Investigation of molecular mechanisms for the regulation of insulin secretion by KCNQ1

2012 Fiscal Year Final Research Report

• Project/Area Number: 22591021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: MAEDA Shiro 独立行政法人理化学研究所, 内分泌・代謝疾患研究チーム, チームリーダー (50314159)
• Project Period (FY): 2010 – 2012
• Keywords: 2型糖尿病 / 膵β細胞 / インスリン分泌 / GLP-1分泌 / 遺伝子

Research Abstract

We identified that inhibition of KCNQ1 enhanced glucose-induced insulin secretion in rat isolated pancreatic beta cells, and bethanecol-induced glucagon like peptide-1 secretion in NCI-H716 cells. In addition, we have found that KCNQ1 risk variants for type 2 diabetes were negatively correlated with beta cell function (HOMA-beta) in non-diabetic individuals, and an accumulation of type 2 diabetes risk variants, including KCNQ1 variants, was associated with requirement of insulin injection in patients with type 2 diabetes.

Research Products

• [Journal Article] Replication study for the association of a single nucleotide polymorphism, rs3746876, within KCNJ15, with susceptibility to type 2 diabetes in a Japanese population (2013)
  • Author(s): Fukuda H, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S
  • Journal Title: J Hum Genet 2013 Volume: (in press)
  • Peer Reviewed
• [Journal Article] Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4 (2013)
  • Author(s): Ma RCW, Hu C, Tam CH, Zhang R, Kwan P, Leung TF, Thomas GN, Go MJ, Hara K, Sim X, Ho JSK, Wang C, Li H, Lu L, Wang Y, Li JW, Wang Y, Lam VKL, Wang J, Yu W, Kim Y, Ng DP, Fujita H, Panoutsopoulou K, Day-Williams A, Lee HM, Ng ACW, Fang Y, Kong APS, Jiang F, Ma X, Hou X, Tang S, Lu J, Yamauchi T, Tsui SKW, Woo JLF, Leung PC, Zhang X, Tang NLS, Sy HY, Liu J, Wong TY, Lee JY, Maeda S, Xu G, Cherny SS, Chan TF, Ng MCY, Xiang K, Morris AP, DIAGRAM Consortium, Keildson S, MuTHER Consortium, Hu R, Ji L, Lin X, Cho YS, Kadowaki T, Tai ES, Zeggini E, McCarthy MI, Hon KL, Baum L, Tomlinson B, So WY, Bao Y, Chan JCN, Jia W
  • Journal Title: Diabetologia Volume: (in press)
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in Sikhs of Punjabi origin from India (2013)
  • Author(s): Saxena R, Saleheen D, Been LF, Garavito ML, Bjonnes A, Young R, Ho WK, Rasheed A, Frossard P, Sim X, Hassanali N, Radha V, Chidambaram M, Liju S, Rees SD, Ng DPK, Wong T-Y, Yamauchi T, Hara K, Tanaka Y, Hirose H, McCarthy MI, Morris AP, DIAGRAM, MuTHER, AGEN, Basit A, Barnett AH, Katulanda P, Matthews D, Mohan V, Wander GS, Singh JR, Mehra NK, Ralhan S, Kamboh MI, Mulvihill JJ, Maegawa H, Tobe K, Maeda S, Cho YS, Tai ES, Kelly MA, Chambers JC, Kooner JS, Kadowaki T, Deloukas P, Danesh J, Sanghera DK
  • Journal Title: Diabetes
  • Peer Reviewed
• [Journal Article] A replication study for the association of rs391300 in SRR and rs17584499 in PTPRD with susceptibility to type 2 diabetes in the Japanese (2013)
  • Author(s): Imamura M, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi A, Kadowaki T, Kawamori R, Maeda S
  • Journal Title: J Diabetes Invest Volume: (in press)
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population (2012)
  • Author(s): Fukuda H, Imamura M, Tanaka Y, Iwata M, Hirose H, Kaku K, Maegawa H, Watada H, Tobe K, Kashiwagi A, Kawamori R, Maeda S
  • Journal Title: PLoS One Volume: 7 Pages: e46263
  • Peer Reviewed
• [Journal Article] KCNQ1 SNPs and susceptibility to diabetic nephropathy in East Asians with type 2 diabetes (2012)
  • Author(s): Lim XL, Nurbaya S, Tai ES, Maeda S. Nakamura Y, Ng DPK
  • Journal Title: Diabetologia Volume: 55 Pages: 2402-2406
  • Peer Reviewed
• [Journal Article] Genetic risk score constructed using 14 susceptibility alleles for type 2 diabetes is associated with the early onset of diabetes and may predict the future requirement of insulin injections among Japanese individuals (2012)
  • Author(s): Iwata M, Maeda S, Kamura Y, Takano A, Kato H, Murakami S, Higuchi K, Takahashi A, Fujita H, Hara K, Kadowaki T, Tobe K
  • Journal Title: Diabetes Care Volume: 35 Pages: 1763-1770
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations (2012)
  • Author(s): Imamura M, Maeda S, Yamauchi T, Hara K, Yasuda K, Morizono T, Takahashi A, Horikosi M, Nakamura M, Fujita H, Tsunoda T, Kubo M, Watada H, Maegawa H, Okada-Iwabu M, Iwabu M, Shojima N, Ohshige T, Omori S, Iwata M, Hirose H, Kaku K, Ito C, Tanaka Y, Tobe K, Kashiwagi A, Kawamori R, Kasuga M, Kamatani N, DIAGRAM consortium, Nakamura Y, Kadowaki T
  • Journal Title: Hum Mol Genet Volume: 21 Pages: 3042-3049
  • Peer Reviewed
• [Journal Article] Expression-based genome-wide association study links CD44 in adipose tissue with type 2 diabetes (2012)
  • Author(s): Kodama M, Horikoshi M, Toda K, Yamada S, Hara K, Irie J, Sirota M, Morgan AA, Chen R, Ohtsu H, Maeda S, Kadowaki T, Butte AJ
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Pages: 7049-7054
  • Peer Reviewed
• [Journal Article] Meta-analysis of genome-wide association studies identifies 8 new loci for type 2 diabetes in East Asians (2012)
  • Author(s): Cho YS, Chen C-H, Hu C, Long J, Ong RTH, Sim X, Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang Y-C, Kwak SH, Ma RCW, Yamamoto K, Adair LS, Aung T, Cai Q, Chang L-C, Chen Y-T, Gao Y, Hu FB, Kim H-L, Kim S, Kim YJ, Lee JJ-M, Lee NR, Li Y, Liu JJ, Lu W, Nakamura J, Nakashima E, Ng DPK, Tay WT, Tsai F-J, Wong TY, Yokota M, Zheng W, Zhang R, Wang C, So WY, Ohnaka K, Ikegami H, Hara K, Cho YM, Cho NH, Chang TJ, Bao Y, Hedman AK, Morris AP, McCarthy MI, DIAGRAM consortium, MuTHER consortium, Takayanagi R, Park KS, Jia W, Chuang L-M, Chan JCN, Maeda S, Kadowaki T, Lee J-Y, Wu J-Y, Teo YY, Tai ES, Shu XO, Mohlke KL, Kato N, Han B-G, Seielstad M
  • Journal Title: Nature Genetics Volume: 44 Pages: 67-72
  • Peer Reviewed
• [Journal Article] Association of New Loci Identified in European Genome-wide Association Studies with Susceptibility to Type 2 Diabetes in the Japanese (2011)
  • Author(s): Ohshige T, Iwata M, Omori S, Tanaka Y, Hirose H, Kaku K, Maegawa H, Watada H, Kashiwagi A, Kawamori R, Tobe T, Kadowaki T, Nakamura Y, Maeda S
  • Journal Title: PLoS One Volume: 6 Pages: e26911
  • Peer Reviewed
• [Journal Article] Genetic variants at CDC123/CAMK1D and SPRY2 are associated with susceptibility to type 2 diabetes in the Japanese population (2011)
  • Author(s): Imamura M, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi A, Kawamori R, Nakamura Y, Maeda S
  • Journal Title: Diabetologia Volume: 54 Pages: 3071-3077
  • Peer Reviewed
• [Journal Article] Genetics of type 2 diabetes; GWAS era and the future perspectives (2011)
  • Author(s): Imamura M, Maeda S
  • Journal Title: Endocrine J Volume: 58 Pages: 723-739
  • Peer Reviewed
• [Journal Article] The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals (2011)
  • Author(s): Grarup N, Overvad M, SparsφT, Witte DR, Pisinger C, Jφrgensen T, Yamauchi T, Hara K, Maeda S, Kadowaki T, Hansen T
  • Journal Title: Diabetologia Volume: 54 Pages: 789-794
  • Peer Reviewed
• [Journal Article] A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A/B (2010)
  • Author(s): Yamauchi T, Hara K, Maeda S, Yasuda K, Takahashi A, Horikoshi M, Nakamura M, Fujita H, Grarup N, Cauchi S, Ng DPK, Ma RCW, Tsunoda T, Kubo M, Watada H, Maegawa H, Okada-Iwabu M, Iwabu M, Shojima N, Shin HD, Andersen G, Witte DR, Jφrgensen T, Lauritzen T, Sandbaek A, Hansen T, Ohshige T, Omori S, Saito I, Kaku K, Hirose H, So WY, Beury D, Chan JCN, Park KS, Tai ES, Ito C, Tanaka Y, Kashiwagi A, Kawamori R, Kasuga M, Frogue P, Pedersen O, Kamatani N, Nakamura Y & Kadowaki T
  • Journal Title: Nat Genet Volume: 42 Pages: 864-868
  • Peer Reviewed
• [Journal Article] A single nucleotide polymorphism in KCNQ1 is associated with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes (2010)
  • Author(s): Ohshige T, Tanaka Y, Araki S, Babazono T, Toyoda M, Umezono T, Watada H, Suzuki D, Iwamoto Y, Kawamori R, Nakamura Y, Maeda S
  • Journal Title: Diabetes Care Volume: 33 Pages: 842-846
  • Peer Reviewed
• [Presentation] Genetic variations in DUSP9 locus and CMIP locus are associated with type 2 diabetes in a Japanese population (2012)
  • Author(s): Imamura M, Fukuda H, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi A, Kawamori R, Maeda S
  • Organizer: 47th Annual Meeting of the European Association for the Study of Diabetes
  • Place of Presentation: Berlin, Germeny
  • Year and Date: 2012-10-03
• [Presentation] Imputationに基づくゲノムワイド関連解析による2型糖尿病疾患感受性遺伝子領域の同定 (2012)
  • Author(s): 今村美菜子, 前田士郎, 山内敏正, 原一雄, 安田一基, 綿田裕孝, 前川聡, 岩田実, 広瀬寛, 加来浩平, 伊藤千賀子, 田中逸, 戸辺一之, 柏木厚典, 河盛隆造, 春日雅人, 中村祐輔, 門脇孝
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2012-05-18
• [Presentation] Rs10906115 in CDC123/CAMK1D locus and rs1359790 near SPRY2 are associated with susceptibility to type 2 diabetes in a Japanese population (2011)
  • Author(s): Imamura M, Iwata M, Maegawa H, Watada H, Hirose H, Tanaka Y, Tobe K, Kaku K, Kashiwagi A, Kawamori R, Nakamura Y, Maeda S
  • Organizer: 46th Annual Meeting of the European Association for the Study of Diabetes
  • Place of Presentation: Lisbon, Portugal
  • Year and Date: 2011-09-15
• [Presentation] 2型糖尿病感受性候補領域23領域の日本人集団における検証 (2011)
  • Author(s): 大重 聡彦, 大森 慎太郎, 田中 逸, 柏木 厚典, 加来 浩平, 広瀬 寛, 河盛 隆造, 中村 祐輔, 前田 士郎
  • Organizer: 第53回日本糖尿病学会
  • Place of Presentation: 岡山
  • Year and Date: 2011-05-27
• [Presentation] 2型糖尿病感受性候補領域33領域の日本人集団における検証 (2011)
  • Author(s): 今村美菜子、田中逸、前川 聡、綿田 裕孝、柏木厚典、加来浩平、広瀬寛、河盛 隆造、中村祐輔、前田士郎
  • Organizer: 第54回日本糖尿病学会
  • Place of Presentation: 札幌
  • Year and Date: 2011-05-21
• [Presentation] 全ゲノム解析と発現解析による2型糖尿病関連遺伝子同定の試み (2011)
  • Author(s): 原 一雄、藤田 逸人、庄嶋 伸浩、掘越 桃子、岡崎 由希子、前田 士郎、山内 敏正、植木 浩二郎、門脇 孝
  • Organizer: 第54回日本糖尿病学会
  • Place of Presentation: 札幌
  • Year and Date: 2011-05-21
• [Presentation] Effects of KCNQ1 on glucose-induced insulin secretion in rat pancreatic beta cells or on glucagon-like peptide-1 secretion in cultured NCI-H716 cells (2010)
  • Author(s): Maeda S, Tsukada S
  • Organizer: 46th Annual Meeting of the European Association for the Study of Diabetes
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2010-09-22
• [Presentation] Replication Study for the Association of 23 Susceptibility Loci for Type 2 (2010)
  • Author(s): Oshige T, Omori S, Tanaka Y, Kashiwagi A, Kaku K, Hirose H, Kawamori R, Nakamura Y, Maeda S
  • Organizer: Diabetes in the Japanese American Diabetes Association 70th Scientific Sessions
  • Place of Presentation: Orland U.S.A.
  • Year and Date: 2010-06-26
• [Presentation] 2型糖尿病患者のゲノム解析 (2010)
  • Author(s): 前田 士郎
  • Organizer: 第53回日本糖尿病学会
  • Place of Presentation: 岡山
  • Year and Date: 2010-05-29
• [Presentation] single nucleotide polymorphism in KCNQ1 is associated with diabetic nephropathy in Japanese subjects with type 2 diabetes" (2010)
  • Author(s): Maeda S., Oshige T., Araki S., Tomoya U., Toyoda M.,Kawai K., Imanishi M., Uzu T., Babazono T., Watada H., Suzuki D., Tanaka Y., Kashiwagi A., Iwamoto Y.,Kawamori R., and Nakamura Y
  • Organizer: International Society of Nephrology (ISN-nexus), (International Society of Nephrology)
  • Place of Presentation: Kyoto
  • Year and Date: 2010-04-16