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Molecular physiological and biological studies on the effect of free fatty acids on pancreatic β cell function

Research Project

Project/Area Number 12671126
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionKyorin University

Principal Investigator

ISHIDA Hitoshi (2002)  Professor, Third Department of Internal Medicine, Kyorin University, 医学部, 教授 (80212893)

古川 尚志 (2000-2001)  杏林大学, 医学部, 助手 (90322445)

Co-Investigator(Kenkyū-buntansha) NAGAMATSU Shinya  Professor, Second Department of Biochemistry, Kyorin University, 医学部, 教授 (80231489)
石田 均  杏林大学, 医学部, 教授 (80212893)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordsproinsulin / free fatty acids / insulin secretion / intracellular calcium / PPARγ / glucagon secretion / exocytotic system / insulin biosynthesis / カルシウムイオン
Research Abstract

In order to determine whether free fatty acids affect pancreatic βcell functions, the effect of palmitic acid on proinsulin biosynthesis and insulin secretion was studied using isolated rat islets. Expose of islets to palmitic acid for 1 hour reduced glucose-stimulated insulin biosynthesis, whereas no change in insulin secretion was observed. Thus, palmitic acid primarily suppress glucose-induced proinsulin prior to alteration of insulin release. It has been known that long expose of free fatty acids leads the overexpression of peroxisome proliferator-activated receptor γ (PPAR γ) in pancreatic islets. Then, the effect of PPAR γ overepression on the secretion of insulin and glucagon was investigated in vitro. The glucose-stimulated and high potassium-induced insulin secretion was markedly reduced through PPAR γ overexpression. However, the glucagon release by high-potassium depolarization was not changed. The deteriorative effect seems to be, therefore, β-cell specific. Recently, many research groups have tried to expand or regenerate pancreatic β cells by genetic engineering techniques, however, a definite way to regulate insulin secretion was not established. We took advance to facts that adopocytes characteristically secrete many cytokines such as TNF-α and adiponectin, and that the regulated exocytotic pathway to GLUT4 can be triggered by insulin stimulation. Interestingly, when adenovirus-mediated preproinsulin gene was transferred into 3T31_l adipocytes, expressed proinsulin was co-localized with GLUT4 vesicle and was found to be processed into insulin. The gene transfer into adipose tissues ameliorates hyperglycemia in obese diabetic KKAy mice for at least 2 weeks. The subsequent elimination of glucose toxicity can be expected to restore pancreatic β cell function in diabetes.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Y.Nakamichi, H.Ishida, et al.: "An insulin-related peptide expressed in 3T3L1 adipocytes is loclized in GLUT4 vesicles and secreted in response to exogenous insulin, which augments the insulin-stimulated glucose uptake"J Cell Sci. 116. 73-79 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Kimoto, H.Ishida, et al.: "Gliclazide protects pancreatic beta-cells from damage by hydrogen peroxide"Biochem Biophys Res Commun. 303. 112-119 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Ohara-Imaizumi, H.Ishida, et al.: "Monitoring of exocytosis and endocytosis of insulin secretory granules in the pancreatic β-cell line MIN6 using pH-sensitive green fluorescent protein"Biochem J. 363. 73-80 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Ohara-Imaizumi, H.Ishida, et al.: "Imaging exocytosis of single insulin secretory granules with evanescent wave microscopy -Distinct behavior of granule motion in biphasic insulin release-"J Biol Chem. 277・6. 3805-3808 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Katahira, H.Ishida, et al.: "Acute inhibition of proinsulin biosynthesis at the translational level by palmitic acid"Biochem Biophys Res Commun. 282. 507-510 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Nagamatsu, H.Ishida, et al.: "Localization of cellubrevin-related peptide, endobrevin, in the early endosomc in pancreatic β cells and its physiological function in exo-endocytosis of secretory granutes"J Cell Sci. 114・1. 219-227 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Nakamichi., H.Ishida., et al.: "An insulin-related peptide expressed in 3T3L1 adipocytes is localized in GLUT4 vesicles and secreted in response to exogenous insulin, which augments the insulin-stimulated glucose uptake"J Cell Sci. 116. 73-79 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] K.Kimoto., H.Ishida., et al.: "Gliclazide protects pancreatic beta-cells from damage by hydrogen peroxide"Biochem Biophys Res Commun. 303. 112-119 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Ohara-Imaizumi., H.Ishida., et al.: "Monitoring of exocytosis and endocytosis of insulin secretory granules in the pancreatic β-cell line MIN6 using pH-sensitive green fluorescent protein (pHuorin) and confocal laser microscopy"Biochem J. 363. 73-80 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Ohara-Imaizumi., H.Ishida., et al.: "Imaging exocytosis of single insulin secretory granules with evanescent wave microscopy - Distinct behavior of granule motion in biphasic insulin release -"J Biol Chem. 277(6). 3805-3808 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Nagamatsu., H.Ishida., et al.: "Adenovirus-mediated preproinsulin gene transfer into adipose tissues ameliorates hyperglycemia in obese diabetic KKAy mice"FEBS lett. 509. 106-110 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] T.Miura., H.Ishida., et al.: "Impairment of insulin-stimulated GLUT4 translocation in skeletal muscle and adipose tissue in the Tsumura Suzuki obese diabetic mouse: a new genetic animal model of type 2 diabetes"Eur J Endocrinol. 145. 785-790 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] M.Ohara-Imaizumi., H.Ishida., et al.: "Mastoparan stimulates GABA release from MIN6 cells -relationship between SNARE proteins and mastoparan action-"Biochem Biophys Res Commun. 289. 1025-1030 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Katahira., H.Ishida., et al.: "A cute inhibition of proinsulin biosynthesis at the translational level by palmitic acid"Biochem Biophys Res Commun. 282. 507-510 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Nagamatsu., H.Ishida., et al.: "Localization of cellubrevin-related peptide, endobrevin, in the early endosome in pancreatic β cells and its physiological function in exoendocytosis of secretory granules"J Cell Sci. 114(1). 219-227 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Fujimoto., H.Ishida., et al.: "Augmentation of basal insulin release from rat islets by preexposure to a high concentration of glucose"Am J Physiol. 279. E927-E940 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Y.Nakamichi, H.Ishida, et al.: "An insulin-related peptide expressed in 3T3L1 adipocytes is localized in GLUT4 vesicles and secreted in response to exogenous insulin, which augments the insulin-stimulated"J Cell Sci. 116. 73-79 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Kimoto, H.Ishida, et al.: "Gliclazide protects pancreatic beta-cells from damage by hydrogen peroxide"Biochem Biophys Res Commun. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] A.W.Norman, H.Ishida, et al.: "Molecular tools for stydy of genomic and rapid signal transduction responses initiated by 1α, 25(OH)2-vitamin D3"Steroids. 67・6. 457-466 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] N.Abe, H.Ishida, et al.: "Pancreatic endocrine function and glucose transporter(GLUT)-2 expression in rat acute pancreatitis"Pancreas. 25・2. 149-153 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Ohara-Imaizumi, H.Ishida, et al.: "Monitoring of exocytosis and endocytosis of insulin secretory granules in the pancreatic β-cell line MIN6 using pH-sensitive green fluorescent protein(pHuorin) and confocal laser microscopy"Biochem J. 363. 73-80 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Ohara-Imaizumi, H.Ishida, et al.: "Imaging exocytosis of single insulin secretory granules with evanescent wave microscopy -Distinct behavior of granule motion in biphasic insulin release-"J Biol Chem. 277・6. 3805-3808 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 古川尚志, 石田均: "インスリン分泌促進薬"Medical Practice. Vol.18 No10. 1707-1710 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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