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Fundamental studies on the pathogenesis of diabetic complications using transgenic mice expressing human aldose reductase

Research Project

Project/Area Number 07457055
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionHirosaki University

Principal Investigator

YAGIHASHI Soroku  Hirosaki University, School of Medicine, Professor, 医学部, 教授 (40111231)

Co-Investigator(Kenkyū-buntansha) BABA Masayuki  Hirosaki University, School of Medicine, Associate Professor, 医学部, 助教授 (90106849)
WADA Ryuichi  Hirosaki University, School of Medicine, Assistant, 医学部, 助手 (20260408)
YAGIHASHI Norito  Hirosaki University, School of Medicine, Assistant, 医学部, 助手 (10250622)
KUROTAKI Hidekachi  Hirosaki University, School of Medicine, Lecturer, 医学部, 講師 (40215108)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1996: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1995: ¥3,200,000 (Direct Cost: ¥3,200,000)
KeywordsDiabetes / Aldose Reductase / Polyol Pathway / Complication / Transgenic Mice / Nephropathy / Inhibitor / Neuropathy
Research Abstract

We have established transgenic mice, which express large amount of human aldose reductase, to explore the role of an enhanced polyol-pathway in the pathogenesis of diabetic complications. In our preceding studies, these transgenic mice exhibited significant accumulation of polyols by galactose feeding for 16 weeks associated with significant delay of motor nerve conduction velocity and nerve fiber atrophy of the peripheral nerve, thus demonstrating the implication of polyol pathway in the etiology of diabetic neuropathy. In the current study, we made transgenic mice diabetic for 8 weeks by intraperitoneal injection of streptozotocin and examined biochemical, electrophysiological and structural abnormalities in the peripheral nerve as well as renal lesions. Comparison was made with the changes in non-transgenic littermate control mice. Both transgenic and littermate control mice showed comparable levels of reduced body weight and hyperglycemia. By contrast, motor nerve conduction was mo … More st severely slowed in diabetic trasgenic mice followed by diabetic littermate mice compared to non-diabetic transgenic and littermate control mice. Biochemical measurements disclosed marked accumulation of sorbitol and fructose in diabetic transgenic mice, but such sugar levels were only modestly elevated in diabetic littermate mice. Myo-inositol levels were not altered in both diabetic groups. Morphometric analysis demonstrated significant myelinated fiber atrophy in diabetic transgenic mice compared with diabetic littermate and non-diabetic groups. These findings confirmed that transgenic mice for human aldose reductase developed severe neuropathic changes compared with diabetic littermate mice even under similar levels of hyperglycemia, suggesting that the aldose reductase expression is a critical determinant for the development of neuropathy and its severity. On the other hand, glomerular hypertrophy and mesangial expansion are characteristic changes of early renal lesions in human and animal diabetic nephropathy. Morphometric analysis on the kidney demonstrated significant enlargement of glomerular size and mesangial area in diabetic transgenic and littermate control mice as compared with ion-diabetic groups, while the values of diabetic transgenic mice were the greatest. These findings again indicate that an enhanced polyol pathway influences the development of diabetic glomerulopathy and an expression of aldose reductase mediates such an enhaneced activity of polyol pathway. Preliminary trials with aldose reductase inhibitors significantly inhibited neuropathic and glomerular changes in diabetic transgenic mice but not in diabetic littermate mace. It was thus concluded that the polyol pathway regulated by aldose reductase is an important determinant of the progression of diabetic complications and its effective inhibition may be valuable for the prevention and treatment of diabetic complications. Less

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Yagihashi S et al: "Galactosemic Neuropathy in Transgenic Mice for Human Aldose Reductase." Diabetes. 45. 56-59 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sugimoto K, Yagihashi S: "Peripheral nerve pathology in rats with streptozotocin-induced insulinoma." Acta Neuropathol. 91. 616-623 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sagara M et al: "Inhibition of development of peripheralneuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine." Diabetologia. 39. 263-269 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi N et al: "Expression of nitric oxide synthase in macula densa in streptozotocin diabetic rats." Diabetologia. 39. 793-799 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S: "Pathogenetic mechanisms of diabetic neuropathy: Lessons from amimal models." J Periph Nervous Syst. 2. 1-20 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sugimoto K, Yagihashi S: "Effects of aminoguanidine on endoneurial microvessel abnormalities in streptozotocin-induced diabetic rats." Microvasc Res. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S et al: "Lessons from animal diabetes VI" Birkhauser, Boston, 375-393 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S et al: "Lessons from animal Diabetes VII" Birkhauser, Boston (in press),

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihasi S,Yamagishi S,Wada R,Sugimoto K,Baba M,Wong H-G,Fujimoto J,Nishimura C,Kokai Y: "Galactosemic neuropathy in transgenic mice for human aldose reductases" Diabetes. 45. 56-59 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sugimoto K,Yagihashi S: "Peripheral nerve pathology in rats with streptozotocin-induced insulinoma." Acta Neuropathol. 91. 616-623 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sagara M,Satoh J,Wada R,Yagihashi S,Takahashi K,Fukuzawa M,Muto G,Toyoda T: "Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-aectylcysteine." Diabetologia. 39. 263-269 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi N,Nishida N,Geuk Seo H,Taniguchi N,Yagihashi S: "Expression of nitric oxide synthase in macula densa in streptozotocin diabetic rats." Diabetologia. 39. 793-799 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S: "Pathogenetic mechanisms of diabetic neuropathy : Lessons fro m animal models." J Periph Nervous Syst. 2. 1-20 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sugimoto K,Yagihashi S: "Effects of aminoguanidine on endoneurial microvessel abnormalities in streptozotocin-induced diabetic rats.19GC06 : Microvasc Res" (In press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S,Sugimoto K,Wada R: "Endoneurial vessel abnormalities in diabetic animal models." Lessons from Animal Diabetes VI, (ed by E.Shafrir), Birkhauser, Boston. 375-393 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S,Yamagishi S,Nishimura C.: "Utility of transgenic mouse for diabetes research." Lessons from Animal Diabetes VII, (ed by Sima AAF) Birkhauser, Boston. (In press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yagihashi S et al: "Galactosemic Neuropathy in Transgenic Mice for Human Aldose Reductase." Diabetes. 45. 56-59 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sugimoto,Yagihashi S: "Peripheral nerve pathology in rats with streptozotocin-induced insulinoma." Acta Neuropathol. 91. 616-623 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yagihashi N et al: "Expression of nitric oxide synthase in macula densain str eptozotocin diabetic r ats." Diabetologia. 39. 793-799 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 山岸晋一郎,八木橋操六: "糖尿病合併症モデルとしてのヒトアルドース還元酵素トランスジェニックマウスの解析:ポリオール代謝亢進とアルドース還元酵素発現との関連について." 糖尿病性合併症. 9. 66-73 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yagihashi S at al: "Lessons from animal diabetes VII" Birkhauser, Boston (in press), (inpress)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yagihashi S: "Pathology and pathogenetic mechanisms of diabetic neuropathy" Diabetes Metabolism Reviews. 11. 193-225 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yagihashi S et al: "Polyol-related pathway and its pathological abnormality" Diabetes 1994(Baba S,Kaneko T,ed Elsevier Sci.). 326-330 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yagihashi S et al: "Galactosemic neuropathy in transgenic mice for human aldose reductase21GC03:Diabetes" 45. 56-59 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yagihashi N: "Expression of nitric oxide synthase in macula densa in STZ-induced diabetic rats" Diabetologia. 39(印刷中). (1996)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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