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Yamauchi, Toshimasa,Hara, Kazuo,Maeda, Shiro,Yasuda, Kazuki,Takahashi, Atsushi,Horikoshi, Momoko,Nakamura, Masahiro,Fujita, Hayato,Grarup, Niels,Cauchi, Stephane,Ng, Daniel P K,Ma, Ronald C W,Tsunoda, Nature Publishing Group, a division of Macmillan P 2010 Nature genetics Vol.42 No.10
We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 ? 10<SUP>??9</SUP>; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 ? 10<SUP>??9</SUP>). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 ? 10<SUP>??14</SUP>, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.
Intensified Multifactorial Intervention in Patients with Type 2 Diabetes Mellitus
Takayoshi Sasako,Toshimasa Yamauchi,Kohjiro Ueki 대한당뇨병학회 2023 Diabetes and Metabolism Journal Vol.47 No.2
In the management of diabetes mellitus, one of the most important goals is to prevent its micro- and macrovascular complications, and to that end, multifactorial intervention is widely recommended. Intensified multifactorial intervention with pharmacotherapy for associated risk factors, alongside lifestyle modification, was first shown to be efficacious in patients with microalbuminuria (Steno-2 study), then in those with less advanced microvascular complications (the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care [ADDITION]-Europe and the Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases [J-DOIT3]), and in those with advanced microvascular complications (the Nephropathy In Diabetes-Type 2 [NID-2] study and Diabetic Nephropathy Remission and Regression Team Trial in Japan [DNETT-Japan]). Thus far, multifactorial intervention led to a reduction in cardiovascular and renal events, albeit not necessarily significant. It should be noted that not only baseline characteristics but also the control status of the risk factors and event rates during intervention among the patients widely varied from one trial to the next. Further evidence is needed for the efficacy of multifactorial intervention in a longer duration and in younger or elderly patients. Moreover, now that new classes of antidiabetic drugs are available, it should be addressed whether strict and safe glycemic control, alongside control of other risk factors, could lead to further risk reductions in micro- and macrovascular complications, thereby decreasing all-cause mortality in patients with type 2 diabetes mellitus.
Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity
Miki Okada-Iwabu,Masato Iwabu,Kohjiro Ueki,Toshimasa Yamauchi,Takashi Kadowaki 대한당뇨병학회 2015 Diabetes and Metabolism Journal Vol.39 No.5
Obesity associated with unhealthy diet and lack of exercise is shown to contribute to the onset and/or aggravation of the metabolic syndrome and diabetes, thus placing affected individuals at increased risk of cardiovascular disease and cancer. Plasma adiponectin levels are decreased in obesity, which causes insulin resistance and diabetes. Therefore, we identified adiponectin receptors (AdipoRs) as the therapeutic target. It was suggested that, similarly to caloric restriction and exercise, activation of the AdipoRs may have the potential not only to improve lifestyle-related diseases but to contribute to prolonged the shortened lifespan on a high caloric unhealthy diet. To this end, we have identified “AdipoRon” as an adiponectin receptor agonist. Indeed, AdipoRon ameliorated diabetes associated with obesity as well as to increase exercise endurance, thus prolonging shortened lifespan of obese mice fed on a high fat diet. Additionally, we have recently determined the crystal structures of the human AdipoRs. The seven-transmembrane helices of AdipoRs are structurally distinct from those of G-protein coupled receptors. It is expected that these findings will contribute not only to the elucidation of the AdipoR-related signal transduction but to the development and optimization of AdipoR-targeted therapeutics for obesity-related diseases such as diabetes.
Narasimhan, Meena L.,Coca, Maria A.,Jin, Jingbo,Yamauchi, Toshimasa,Ito, Yusuke,Kadowaki, Takashi,Kim, Kyeong-Kyu,Pardo, Jose M,Damsz, Barbara,Hasegawa, Paul M.,Yun, Dae-Jin,Bressan, Ray A. Plant molecular biology and biotechnology research 2005 Plant molecular biology and biotechnology research Vol.2005 No.
The antifungal activity of the PR-5 family of plant defense proteins has been suspected to involve specific plasma membrane component(s) of the fungal target. Osmotin is a tobacco PR-5 family protein that induces apoptosis in the yeast Saccharomyces cerevisiae. We show here that the protein encoded by ORE20/PHO36(YOL002c), a seven transmembrane domain receptor-like polypeptide that regulates lipid and phosphate metabolism, is an osmotin binding plasma mrmbrane protein that is required for full sensitivity to osmotin. PHO36 functions upstream of RAS2 in the osmotin-induced apoptotic pathway. The mammalian homolog of PHO36 is a receptor for the hormone adiponectin and regulates cellular lipid and sugar metabolism. OS-motion and adiponectin, the corresponding "receptor" binding proteins, do not share sequence similarity. However, the β barrel domain of both proteins can be overlapped, and osmotin, like adiponectin, activates AMP kinase in C2C12 myocytes via adiponectin receptors.
Cho, Yoon Shin,Chen, Chien-Hsiun,Hu, Cheng,Long, Jirong,Hee Ong, Rick Twee,Sim, Xueling,Takeuchi, Fumihiko,Wu, Ying,Go, Min Jin,Yamauchi, Toshimasa,Chang, Yi-Cheng,Kwak, Soo Heon,Ma, Ronald C W,Yamamo Nature Publishing Group, a division of Macmillan P 2012 Nature genetics Vol.44 No.1
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.