Laboratories
301K Laboratory
Principal Investigator, Takashi Kadowaki MD, PhD
EDUCATION:
1978 M.D. Tokyo University Medical School
1997 Ph.D. (Medicine) The University of Tokyo
POSITIONS HOLD:
1978-1980 Resident in Internal Medicine, Tokyo University Medical
School
1980-1986 Clinical Research Fellow, Diabetes Section, the Third
Department of Internal Medicine, Faculty of Medicine,
The University of Tokyo
(Section Chief: Dr. Masato Kasuga)
1986-1990 Visiting Fellow, Biochemistry and Molecular
Pathophysiology Section, Diabetes Branch, National
Institute of Diabetes, Digestive, and Kidney, Disease,
National Institutes of Health, Bethesda, MD, U.S.A.
(Branch Chief: Dr. Simeon Taylor)
1990-1998 Chief, Diabetes Branch, Assistant Professor, the Third
Department of Internal Medicine, Faculty of Medicine,
The University of Tokyo
1998-2000 Chief, Diabetes Branch, Lecturer, the Department of
Diabetes and Metabolic Diseases, Graduate School of Medicine,
The University of Tokyo
2001-2003 Chief, Diabetes Branch, Associate Professor,
the Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine, The University of Tokyo
2003-present Professor and Chairman,
the Department of Diabetes and Metabolic Diseases,
Graduate School of Medicine, The University of Tokyo
2004-2006 Advisor to the President of the University of Tokyo
2005-2010 Vice-director of The University of Tokyo Hospital
2008-present Chairman of the Board of Directors,
The Japan Diabetes Society
2011-present Director of The University of Tokyo Hospital
2012-present Head of Translational Research Initiative,
The University of Tokyo
SOCIETIES:
The Japan Diabetes Society (Chairman of the Board of Directors)
The Japan Endocrine Society (Board Member)
Japan Society for the Study of Obesity (Board Member)
American Diabetes Association
The Endocrine Society
Asian Association for the Study of Diabetes
HONORS AND FELLOWSHIPS:
Fogarty International Fellowship (1986-1990)
Young Investigator Award of the Japanese Society of Internal
Medicine (1992)
Research Award of the Japan Endocrine Society (1993)
Shionogi-Lilly Award of the Japan Diabetes Society (1993)
Research Support Award of the Japan Medical Association (1993)
Research Award of the Tokyo Medical Association (1995)
Research Award of the Association of Tokyo University Medical
School (1995)
Erwin von Baelzprize (2001)
The Best Teacher's Award of Tokyo University Medical School
(2001)
Academic Award of the Mochida Memorial Foundation (2002)
Hagedorn Award of the Japan Diabetes Society (2004)
Sankyo Takamine Memorial Award (2004)
Medical Award of The Japan Medical Association (2007)
The Uehara Prize (2007)
Award of the Japan Society of Experimental Diabetes and Obesity
(2008)
Awardee of a Medal with Purple Ribbon (2010)
Takeda Medical Science Prize (2011)
Japan Endocrine Society Award (2012)
Kroc Lecture in Diabetes, University of Chicago (2012)
EDITORIAL BOARD:
Endocrine J. (Editorial Board, 1990-1999)
Diabetologia (Associate Editor, 2000-2002)
Diabetes (Editorial Board, 2002-)
J. Clin. Invest. (Editorial Board, 2002-2012)
Metabolic Syndrome and Related Disorders
(Editorial Board, 2002-)
The Journal of Endocrine Genetics (Editorial Board, 2003-)
Diabetes, Obesity and Metabolism (Editorial Board, 2004-)
Current Diabetes Reviews (Editorial Board, 2004-)
Arteriosclerosis Thrombosis and Vascular Biology
(Editorial Board, 2004-2007)
Endocrinology (Editorial Board, 2004-2007)
Diabetes Care (Editorial Board, 2007-)
The Journal of Clinical Endocrinology & Metabolism
(Editorial Board, 2007-)
Best Practice & Research Clinical Endocrinology & Metabolism
(Editorial Board, 2007-)
Journal of Diabetes (Editorial Board, 2009-)
Journal of Diabetes Investigation (Executive Editor, 2010-)
Diabetology International (Editorial Board Member, 2010-)
Cell Metabolism (Editorial Board, 2012-)
Molecular Metabolism (Regional Editor for Asia,2012-)
Research
We research insulin signaling, adiponectin action and genome analysis of diabetes to elucidate the mechanism of onset of diabetes with cutting-edge scientific methods.
Topics
- Mechanism of onset of diabetes
- Role of insulin signaling ( IRS-1/2, PI-3 kinase, akt signaling)
- Mechanism of adiponectin action
- Human genome study
Yamauchi Group
We identified adiponectin as therapeutic target adipokine for insulin resistance, metabolic syndrome and type 2 diabetes by using the combination of genome-wide scanning and DNA chips, and showed that adiponectin exerts its insulin sensitizing action via several key molecules such as AMPK and PPAR. Genetic studies on SNP of adiponectin gene as well as functional analyses including transgenic or knockout mice suggested that reduced adiponectin levels play a causal role in the development of metabolic syndrome and type 2 diabetes （Nat.Med.7: 941, 2001; Nat.Genet.30: 221, 2002; Nat.Med.8: 1288, 2002）.
We discovered adiponectin receptors (AdipoR1 and R2) by expression cloning （Nature 423: 762, 2003）and found that AdipoRs are also decreased in obesity. We generated AdipoR1 and R2 double knockout mice and showed that AdipoR1 and R2 serve as the major receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress （Nat.Med.13: 332, 2007）. From these data, we have been proposing “adiponectin hypothesis” that reduced plasma adiponectin levels as well as reduced adiponectin receptors play important roles in insulin resistance, metabolic syndrome and type 2 diabetes linked to obesity (Endocrine Reviews 26: 439, 2005).
We found that osmotin, present in fruits and vegetables, activated AMPK via AdipoRs in myocytes (Mol.Cell 17: 171, 2005). Moreover, the human adiponectin mutations analyses led to identification of high molecular weight (HMW) adiponectin as most active form, and then we developed an ELISA system (J.Biol.Chem. 278: 40352, 2003) and showed that measurement of HMW is useful for the prediction of insulin resistance and metabolic syndrome (Diabetes Care 29:1357, 2006).
Recently, we found that adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1 like exercise, and reported that decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes (Nature 464: 1313, 2010). These data suggested that agonism of AdipoR1 as well as strategies to increase AdipoR1 in muscle could be exercise-mimetics.
We are now trying to develop orally acitve AdipoR activators as exercise-mimetics for treatment of diabetes.
Hara Group
Genetics of type 2 diabetes
We currently have research projects to identify the type 2 diabetes susceptibility genes in the Japanese population
T2D (T2D) is a multi-factorial disease whereby susceptibility is determined by the interactions of multiple genetic and environmental factors. We have research projects that aim to dissect the genetic architecture of T2D and focus on the role of susceptibility genes in the pathogenesis of T2D.
We explored T2D susceptibility genes by genome-wide linkage and association approaches in the last decade. We mapped 9 chromosomal regions that were likely to be linked to T2D, followed by identifying the adiponectin gene, HNF4A, and PRKAA2 as T2D susceptibility genes in each three regions out of those 9 regions respectively.
The genome-wide association has now replaced genome-wide linkage approach as the hypothesis-generating approach for genetics of common diseases. We promptly carried out a genome-wide association study of T2D using a database of common genetic variations of the Japanese. We found the most significant association between SNPs in KCNQ1 and T2D in the Japanese population and replicated extensively in other populations including people of European descent. The risk allele of KCNQ1 polymorphism was associated with impairment of insulin secretion.
We have conducted a multistage genome-wide association study with 459,359 SNPs and a large sample size at first stage (4,470 cases and 3,071 controls) and succeeded in replicating previously reported susceptibility loci to T2D and identifying two novel type 2 susceptibility genes, UBE2E2 and C2CD4A/B. Taking into account that the risk allele frequencies of these genes are high, UBE2E2 and C2CD4A/B play substantial roles in the development of T2D in the Japanese population.
We are currently performing QTL (quantitative trait loci) mapping of diabetes and obesity-related traits. We are carrying out subgroup analysis and logistic regression analysis taking the interaction between genes and environmental factors into the model to clarify the gene-environmental interactions in the pathogenesis of T2D.
We are also investigating the function of T2D susceptibility genes. Recent data in our laboratory demonstrates that a novel gene in the highest LOD score in our previous genome-wide linkage scan is related to beta cell function.
Future directions
We will perform resequencing and fine mapping in a step towards characterizing functional variants which would explain the missing heritability of T2D. We hope we can develop the method to predict development of T2D in each individual accurately based on the genetic information. It is also expected that we can develop the genetic profiling of the pathogenesis involved in individuals to tailor therapeutic and life-style intervention. Implementation of these approaches in mainstream healthcare will contribute to personalized medicine in the near future.
Kubota Group
301S Laboratory
Midori Fujishiro MD, PhD
311 Laboratory
Hiroaki Okazaki MD, PhD
101 Laboratory
Makoto Kurano MD, PhD