NeuroD/betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15390055
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General anatomy (including Histology/Embryology)
• Research Institution: Shiga University of Medical Science
• Principal Investigator: FUJIMIYA Mineko Shiga Univ.Med.Sci., Dept.Anatomy, Associate Professor, 医学部, 助教授 (10199359)
• Co-Investigator(Kenkyū-buntansha): KOJIMA Hideto Shiga Univ.Med.Sci., Dept.Molecular Genetics in Medicine, Associate Professor, 医学部, 助教授 (00225434) ; NAKAMURA Takaaki Shiga Univ.Med.Sci., Dept.Anatomy, Assistant Professor, 医学部, 助手 (30314157)
• Project Period (FY): 2003 – 2004
• Keywords: organogenesis / panereatic β cells / Helper dependent adenovirus / insulin / NeuroD / Pdx-1 / Pdx1

Research Abstract

First-generation adenovirus(FGAd)-mediated transfer of the homeobox gene Pdx-1 was reported to induce hepatic insulin production and transient hypoglycemia in streptozotocin(STZ)-treated diabetic mice. Unlike FG-Ads whose effects are short-lived, helper-dependent(HD) Ads produce prolonged transgene expression. We used HDAd to deliver Pdx-1 to STZ mice and observed partial amelioration of hyperglycemia, but severe, fatal, hepatitis, caused by expression of trypsin, resulting from the exocrine-differentiating action of Pdx-1. HDAd-mediated transfer of NeuroD, a developmental factor downstream of Pdx-1,partially reversed the hyperglycemia of STZ mice without inducing hepatitis. The addition of an islet growth factor betacellulin to NeuroD completely corrected the diabetes. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 days). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta cell-specific glucokinase, and sulfonylurea receptor. Immunohistochemistry revealed the presence of insulin, glucagon, pancreatic polypeptide(PP) and somatostatin-producing cells organized into islet clusters, and immuno-electron microscopy showed typical insulin-specific granules. Our data suggest that NeuroD/betacellulin is a promising gene therapy regimen for the treatment of insulin-dependent diabetes. These results were published in Nat. Med 9,596,2003 and many review articles as shown in the publication records.

Research Products

• [Journal Article] Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. (2005)
  • Author(s): Asakawa, A., Inui, A., Fujimiya, M., Sakamaki, R., Shinfuku, N., Ueta, Y., Meguid, M.M., Kasuga, M.
  • Journal Title: Gut. 54 Pages: 18-24
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Diet high in lipid hydroperoxide by vitamin E deficiency induces insulin resistance and impaired insulin secretion in normal rats. (2005)
  • Author(s): Tsujinaka, K., Nakamura, T., Maegawa, H., Fujimiya, M., Nishio, Y., Kudo, M., Kashiwagi, A.
  • Journal Title: Diabetes Res clin Pract. 67 Pages: 99-109
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intracerebroventriculariy administered urocortin inhibits gastric emptying in mice. (2005)
  • Author(s): Nagata, T., Uemoto, M., Yuzuriha, H., Asakawa A., Inui, A., Fujimiya, M., Sakamaki, R., Shinfuku, N., Kasuga, M.
  • Journal Title: Int.J.Mol.Med. 15 Pages: 1041-1043
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A free radical scavenger, edaravone (MCI-186), diminishes intestinal neutrophil lipid peroxidation and bacterial translocation in a rat hemorrhagic shock model. (2005)
  • Author(s): Mori T, Yamamoto H, Tabata T, Shimizu T, Endo Y, Hanasawa K, Fujimiya M., Tani
  • Journal Title: Crit Care Med. 33 Pages: 1064-1069
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Extrapancreatic insulin-producing cells in multiple organs in diabetes. (2004)
  • Author(s): Kojima, H., Fuiimiya, M., Matsumura, K., Nakahara, T., Hara, M., Chan, L.
  • Journal Title: Proc Natl Acad Sci U S A 101 Pages: 2458-2463
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 特集「膵島移植と再生医療」 In vivoベクター投与による糖尿病の遺伝子治療 (2004)
  • Author(s): 藤宮峯子, 小島秀人
  • Journal Title: 肝と膵 25 Pages: 299-301
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 「膵再生医療実用化への新しい展望と将来展望」糖尿病マウス肝臓における膵ラ氏島の新生 (2004)
  • Author(s): 藤宮峯子, 小島秀人
  • Journal Title: 再生医療 3 Pages: 91-94
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ghrelin, appetite, and gastric motility-the emerging role of the stomach as an endocrine organ. (2004)
  • Author(s): Inui, A., Asakawa, A., Bowers, C.Y., Mantovani, G., Laviano, A., Meguid, M.M., Fujimiya, M.
  • Journal Title: FASEB J. 18 Pages: 439-456
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Extrapancreatic insulin-producing cells in multiple organs in diabetes. (2004)
  • Author(s): Kojima, H., Fujimiya, M., Matsumura, K., Nakahara, T., Hara, M., Chan, L.
  • Journal Title: Proc Natl Acad Sci U S A. 101 Pages: 2458-2463
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastric distention-induced release of serotonin stimulates c-fos expression in specific brain nuclei via 5-HT3 receptors in conscious rats. (2004)
  • Author(s): Mazda, T., Yamamoto, H., Fujimura, M., Fujimiya, M.
  • Journal Title: Am.J.Physiol.Gastrointest.Liver Physiol. 287 Pages: G228-G235
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Development of pancreatic islets in pancreatic polypeptide-overexpressing mice. (2004)
  • Author(s): Yuzuriha, H., Inui, A., Asakawa, A., Ueno, N., Sakamaki, R., Shinfuku, N., Kasuga, M., Fujimiya, M.
  • Journal Title: Int J Mol Med. 14 Pages: 201-205
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased BBB permeability by parasympathetic sphenopalatine ganglion stimulation in dogs. (2004)
  • Author(s): Yamitsky, D., Gross, Y., Lorian, A., Shalev, A., Shorer, S., Tanaka, T., Ayajiki, K., Fujimiya.M., Okamura, T.
  • Journal Title: Brain Res. 1018 Pages: 236-240
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. (2003)
  • Author(s): Kojima, H., Fujimiya, M., Matsumura, K., Younan, P., Imaeda, H., Maeda, M., Chan, L
  • Journal Title: Nat.Med 9 Pages: 596-603
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In-vivo gene therapy for diabetes mellitus. (2003)
  • Author(s): Chan L., Fujimiya, M., Kojima H.
  • Journal Title: Trends in Mol.Med 9 Pages: 430-435
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] マウス肝臓内で膵島新生により糖尿病の改善を導くニューロD-ベータセルリン遺伝子治療 (2003)
  • Author(s): 小島秀人, 藤宮峯子
  • Journal Title: 実験医学 21 Pages: 1760-1763
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori cytotoxin : a novel ligand for receptor-like protein tyrosine phosphatase beta. (2003)
  • Author(s): Inui, T., Mizuno, S., Takai, K., Nakagawa, M., Uchida, M., Fujimiya, M., Asakawa, A., Inui A.
  • Journal Title: Int J Mol Med. 12 Pages: 917-921
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In-vivo gene therapy for diabetes mellitus. (2003)
  • Author(s): Chan L., Fujimiya, M., Kojima H.
  • Journal Title: Trends in Mol. 9 Pages: 430-435
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serotonin stimulates endotoxin translocation via 5-HT3 receptors in the rat ileum. (2003)
  • Author(s): Yamada, T., Inui, A., Hayashi, N., Fujimura, M., Fujimiya, M.
  • Journal Title: Am.J.Physiol.Gastrointest.Liver Physiol. 284 Pages: G782-G788
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. (2003)
  • Author(s): Kojima, H., Fujimiya, M., Matsumura, K., Younan, P., Imaeda, H., Maeda, M., Chan, L.
  • Journal Title: Nat.Med. 9 Pages: 596-603
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. (2003)
  • Author(s): Fujino, K., Inui, A., Asakawa, A., Kihara, N., Fujimura, M., Fujimiya, M.
  • Journal Title: J.Physiol. 550 Pages: 227-240
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Anovel diamino-pyridine derivative (IS-741) attenuates rat ileitis induced by trinitrobenzene sulfonic acid. (2003)
  • Author(s): Fukunaga, T., Tsujikawa, T., Sasaki, M., Fujiyama, Y, Bamba, T., Fujimiya, M.
  • Journal Title: J.Gastroenterol. 38 Pages: 451-459
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. (2003)
  • Author(s): Fukumoto, S., Tatewaki, M., Yamada, T., Fujimiya, M., Mantyh, C., Voss, M., Eubanks, S., Harris, M., Pappas, T.N., Takahashi, T.
  • Journal Title: Am.J.Physiol.Regul.Integr.Comp.Physiol. 284 Pages: R1269-R1276
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intracerebroventricular administration of NPY stimulates resistin gene expression in mice. (2003)
  • Author(s): Yuzuriha, H., Inui, A., Goto, K., Asakawa, A., Fujimiya, M., Kasuga, M.
  • Journal Title: Int.J.Mol.Med. 11 Pages: 675-676
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. (2003)
  • Author(s): Asakawa, A., Inui, A., Yuzuriha H., Ueno, N., Katsuura G., Fujimiya, M., Fujino, M.A., Niijima, A., Meguid, M.M., Kasuga, M.
  • Journal Title: Gastroenterology 124 Pages: 1325-1336
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EM574, a motilide, has an orexigenic activity with affinity for growth-hormone secretagogue receptor. (2003)
  • Author(s): Asakawa, A., Inui, A., Ohinata, K., Fujimiya, M., Meguid, M.M., Yoshikawa, M.
  • Journal Title: J.Gastroenterol.Hepatol. 18 Pages: 881-882
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. (2003)
  • Author(s): Asakawa, A., Inui, A., Kaga, T., Katsuura, G., Fujimiya, M., Fujino, M.A., Kasuga, M.
  • Journal Title: Gut 52 Pages: 947-952
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In vivo functioning and transplantable mature pancreatic islet-like cell clusters differentiated from embryonic stem cell. (2003)
  • Author(s): Kim, D., Gu, Y., Ishii, M., Fujimiya, M., Qi, M., Nakamura, N., Yoshikawa, T., Sumi, S., Inoue, K.
  • Journal Title: Pancreas 27 Pages: E34-E41
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 糖尿病学2005 (2005)
  • Author(s): 小島秀人, 藤宮峯子, 木村 博
  • Total Pages: 154
  • Publisher: 診断と治療社
  • Description: 「研究成果報告書概要(和文)」より