Laboratory for Endocrinology and Metabolism

Developing effective strategies for treating and preventing lifestyle-related diseases such as diabetes, diabetic nephropathy and obesity

Diabetes mellitus affects more than 200 million individuals worldwide, and this number is steadily growing. The number of people with diabetes-induced complications also continues to increase, and over 10,000 people newly require renal replacement therapies due to diabetic nephropathy per year in Japan. It has been recognized that some individuals are more susceptible to developing lifestyle-related diseases such as diabetes, diabetic nephropathy and obesity, but little is known about the nature of the contributing genetic variations.

The Laboratory for Endocrinology and Metabolism analyzes data from patients with diabetic nephropathy and controls to elucidate the pathogenetic mechanisms of diabetic nephropathy. Analyzing data from about 1,200 diabetic patients, we have identified subtle variations in the SLC12A3, ELMO1, and NCALD genes that may contribute to conferring susceptibility to diabetic nephropathy. We have also identified TFAP2B, WNT5B, KLF7, and KCNQ1 as candidate genes for susceptibility to type II diabetes, and SCG3 and MTMR9 for obesity, although it remains unclear how these genes are related to diabetes or obesity. We will further conduct comprehensive studies on susceptibility genes to the diseases to identify more novel candidate genes, and our research will continue to provide vital insights into the development of new strategies for the treatment and prevention of these diseases.

Research Subjects

• (1)   The identification of the gene conferring susceptibility to diabetic nephropathy
• (2)   The identification of the gene conferring susceptibility to type 2 diabetes
• (3)   The identification of the gene conferring susceptibility to obesity

List of Selected Publications

• (1)   Simazaki, S., Kawamura, Y., Kanazawa, A., Sekine, A., Saito, S., Tsunoda, T., Koya, D., Babazono, T., Tanaka, Y., Matsuda, M., Kawai, K., Iiizumi, T., Imanishi, M., Shinosaki, T., Yanagimoto, T., Ikeda, M., Omachi, S., Kashiwagi, A., Kaku, K., Iwamoto, Y.
  Genetic variations in the gene encoding engulfment and cell motility 1 (ELMO1) are associated with susceptibility to diabetic nephropathy
  Diabetes, 54, 1171-1178 (2005).
• (2)   Kanazawa, A, Kawamura, Y, Sekine, A, Iida, A, Tsunoda, T, Kashiwagi, A, Tanaka, Y, Babazono, T, Matsuda, M, Kawai, K, Iiizumi, T, Fujioka, T, Imanishi, M, Kaku, K, Iwamoto, Y, Kawamori, R, Kikkawa, R, Nakamura, Y, Maeda, S.:
  Single Nucleotide Polymorphisms in the Gene Encoding Kruppel-like Factor 7 are Associated with Type 2 Diabetes
  Diabetokogia, 48, 1315-1322 (2005).
• (3)   Maeda, S, Tsukada, S, Kanazawa, A, Sekine, A, Tsunoda, T, Koya, D, Maegawa, H, Kashiwagi, A, Babazono, T, Matsuda, M, Tanaka, Y, Fujioka, T, Hirose, H, Eguchi, T, Ohno, Y, Groves, CJ, Hattersley, AT, Hitman, GA, Walker, M, Kaku, K, Iwamoto, Y, Kawamori, R
  Genetic variations in the gene encoding TFAP2B are associated with type2 diabetes
  J. Hum. Genet., 50, 283-292 (2005).
• (4)   Kanazawa, A., Tsukada, S., Sekine, A., Tsunoda, T., Takahashi, A., Kashiwagi, A., Tanaka, Y., Babazono, T., Matsuda, M., Kaku, K., Iwamoto, Y., Kawamori, R., Kikkawa, R., Nakamura, Y., and Maeda, S.:
  Association of the Gene Encoding Wingless-Type Mammary Tumor Virus Integration-Site Family Member 5B (WNT5B) with Type 2 Diabetes
  Am. J. Hum. Genet., 75, 832-843 (2004).
• (5)   Tanaka, N., Babazono, T., Saito, S., Sekine, A., Tsunoda, T., Haneda, M., Tanaka, Y., Fujioka, T., Kaku, K., Kawamori, R., Kikkawa, R., Iwamoto, Y., Nakamura, Y., and Maeda, S.:
  The association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of SNPs
  Diabetes, 52, 2848-2853 (2003).
• (6)   Shimazaki, A., Tanaka, Y., Shinosaki, T., Ikeda, M., Watada, H., Hirose, H., Kawamori, R., Maeda, S.
  ELMO1 increases expression of extracellular matrix (ECM) proteins and inhibits cell adhesion to ECMs.
  Kidney Int., 70: 1769-1776 (2006)
• (7)   Kamiyama M, Kobayashi M, Araki S, Iida A, Tsunoda T, Kawai K, Imanishi M, Nomura M, Babazono T, Iwamoto Y, Kashiwagi A, Kaku K, Kawamori R, Ng DPK, Hansen T, Gaede P, Pedersen O, Nakamura Y, Maeda S
  Polymorphisms in the 3' UTR in the neurocalcin d gene affect mRNA stability, and confer susceptibility to diabetic nephropathy.
  Human Genetics 122; 397-407 (2007)
• (8)   Tanabe A, Yanagiya T, Iida A, Saito S, Sekine A, Takahashi A, Nakamura T, Tsunoda T, Kamohara S, Nakata Y, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Funahashi T, Miyazaki S, Tokunaga K, Hamaguchi K, Shimada T, Tanaka K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Sakata T, Matsuzawa Y, Kamatani N, Nakamura Y, Hotta K
  Functional single-nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite-related neuropeptides are associated with obesity.
  J Clin Endocrinol Metab 92: 1145-1154 (2007)
• (9)   Yanagiya T, Tanabe A, Iida A, Saito S, Sekine A, Takahashi A, Tsunoda T, Kamohara S, Nakata Y, Kotani K, Komatsu R, Itoh N, Mineo I, Wada J, Masuzaki H, Yoneda M, Nakajima A, Miyazaki S, Tokunaga K, Kawamoto M, Funahashi T, Hamaguchi K, Tanaka K, Yamada K, Hanafusa T, Oikawa S, Yoshimatsu H, Nakao K, Sakata T, Matsuzawa Y, Kamatani N, Nakamura Y, Hotta K
  Association of single-nucleotide polymorphisms in MTMR9 gene with obesity.
  Hum Mol Genet 16: 3017-3026 (2007)
• (10) Unoki1 H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G, Ng DPK, Holmkvist J, Borch-Johnsen K, Jørgensen T, Sandbæk A, Lauritzen T, Hansen T, Nurbaya S, Tsunoda T, Kubo M, Babazono T, Hirose1 H, Hayashi1 M, Iwamoto Y, Kashiwagi A, Kaku K, Kawamori R, Tai ES, Pedersen O, Kamatani N, Kadowaki T, Kikkawa R, Nakamura Y, Maeda S
  SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations.
  Nat Genet 40: 1097-1102 (2008)