Investigation of the mechanism of beta-cell failure in diabetes using Wolfram Syndrome as a model

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390080
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Yamaguchi University
• Principal Investigator: TANIZAWA Yukio 山口大学, 医学(系)研究科(研究院), 教授 (00217142)
• Co-Investigator(Kenkyū-buntansha): OHTA Yasuharu 山口大学, 医学部, 准教授 (60448280) ; TANABE Katsuya 山口大学, 医学部附属病院, 助教 (00397994) ; TAGUCHI Akihiko 山口大学, 医学部, 講師 (20634744)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 糖尿病 / インスリン / アポトーシス / ストレス

Research Abstract

Wolfram syndrome is an autosomal recessive disorder characterized by insulin deficient diabetes and optic atrophy. Diabetes is caused by pancreatic b-cell apoptosis. In most patients, WFS1 gene is mutated. WFS1 gene is also a type 2 diabetes gene. We conducted a nation-wide survey for the Wolfram syndrome in Japan. In the patients, pancreatic b-cell death is caused by ER stress. In addition, beta-cells are functionally abnormal. That functional failure is at least in part, due to acidification defects inside the secretory granules. WFS1 protein exists on the secretory granule membrane, in addition to the ER membrane. In the secretory granule, it maintains intra-granular acidic milieu, that is important for "priming" of the granule exocytosis. We also studied the mechanism whereby ER stress causes b-cell apoptosis. We found that excessive Gsk-3b activity enhances ATF4 degradation leading to the apoptosis. We also studied relationship between clock genes and b-cell function.

Research Products

• [Journal Article] Impairment of Visual Function and Retinal ER Stress Activation in Wfs1-Deficient Mice (2014)
  • Author(s): Bonnet Wersinger D., Benkafadar N., Jagodzinska J., Hamel C., Tanizawa Y., Lenaers G., Delettre C
  • Journal Title: PLoS One Volume: 9(5) Pages: e97222
  • DOI: 10.1371/journal.pone.0097222
  • Peer Reviewed
• [Journal Article] A sibling case of Wolfram syndrome with a novel mutation Y652X in WFS1 (2013)
  • Author(s): Iwasaki N., Fukawa K., Matsuo M., Urano M., Watanabe M., Ono Y., Tanabe K., Tanizawa Y., Ogata M., Ide R., Takizawa M., Nagata S., Osawa M., Uchigata Y., Saito K.
  • Journal Title: Diabetology International
  • DOI: 10.1007/s13340-013-0145-8
  • Peer Reviewed
• [Journal Article] Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1 β gene expression in pancreatic islet β -cells (2013)
  • Author(s): Nakabayashi H., Ohta Y., Yamamoto M., Susuki Y., Taguchi A., Tanabe K., Kondo M.,Hatanaka M., Nagao Y., Tanizawa Y.
  • Journal Title: Biochem Biophys Res Commun Volume: 434(2) Pages: 370-5
  • Peer Reviewed
• [Journal Article] Activation of the unfolded protein response in primary acute myeloid leukemia cells (2011)
  • Author(s): Tanimura A., Yujiri T., Tanaka Y., Tanaka M., Mitani N., Nakamura Y., Ariyoshi K., Tanizawa Y
  • Journal Title: Int J Hematol Volume: 94(3) Pages: 300-2
  • Peer Reviewed
• [Journal Article] Glucose and Fatty Acids Synergize to Promote B-Cell Apoptosis through Activation of Glycogen Synthase Kinase 3β Independent of JNK Activation (2011)
  • Author(s): Tanabe K, Liu Y, Hasan SD, Martinez SC, Cras-Méneur C, Welling CM, Bernal-Mizrachi E, Tanizawa Y, Rhodes CJ, Zmuda E, Hai T, Abumrad NA, Permutt MA
  • Journal Title: PLoS ONE Volume: 6(4) Pages: e18146
  • Peer Reviewed
• [Journal Article] Wolfram syndrome 1 gene (WFS1) product localizes to secretory granules and determines granule acidification in pancreatic β-cells (2011)
  • Author(s): Hatanaka M, Tanabe K, Yanai A, Ohta Y, Kondo M, Akiyama M, Shinoda K, Oka Y, Tanizawa Y
  • Journal Title: Hum Mol Genet Volume: 20(7) Pages: 1274-84
  • Peer Reviewed
• [Presentation] Role of GSK3 in the development of β-cell failure (2014)
  • Author(s): Tanabe K., Nagao Y., Shiinoki-Amo K., Ma Permutt, Tanizawa Y
  • 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
  • Year and Date: 20140522-24
• [Presentation] 膵島炎症にたいする n-3PUFA の抑制効果とその発現機構の解明 (2014)
  • Author(s): 椎木幾久子,田部勝也,永尾優子,秋山優,太田康晴,谷澤幸生
  • 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
  • Year and Date: 20140522-24
• [Presentation] 膵β 細胞でのアドデノメデュリンシグナルは小胞体ストレスに対して保護作用を示す (2014)
  • Author(s): 末冨吏佐,秋山 優,太田康晴,中林容子,近藤 学,幡中雅行,谷澤幸生
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 第 57 回日本糖尿病学会年次学術集会
  • Year and Date: 20140522-24
• [Presentation] 膵 β 細胞特異的E4BP4 過剰発現マウスを用いた時計遺伝子を介する新たなインスリン分泌調節機構の解明 (2014)
  • Author(s): 太田康晴,田口昭彦,中林容子,秋山 優,末冨吏佐,谷澤幸生
  • 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
  • Year and Date: 20140522-24
• [Presentation] 全エキゾーム解析による Wolfram 症候群の新たな原因遺伝子同定の試み (2014)
  • Author(s): 田口昭彦,田部勝也,松永仁恵,太田康晴,細道一善,井ノ上逸朗,谷澤幸生
  • 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
  • Year and Date: 20140522-24
• [Presentation] GLUT4 調節因子DOC2b は aPKC により調節され個体糖恒常性を維持する (2014)
  • Author(s): 野見山隆太,江本政広,福田尚文,松井久未子,坂根亜由子,三好 淳,佐々木卓也,谷澤幸生
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 20140424-26
• [Presentation] 時計遺伝子DBP/E4BP4 による膵 β 細胞機能調節 (2014)
  • Author(s): 田口昭彦,太田康晴,山本将義,薄 陽祐,中林容子,谷澤幸生
  • Organizer: 第87回日本内分泌学会学術総会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 20140424-26
• [Presentation] Clock-controlled output gene Dbp is a regulator of Arnt/Hif- 1β gene expression in pancreatic islet β-cells (2013)
  • Author(s): Tanizawa Y., Nakabayashi H., Ohta Y., Yamamoto M., Susuki Y., Taguchi A., Tanabe K., Kondo M., Hatanaka M., Nagao Y.
  • Organizer: EASD ISLET STUDY GROUP ANNUAL MEETING 2013 (Beta-cell Regeneration and Genome Regulation)
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 20130927-29
• [Presentation] Clock-Controlled Output Gene Dbp is a Regulator of Arnt/Hif-1β Gene Expression in Pancreatic Islet β-Cells (2013)
  • Author(s): Nakabayashi H., Ohta Y., Yamamoto M., Susuki Y., Taguchi A., Tanabe K., Kondo M., Hatanaka M., Nagao Y., Tanizawa Y
  • Organizer: 73th Annual Meeting and Scientific Sessions of the American Diabetes Association
  • Place of Presentation: Chicago, IL, USA
  • Year and Date: 20130621-25
• [Presentation] SCF^<βTrC> and GSK3-mediated degr -adation of ATF4 is a pro-apoptotic mechanism in pancreatic beta cell under ER stress (2013)
  • Author(s): Tanabe K., Nagao Y., Tanizawa Y
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: メルパルク熊本
  • Year and Date: 20130516-18
• [Presentation] SNARE 関連蛋白質DOC2b の糖代謝への役割 (2013)
  • Author(s): 野見山隆太,江本政広,福田尚文,松井久未子,坂根亜由子,三好 淳,佐々木卓也,谷澤幸生
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本市民会館
  • Year and Date: 20130516-18
• [Presentation] Gsk-3 modulates ER stress-induced apoptosis by regulating ATF4 protein stability in pancreatic β-cell (2013)
  • Author(s): Nagao Y., Tanabe K., Hatanaka M., Nakabayashi H., Ohta Y., Emoto M., Tanizawa Y
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本ホテルキャッスル
  • Year and Date: 20130516-18
• [Presentation] 膵 β 細胞において時計遺伝子 DBP と E4BP4 は ARNT の発現を抑制する (2013)
  • Author(s): 中林容子,太田康晴,山本将義,薄 陽祐,谷澤幸生
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本ホテルキャッスル
  • Year and Date: 20130516-18
• [Presentation] 膵 β 細胞特異的 E4BP4 過剰発現マウスを用いた DBP 及び E4BP4 の膵 β細胞機能における役割の解明 (2013)
  • Author(s): 太田康晴,中林容子,近藤 学,谷澤幸生
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本ホテルキャッスル
  • Year and Date: 20130516-18
• [Presentation] Rac1 and its novel effector regulate insulin stimulated glucose transport (2013)
  • Author(s): Emoto M., Fukuda N., Nomiyama R., Yamada K., Tanizawa Y
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本ホテルキャッスル
  • Year and Date: 20130516-18
• [Presentation] Molecular pathophysiol -ogy of beta-cell failure in diabetes mellitus (2013)
  • Author(s): Tanizawa Y
  • Organizer: The 26th Spring Congress of Korean Diabetes Association / The 1st Korea-Japan Diabetes Forum
  • Place of Presentation: ICC Jeju, Korea
  • Year and Date: 20130510-11
• [Presentation] Both quantitative and qualitative abnormalities of beta-cells in patients with Wolfram syndrome (2013)
  • Author(s): Tanizawa Y
  • Organizer: Beta Cell Workshop 2013 Kyoto (Abstract 3P)
  • Place of Presentation: Kyoto International Conference Center, Japan
  • Year and Date: 20130423-26
• [Presentation] Clock-controlled output gene Dbp is a regulator of Arnt/Hif-1β gene expression in pancreatic islet β-cells (2013)
  • Author(s): Ohta Y., Nakabayashi H., Tanabe K., Tanizawa Y
  • Organizer: Keystone Symposia Molecular Clockworks and the Regulation of Cardio-Metabolic Function
  • Place of Presentation: Snowbird Resort - Snowbird, Utah USA
  • Year and Date: 20130403-07
• [Presentation] Role of Gsk-3β βin the Development of β-Cell Failure (2012)
  • Author(s): Tanabe K., Tanizawa Y
  • Organizer: The 4th Scientific Meeting of the Asian Association for the Study of Diabetes, 9th International Diabetes Federation Western Pacific Region Congress
  • Place of Presentation: Kyoto International Conference Center, Japan
  • Year and Date: 20121124-27
• [Presentation] GSK3-SCF^<βTrCP> Modulates ER Stress-Induced Apoptosis by Targeting ATF4 for Ubiquitination and Degradation in Pancreatic β-Cell (2012)
  • Author(s): Nagao Y., Tanabe K., Hatanaka M., Emoto M., Tanizawa Y.
  • Organizer: The 4 th Scientific Meeting of the Asian Association for the Study of Diabetes, 9 th International Diabetes Federation Western Pacific Region Congress
  • Place of Presentation: Kyoto International Conference Center, Japan
  • Year and Date: 20121124-27
• [Presentation] Coock-Controlled Output Gene Dbp is a Regulator of Arnt/Hif-1βGene Expression in Pancreatic Islet β-Cells (2012)
  • Author(s): Nakabayashi H., Ohta Y., Yamamoto M., Susuki Y., Tanabe K., Kondo M., Hatanaka M., Nagao Y., Tanizawa Y.
  • Organizer: The 4th Scientific Meeting of the Asian Association for the Study of Diabetes, 9th International Diabetes Federation Western Pacific Region Congress
  • Place of Presentation: Kyoto International Conference Center, Japan
  • Year and Date: 20121124-27
• [Presentation] Adrenomedullin is Induced by ER Stress and Protects β-Cells as Endogenous Antiapoptotic Substance in Islets (2012)
  • Author(s): Ohta Y., Nakabayashi H., Kondo M., Hatanaka M., Tanabe K., Tanizawa Y.
  • Organizer: The 4th Scientific Meeting of the Asian Association for the Study of Diabetes, 9th International Diabetes Federation Western Pacific Region Congress
  • Place of Presentation: Kyoto International Conference Center, Japan
  • Year and Date: 20121124-27
• [Presentation] 糖尿病における β 細胞不全の分子機構 (2012)
  • Author(s): 谷澤幸生
  • Organizer: 第62回日本体質医学会総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 20121103-04
• [Presentation] WFS1 Protein Regulates Insulin Granule Exocytosis via Maintenance of Intragranular Acidification and Modulation of the SNARE Proteins (2012)
  • Author(s): Kondo M., Hatanaka M., Tanabe K, Ohta Y., Tanizawa Y
  • Organizer: 72th Annual Meeting and Scientific Sessions of the American Diabetes Association
  • Place of Presentation: Philadelphia, Pennsyl -vania, USA
  • Year and Date: 20120608-12
• [Presentation] A SNARE Protein p34 Regulates the Intracellular Sequestration of GLUT4 Vesicles in Adipocytes (2012)
  • Author(s): Matsui K., Emoto M., Fukuda N., Nomiyama R., Tanizawa Y
  • Organizer: 72th Annual Meeting and Scientific Sessions of the American Diabetes Association
  • Place of Presentation: Philadelphia, Pennsyl -vania, USA
  • Year and Date: 20120608-12
• [Presentation] GSK-3 enhances ER stress-induces apoptosis by regulation of ATF4 protein stability in pancreatic β-cells (2012)
  • Author(s): 田部勝也,永尾優子,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] WFS1 遺伝子と糖尿病 (2012)
  • Author(s): 太田康晴,田部勝也,松永仁恵,近藤 学,中林容子,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] t-SNARE であるSNAP29 は GULT4 小胞のインスリン感受性コンパートメントを形成し維持する (2012)
  • Author(s): 松井久未子,江本政広,福田尚文,野見山隆太,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] 膵 β 細胞において時計遺伝子 E4bp4 と Dbp は Arnt の発現を制御する (2012)
  • Author(s): 中林容子,太田康晴,山本将義,薄 陽祐,田部勝也,近藤 学,幡中雅行,永尾陽子,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 第 55 回日本糖尿病学会年次学術集会
  • Year and Date: 20120517-19
• [Presentation] W fs 1 欠損マウスにおけるインスリン分泌動態の解析 (2012)
  • Author(s): 近藤 学,幡中雅行,田部勝也,太田康晴,谷澤幸生,岡 芳知
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] 断面調査に基づく Wolfram 症候群の実態解明 (2012)
  • Author(s): 松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,中尾雄三,山田祐一郎,雨宮伸,杉原茂孝,岡 芳知,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] 小胞体ストレス応答調節におけるセリン・スレオニンキナーゼ GSK-3の役割 (2012)
  • Author(s): 永尾優子,田部勝也,幡中雅行,中林容子,近藤 学,太田康晴,江本政広,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] SNARE 関連蛋白DOC2b による糖代謝調節 (2012)
  • Author(s): 福田尚文,江本政広,野見山隆太,松井久未子,坂根亜由子,三好 淳,佐々木卓也,谷澤幸生
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20120517-19
• [Presentation] セリン・スレオニンキナーゼGSK-3 は ATF4 を抑制的に調節する (2012)
  • Author(s): 永尾優子,田部勝也,幡中雅行,中林容子,近藤 学,太田康晴,江本政広,谷澤幸生
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 20120419-21
• [Presentation] シンポジウム7小胞体ストレスと内分泌代謝疾患 : Glycogen synthase kinase-3(Gsk-3) (2012)
  • Author(s): 田部勝也,谷澤幸生
  • Organizer: 第85回日本内分泌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 20120419-21
• [Presentation] SNARE関連蛋白 DOC2b による糖代謝調節 (2012)
  • Author(s): 野見山隆太,江本政広,福田尚文,松井久未子,佐々木卓也,谷澤幸生
  • Organizer: 第24回分子糖尿病学シンポジウム
  • Place of Presentation: 品川インターシティ
  • Year and Date: 2012-12-08
• [Presentation] Pioglitazone Prevents ER Stress-induced Beta-cell Death via Adrenomedullin Expression (2011)
  • Author(s): Ohta Y., Nakabayashi H., Tanabe K., Kondo M., Tanizawa Y
  • Organizer: The 16th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Urayasu, Japan
  • Year and Date: 20111021-22
• [Presentation] The Cross Sectional Analysis on Genetic and Clinical Features of Japanese Patients (2011)
  • Author(s): Matsunaga K., Tanabe K., Ohta Y., Okuya S., Tanizawa Y
  • Organizer: The 16th Japan-Korea Symposium on Diabetes Mellitus
  • Place of Presentation: Urayasu, Japan
  • Year and Date: 20111021-22
• [Presentation] Pioglitazone induces islet adreno -medullin expression and attenuates beta-cell ER stress (2011)
  • Author(s): Ohta Y., Kondo M., Hatanaka M., Tanabe K., Yamamoto M., Nakabayashi H., Tanizawa Y
  • Organizer: The 3th Scientific Meeting of the Asian Association for the Study of Diabetes
  • Place of Presentation: Beijing, China
  • Year and Date: 20110722-24
• [Presentation] Genetic and acquired factors determining natural history of type 2 diabetes mellitus (2011)
  • Author(s): Tanizawa Y
  • Organizer: The 3th Scientific Meeting of the Asian Association for the Study of Diabetes
  • Place of Presentation: Beijing, China
  • Year and Date: 20110722-24
• [Presentation] The cross sectional analysis on genetic and clinical features of Japanese patient with Wolfram syndrome (2011)
  • Author(s): Matsunaga K., Tanabe K., Ohta Y., Okuya S., Tanizawa Y
  • Organizer: The 3th Scientific Meeting of the Asian Association for the Study of Diabetes
  • Place of Presentation: Beijing, China
  • Year and Date: 20110722-24
• [Presentation] GLUT4小胞は CLIP170 を介して微小管からアクチンへ移動する (2011)
  • Author(s): 江本政広,松井久未子,河村由紀江,福田尚文,山田恭子,谷澤幸生
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 20110519-21
• [Presentation] Roles of Wolfram Syndrome 1 Gene Product (WFS1) on Beta Cell Function and its Adaptation to increased Insulin Demand (2011)
  • Author(s): Tanabe K.,Tanizawa Y
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 20110519-21
• [Presentation] Syntaxin 6 結合蛋 p34 は 脂肪細胞におけるインスリン依存性糖輸送を制御する (2011)
  • Author(s): 松井久未子,福田尚文,江本政広,谷澤幸生
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 20110519-21
• [Presentation] Wolfram 症候群の実態調査 (2011)
  • Author(s): 松永仁恵,田部勝也,太田康晴,奥屋 茂,和田安彦,山田祐一郎,雨宮 伸,杉原茂孝,岡 芳知,谷澤幸生
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 20110519-21
• [Presentation] セリン・スレオニンキナーゼ GSK-3 はATF4 を抑制的に調節する (2011)
  • Author(s): 中林容子,田部勝也,太田康晴,幡中雅行,近藤 学,江本政広,谷澤幸生
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 20110519-21
• [Presentation] ピオグリタゾンによる膵ラ氏島でのアドレノメデュリンの発現誘導と膵 β細胞保護作用に関する検討 (2011)
  • Author(s): 田部勝也,中林容子,山本将義,谷澤幸生
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 20110519-21
• [Presentation] Charac -terization of visual impairment in a Wfs1 mouse model of Wolfram syndrome (2011)
  • Author(s): Hamel CP., Cribaillet CD., Lenaers G., Tanizawa Y., Wersinger DB
  • Organizer: ARVO Annual Meeting
  • Place of Presentation: Fort Lauderdale
  • Year and Date: 20110506-10