored by the treatment with pioglitazone. In the db/db mice, gene expression for pancreatic hormones such as glucagons and somatostatin was observed in the core area of islet, indicating deranged islet architecture. In addition, apoptotic gene expression was accerelated in db/db mice. A compensatory up-regulation of insulin gene expression was suggested in the db/+ mice. The present results demonstrate a molecular mechanism of deranged β cell function in db/db mice, and suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the islets in db/db mice. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (19 results)

All 2005 2004 2003 Other

All Journal Article (16 results) Publications (3 results)

  • [Journal Article] Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice.2005

    • Author(s)
      Kawasaki F, et al.
    • Journal Title

      Am. J. Physiol. Endocrinol Metab 288

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] First phase of glucose stimulated insulin secretion frompancreas consits of theree different pathways including ATP-sensitive potassium channel.2005

    • Author(s)
      Shigeto M, et al.
    • Journal Title

      Diabetes 46〔Suppl 1〕

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cellular mechanism of pancreatic b-cell dysfunction in diabetic db/db mice; evidence for deranged gene expression profiles of islet cells obtained by laser capture microdissection.2005

    • Author(s)
      Kanda Y, et al.
    • Journal Title

      Diabetologia 46〔Suppl 1〕

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ATP-sensitive potassium channel independent pathway is involved in action mechanism of meglitinides, but not sulfonylureas.2005

    • Author(s)
      Shigeto M, et al.
    • Journal Title

      Diabetologia 46〔Suppl 1〕

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice2005

    • Author(s)
      Kawasaki F et al.
    • Journal Title

      Am.J.Physiol.Endocrinol Metab 288

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cellular mechanism of pancreatic beta cell dysfunction in diabtic db/db mice ; evidence for deranged gene expression profiles of islet cells.2005

    • Author(s)
      Kanda Y, et al.
    • Journal Title

      Diabetologia 46[Suppl 1]

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] First phase of glucose stimulated insulin secretion frompancreas consits of theree different pathways including ATP-sensitive potassium channel2005

    • Author(s)
      Shigeto M, et al.
    • Journal Title

      Diabetes 54[Suppl 1]

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ATP-sensitive potassium channel independent pathway is involved in action mechanism of meglitinides, but not sulfonylureas.2005

    • Author(s)
      Shigeto M, et al.
    • Journal Title

      Diabetologia 46[Suppl 1]

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice.2005

    • Author(s)
      Kawasaki F, et al.
    • Journal Title

      Am J Physiol (Endocrinol Metab) 288

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Retained capacity of glucose-mediated insulin secretion in patients with type 2 diabetes mellitus inversely correlates with the duration of diabetes.2004

    • Author(s)
      Kaku K, et al.
    • Journal Title

      Diab, Res. Clin. Pract. 64

      Pages: 221-223

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Retained capacity of glucose-mediated insulin secretion in patients with type 2 diabetes mellitus inversely correlates with the duration of diabetes.2004

    • Author(s)
      Kaku K, et al.
    • Journal Title

      Diab, Res.Clin.Pract 64

      Pages: 221-223

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Retained capacity of glucose-mediated insulin secretion in patients with type 2 diabetes mellitus inversely correlates with the duration of diabetes.2004

    • Author(s)
      Kaku K, et al.
    • Journal Title

      Diab Res Clin Prac 64

      Pages: 221-224

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cross-sectional analyses of plasma adipocytokines in Japanese type 2 diabetic subjects : relations with fat localization and diabetic angiopaties.2004

    • Author(s)
      Matsuda M, et al.
    • Journal Title

      Diabtic Med 21

      Pages: 881-888

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effect of apolipoprotein E4 allele on plasma LDL-cholesterol response to diet therapy in type 2 diabetic patients.2004

    • Author(s)
      Saito M, et al.
    • Journal Title

      Diabetes Care 27

      Pages: 1276-1280

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Association of the Gene Encoding Wingless-Type Mammary Tumor Virus Integration-Site Family Member 5B (WNT5B) with Type 2 Diabetes2004

    • Author(s)
      Kanazawa A, et al.
    • Journal Title

      Am J Hum Genet 75

      Pages: 832-843

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of single nucleotide polymorphism2003

    • Author(s)
      Tanaka N, et al.
    • Journal Title

      Diabetes 52

      Pages: 2848-2853

    • Related Report
      2004 Annual Research Report
  • [Publications] Matsuda M, Kaku K, et al.: "Cross-sectional analyses of plasma adipocytokines in Japanese type 2 diabetic subjects : relations with fat localization and diabetic angiopaties"Diabetic Med. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kaku K, Kanda Y, et al.: "Retained capacity of glucose-mediated insulin secretion in patients with type 2 diabetes mellitus inversely correlates with the duration of diabetes"Diab Res Clin Pract. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川崎史子(指導:加来浩平): "薬剤介入による肥満糖尿病マウス膵β細胞機能障害の抑制効果-DiazoxideとPioglitazoneの作用および作用機序の比較検討-"川崎医会誌. 29. 115-130 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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