Elucidation of PPY cell lineage for development of new diabetes treatment

• Project/Area Number: 25860757
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Juntendo University
• Principal Investigator: HARA Akemi 順天堂大学, 医学部, 博士研究員 (60570009)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: PPY細胞 / β細胞 / 分化転換 / 細胞系譜 / 糖尿病 / 高血糖 / 膵ラ氏島 / 細胞系譜の追跡

Outline of Final Research Achievements

Persistent hyperglycemia with obese results in reduced pancreatic beta cell function and mass, and increased pancreatic polypeptide (PP) cells. The aim of this study was to elucidate the mechanism of the fate conversion between beta and PP cells, using lineage traceable mice, which were given high fat diet and STZ. The increased PP cells were found to originate from the pre-existing beta cells. The expression of a-beta cell specific transcription factor, Pdx1 was downregulated. By the knockdown of Pdx1 in MIN6 cells induced increment of PP mRNA expression. These results demonstrate the possibility that persistent hyperglycemia can induce beta to PP cell fate conversion in adult pancreas by the attenuation of Pdx1.
Furthermore, we found evidence that Some beta cells were originated from pre-existing PP cells during development. Hence, we are investigating the mechanisms underlying the reciprocal fate conversion between PP and beta cell lineages in pathophysiological conditions.

Research Products

• [Journal Article] Increased expression of ERp57/GRP58 is protective against pancreatic beta cell death caused by autophagic failure. (2014)
  • Author(s): Yamamoto E, Uchida T, Abe H, Taka H, Fujimura T, Komiya K, Hara A, Ogihara T, Fujitani Y, Ueno T, Takeda S, Watada H.
  • Journal Title: Biochem Biophys Res Commun Volume: 453 Issue: 1 Pages: 19-24
  • DOI: 10.1016/j.bbrc.2014.09.040
  • Peer Reviewed / Open Access
• [Journal Article] Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy. (2014)
  • Author(s): Shigihara N, Fukunaka A, Hara A, Komiya K, Honda A, Uchida T, Abe H, Toyofuku Y, Tamaki M, Ogihara T, Miyatsuka T, Hiddinga HJ, Sakagashira S, Koike M, Uchiyama Y, Yoshimori T, Eberhardt NL, Fujitani Y, Watada H.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 8 Pages: 3634-44
  • DOI: 10.1172/jci69866
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of the parasympathetic nervous system in the initiation of regeneration of pancreatic β-cells. (2013)
  • Author(s): Medina A1, Yamada S, Hara A, Hamamoto K, Kojima I.
  • Journal Title: Endocrine Journal Volume: 60 (5) Pages: 687-696
  • NAID: 10031184537
  • Peer Reviewed
• [Journal Article] The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance (2013)
  • Author(s): Tamaki, M., Fujitani, Y, Uchida, T., Tamura, Y., Takeno, K., Kawaguchi, M., Watanabe, T., Hara, A., Ogihara, T., Shimizu, T., Mita, T., Hirose, T., Ohara-Imaizumi, M., Abe, T., Kiyonari, H., Hojyo, S., Fukada, T., Nagamatsu, S., Hirano, T., Kawamori, R., Watada, H.
  • Journal Title: J Clin Invest Volume: 123 Issue: 10 Pages: 4513-4524
  • DOI: 10.1172/jci68807
  • Peer Reviewed
• [Journal Article] Beneficial effects of vildagliptin combined with miglitol on glucose tolerance and islet morphology in diet-controlled db/db mice. (2013)
  • Author(s): Ishibashi K, Hara A, Fujitani Y, Uchida T, Komiya K, Tamaki M, Abe H, Ogihara T, Kanazawa A, Kawamori R, Watada H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 440 (4) Issue: 4 Pages: 570-575
  • DOI: 10.1016/j.bbrc.2013.09.110
  • Peer Reviewed
• [Journal Article] Exendin-4 improves β-cell function in autophagy-deficient β-cells. (2013)
  • Author(s): Abe H, Uchida T, Hara A, Mizukami H, Komiya K, Koike M, Shigihara N, Toyofuku
  • Journal Title: Endocrinology Volume: 154 Issue: 12 Pages: 4512-24
  • DOI: 10.1210/en.2013-1578
  • Peer Reviewed
• [Presentation] 持続的高血糖は膵β細胞からPP 細胞への分化転換を誘導する (2014)
  • Author(s): 原 朱美、藤谷 与士夫、田蒔 基行、荻原 健、宮塚 健、福中 彩子、小宮 幸次、荻原 健、金澤 昭雄、綿田 裕 孝
  • Organizer: 第10 回Diabetes Research Forum in Tokyo
  • Place of Presentation: パレスホテル東京
  • Year and Date: 2014-10-22
  • Invited
• [Presentation] 持続的高血糖は膵β細胞からPP細胞への分化転換を誘導する (2014)
  • Author(s): 原 朱美、藤谷 与士夫、田蒔 基行、宮塚 健、福中 彩子、小宮 幸次、金澤 昭雄、綿田 裕孝
  • Organizer: 第28回日本糖尿病肥満・肥満動物学会
  • Place of Presentation: 宮崎市民プラザ
• [Presentation] ヒト型IAPPは膵島移植の成功率を低下させる (2014)
  • Author(s): 原 朱美、藤谷 与士夫、荻原 健、宮塚 健、綿田 裕孝
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場、リーガロイヤルホテル、ホテルNCB、堂島リバーフォーラム