1

A promising future of preventive

strategy for diabetes

－Preemptive medicine Takashi Kadowaki, M.D., Ph.D.

The Department of Diabetes and Metabolic Diseases,

Graduate School of Medicine, The University of Tokyo

July 26nd, 2015 at Tokyo

COI Disclosure

The Japan Diabetes Society Speaker：Takashi Kadowaki

Funded research：MSD Corporation, Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd.,

Sanofi K.K., Takeda Pharmaceutical Co., Ltd.

Endowed chair/Community corporative course：Takeda Pharmaceutical Co., Ltd.,

TERUMO Corporation, MSD Corporation, Novo Nordisk Pharma Ltd.,

Nippon Boehringer Ingelheim Co ., Ltd.

Speaking fees： MSD Corporation, Daiichi Sankyo Co., Ltd., Mitsubishi Tanabe Pharma

Corporation, Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Ono

Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., AstraZeneca K.K.,

Sumitomo Dainippon Pharma Co., Ltd., Sanofi K.K., Nippon Boehringer

Ingelheim Co ., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Eli Lilly Japan K.K.,

Kyowa Hakko Kirin Co., Ltd., Taisho Pharmaceutical Co., Ltd.

Background of rapid increase of type 2 diabetes in Japan

Genetic factors Environmental factors

High-fat meal, Lack of exercise

Obesity, Visceral fat accumulation

Fat intake is

4 times in

50 years

4 times in

50 years

23 million people

Insulin resistance Insulin secretion decrease

Insufficient

insulin action

Development of

type 2 diabetes

Interaction

35 times

Gro

wth

ra

te o

f th

e d

iab

eti

c

1 0

10

20

30

35

15

25

5

Liver Skeletal muscle

Pancreas Adipose tissue

70 55 60 80 90 2002 08

（Approximately a half of Westerners）

6.9

million

7.4

million

8.9

million

9.5

million

6.8

million

8.8

million

13.2

million

11.0

million

1997 2002 2007 2012

Pre

-dia

be

tes

Pa

tien

ts

13.7 million

16.2 million

22.1 million 20.5

million

Lack of adiponectin

2

Lifestyle（energy surplus ） High-fat meal, Lack of exercise

Super-aging

Obesity, Visceral fat accumulation Sarcopenia

Ectopic fat deposition

Microangiopathy Cardiovascular and kidney diseases

(Myocaridial infarction, Stroke, CKD), NASH

Hyperlipidemia Hypertension Type 2 diabetes

Metabolic syndrome

Cancer, Dementia, Osteoporosis and Flail

アディポネクチン不足

Insulin resistance/ Hyperinsulinemia

Impaired glucose tolerance

The energy surplus lifestyle and the super-aging makes to increase obesity, visceral fat accumulation and sarcopenia causes insulin resistance, type 2 diabetes, various

complications, flail, and shortening of healthy life expectancy

Lack of adiponectin

Action Plan 2010 of the Japan Diabetes Society（DREAMS） based on the “2nd Strategic Five-Year Plan for Diabetes.“

ーActivity goals for the next five yearsー

Hope and Challenge

① Diagnosis and Care

② Research to Cure

③ Evidence for Optimum Care

④ Alliance for Diabetes

⑤ Mentoring Program for Prevention

⑥ Stop the DM

Action Plan 2010 of

the Japan Diabetes Society (DREAMS)

For you and your loved ones

The 56th Annual Meeting

of the Japan Diabetes

Society

Special Statement 2013

3

Diabetes Measures Promotion Conference

Organization : Japan Medical Association,

The Japan Diabetes Society, Japan Association

for Diabetes Education and Care

Prefectural conference

Municipal conference

Primary prevention of diabetes Diabetes management

Public health center Doctor

Nurse Registered dietitian, Others.

Diabetes Measures Promotion Conference

１．The primary prevention by promoting screening

examination and post-guidance

２．Improvement of diabetes management quality and

promotion of clinical visits

３．Promotion of medical collaboration

Chairman Y. Yokokura

Vice Chairman T. Kadowaki

Y. Seino

M. Takagi

S. Imamura

⑤Mentoring Program for Prevention

⑥Stop the DM

MHLW*

*Ministry of Health, Labour and Welfare

※National correction value only in 2012

Ministry of Health, Labour and Welfare National Health and Nutrition Examination Survey (2012)

2,500

2.000

1,500

1,000

500

0

（ten thousand）

People who strongly

suspected to have diabetes

People who strongly

suspected to have diabetes

and People who have

undeniable possibility of

diabetes

People who have

undeniable possibility of diabetes

H9 H14 H19 H24

690 740

890 950

1,370

1,620

2,210

2,050

680

880

1,320

1,100

Annual change in the number of ‘Diabetic patients’ and ‘Pre-diabetic patients’ （over 20 years old）

H9 H14 H19 H24 H9 H14 H19 H24

Decline of pre-diabetic patients

Yomiuri Newspaper

December 20, 2013 (Fri.)

Diabetic patients

Pre-diabetic patients

⑤Mentoring Program for Prevention

⑥Stop the DM

Percentage of dialysis initiation caused

by diabetic nephropathy has become flat in these few years Annual change in main causative diseases of dialysis

Diabetic nephropathy

Chronic glomerulonephritis

Renal sclerosis

（Japanese Society for Dialysis Therapy Renal Data Registry: JRDR）

⑤Mentoring Program for Prevention

⑥Stop the DM

Diabetic nephropathy

Chronic glomerulonephritis

Renal sclerosis

Polycystic kidney disease

Chronic pyelonephritis

Rapidly progressive glomerulonephritis

SLE nephritis

Unclear

year

4

The 3rd Strategic Five-Year Plan

for Diabetes

Increasing in number of the diabetic patients and the obesity (For the first time, the number of pre-diabetes decreased: By National Health and

Nutrition Examination Survey)

year

10 million

20 million

Diabetes

Pre-

diabetes

Ratio of obese people

Ma

le

fem

ale

Shortening of healthy life expectancy due to various

complications

●Diabetic nephropathy (dialysis initiation)

●Eye sight disturbance by retinopathy

●Myocardial infarction ●Cerebral infarction

●Dementia and bone fracture in

elderly

●Lower limb amputation ●Periodontal disease

Rising medical expenses 15%of medical expense is paid for diabetes.

And diabetes is responsible for 30% of all death

Malignant tumor Associated with diabetes and metabolic syndrome

Ischemic heart disease \0.7 trillion

Medical expenses (2012) \39.2 trillion

Cerebrovascular disease \1.8 trillion

Others 19.4 trillion yen

\3.3 trillion Malignant tumor

Heart Disease

15.9%

Cerebrovascular disease

Associated with diabetes and metabolic syndrome

Hypertension 0.6%

Lack of human resources and epidemiological data

●It is urgently necessary to nurture medical personnel examining and

educating diabetes.

Othesr

●It is necessary to collect data about prevalence of diabetes and

epidemiological data

Necessity of establishment of the 3rd Strategic five-year Plan for Diabetes

Medical cost

\28.3 trillion

Diabetes, CVD

About \3.7 trillion

Hypertension \ 1.9 trillion

Diabetes 1.2%

Diabetes \1.2 trillion

Cause of death (2012)

Diabetes, CVD About 30 %

Fruit of advanced

researches of diabetes

Establishing of a base for the super-aged society

Nurturing medical personnel

considering future countermeasures for diabetes

Educating and Informing for the public

Evidence construction utilizing data

from comprehensive database

An important point and a goal of the 3rd Strategic Five-year Plan for Diabetes

5

Developm-ent

Accurate prediction

Intensive intervention

Progression level of disease

Age

Disease

Presympto-

matic

(Pre-

diseased)

Healthy

Prevention of getting severe

Prevention of relapsing

Accurate prediction Emphasis intervention

Delayed onset

Stop progression

Recovery

Preemptive Medical Care＝ What is personalized

prevention and personalized medicine ?

Personalized

medicine

Personalized

prevention

The concept of diabetic measures

Countermeasures at each step in the whole process of diabetes development

H

e

a

l

t

h

y

Aging

Life style

Genetic factors

Metabolic syndrome

D

i

a

b

e

t

e

s

Related disease・ complications

Myocardial

infarction Neuropathy

Stroke Nephro-

pathy

Retino-

pathy

Foot

gangrene Cancer Dementia

Perio-

dontitis Osteo-

porosis

Shortening of

healthy life

expectancy

0-order prevention

(Education)

High-risk intervention (Specific medical checkups

and specific health

guidance)

Intervention・ Progress suppression

Intensive treatment for prevention of

severity

Therapeutic intervention ・ related disease prevention

“Preemptive medicine” in each stage Regional

cooperation

Japan Diabetes

Measures Promotion

Conference

Home・school ・workplace

Primary care doctor Diabetoligst

Other area’s specialist

Therapeutic goal Consolidation cure group

n = 1271

Conventional treatment group

n = 1271

Blood sugar HbA1c < 6.2% HbA1c < 6.9%

Blood pressure < 120 / 75mmHg < 130 / 80mmHg

Lipid LDL-C < 80mg/dL

(*LDL-C < 70mg/dL)

LDL-C < 120mg/dL

(*LDL-C < 100mg/dL)

* History of CHD

Subjects Type 2 diabetes with high blood pressure or dyslipidemia（Age 45-69） HbA1c ≧6.9% 〔n=2542, Initial prevention 89%, Prevention of recurrence 11%〕

The primary endpoint Death, Myocardial infarction, Stroke, Coronary revascularization, Cerebral artery revascularization

The Secondary

endpoints

The onset or progression of renal disease, Lower limb amputation, the onset and progression of retinopathy

Test period Registration period for 2.5 years, Follow-up period is until the primary endpoint reaches 250 cases (It is expected to be 7 years after the final registration)

Japan Diabetes Outcome Intervention Trial 3・J-DOIT3 Overview

NCT00300976

6

っ強力な

Evidence that was directed to the diabetic complications suppression in

daily practice (Target for blood sugar, pressure, & lipid How to proceed lifestyle improvement and

medication)

Brain infarction

Vascular Complications in the Diabetic Patients

Myocardial infarction

Before J-DOIT3

Medical care cost

Healthy life expectancy

QOL of patient

After J-DOIT3

This is the first evidence in the treatment of diabetes in all over the world that showed the safe normalization of multi-risk factors had made improvement of healthy life expectancy and QOL in diabetic patients

Prevention of vascular complications

Medical expenses

Healthy life expectancy

QOL of patient

Intensive intervention on lifestyle and

integrated treatment for risk factors

Purpose and spillover effects of J-DOIT3

The further promotion of diabetes research

~ Construction of personalized countermeasures based on genetic information ~

Current situation

About 80 related gene region of has been identified Around 10% of the genetic predisposition

to type 2 diabetes Risk prediction based on genetic information

Useful for the diagnosis of a few percent of

the high-risk group

Based on genetic information

Pharmaco-

genomics

●Whole genome sequencing

●Entire exon sequence

●Epigenomic analysis

●Metagenomic analysis

●Prospective cohort

Development of novel

therapeutic drug Avoidance of side effects Diabetes drug selection Personalized prevention

Genetic information

Genetic

information Lifestyle

Diet

Epigenome control

SNP

analysis

Meta-

genomic

analysis

Microflora

Integrated analysis of genetic and environmental factors

5

Years

later

1.40

1.35

1.30

1.25

1.20

1.15

1.10

1.05

1.00

od

ds r

ati

o

History of identification of type 2 diabetes susceptibility genes

Initially identified in Caucasian

Initially identified in Asian

~2003 2004 2005 2006 2007 2008 2009 2010

PPARG

2011

Those blue characters showed genes that have been identified in Asian

TCF7L2

2012

KCJN11 (Kir6.2)

CDKN2A-2B

FTO

HHEX-IDE

SLC30A8

CDKAL1

IGF2BP2

WFS1

TCF2

KCNQ1

HNF1B

CDC123 JAZF1

ADAMTS9

THADA

NOTCH2

MTNR1B

DCD VEGFA

PPP2R2C

CETN3

CENT2D

BCL11A ZBED3

PRC1

DUSP9 GCK

GCKR

PROX1 DGKB

ADCY5

C2CD4A/B

KLF14

UBE2E2

TP53INP1 ZFAND6 HMGA2

CHCHD9 TSPAN8 IRS

1 HNF1A HNF4A

VPS26A

ST6GAL1

HMG20A/B

AP3S2

GRB14

ZFAND3

PEPD

GCC1-PAX4

GLIS3

KCNK16

PSMD6

MAEA

FITM2-R3HDML- HNF4A

2013

ZMIZ1

KLHDC5

ANK1

TLE1

CLIP2

MC4R

BCAR1

ANKRD55

RASGRP1

SLC16A13

LPP

FAF1

MPHOSPH9

SSR1/RREB1

ARL15

POU5F1/TCF19

TMEM154

PAX4

GPSM1

MIR129-LEP

2014

7

In this study, we will reveal the overall picture of the pathogenesis and severity for

genetic basic factor about missing heritability

50.0

5.0

2.0

1.1

Large

Middle

Small

0.001 0.05 0.005 Allele

frequency very rare rare Low frequency High frequency

・Rare variants

・Large effect for disease

Range covered

with conventional

GWAS

Range covered by this project

Current status and issues

for personalized prevention and medicine (missing heritability)

・ Large number of low frequency variants

・Moderate effect for disease

Range that we

reveal

by this high-

density

polymorphism

GWAS

・common variants

・Small effect for disease

Size of

efficacies

TCF7L2 SNP TT type has significantly

higher diabetes risk compared to the

CC type

A group with

normal daily-

living

Examples of disease prevention based on genetic information

Type 2 diabetes gene TCF7L2 and diabetes prevention (USA)

The influence of the gene can be minimized by improving lifestyle

years

Ra

tio o

f dia

be

tes

de

ve

lop

me

nt

(%)

Those who have TCF7L2 SNP TT

type were also suppressed like those

in CC type by weight loss related to

lifestyle change

Active lifestyle

improvement group

(5% weight loss)

years

Ra

tio o

f dia

be

tes

de

ve

lop

me

nt

(%)

(NEJM 2006)

Future prospects:

The personalized prevention & medicine for the metabolic syndrome-related diseases

KCNQ1, CDKAL1, CDKN2B, TCF7L2, UBE2E2, C2CD4A/B, IGF2BP2, PPARg, HHEX, SLC30A8, FTO, GCKR, DGKB, MIR-LEP, SLC16A13, GPSM1 ………

Exhaustive

identification Development of

the predictive method

The number of risk allyl

On

se

t ri

sk

37~ 46~ 60~69

2

8

6

4

48~ 50~ 54~ 56~ 58~

10

A risk rises

conspicuously

Application to

the medical practice Verification

発症率

Heredity (-) Lifestyle risk(-)

Heredity (-) Lifestyle risk(+)

Heredity (+) Lifestyle risk(-)

Heredity (+) Lifestyle risk(+)

Lifestyle improvement

⇒Risk↓

Hypothesis Verificatio

n

Realizati

on

2013 2014 2015 2016 2017

Biobank Japan pursuing

check-up

Other co-Hort ・International consortium

Comparison

between races

Genes associated with onset of the diseases

重症化率

Heredity(-) Therapy(+)

Heredity (-) Therapy(-) Heredity (+) Therapy(+)

Heredity (+) Therapy(-)

therapia ⇒Risk↓

（e.g.） 40,000 people with dibetes , 6-year follow-up

The number of risk allyl

Se

ve

rity

ris

k

6~10 11 18 19~21

2

8

6

4

12 13 14 15 16 17

Severe disease related genes

6~10 11 18 19~21 12 13 14 15 16 17

………

Inc

ide

nc

e r

ati

o

Se

ve

rity

ra

tio

The increase of

susceptible genes links

the increase of predictive

ability in gene risk score

8

Preemptive medicine based on genome information and medical health checkups

and health claim information

(Personalized prevention & personalized medicine

Personalized

prevention

Medical checkups

information

Genome

information

Everyday walk

effective prevention of development

Drug choice in line with the molecular

condition of a patient

Effective blood

sugar control

Intensive

blood vessel dock

Extend healthy life expectancy

in the nation

Personalized

medicine

Personalized medicine

Prediction of severity Molecular pathological diagnostics

＋ ＋

Predictive diagnosis Predictive medicine

Improvement of therapy Personalized prevention

Developm-

ent

Accurate prediction

Intensive intervention

Progression level

of diseases

年齢

Disease

Pre-sympto-

matic

(pre-

diseaed)

Healthy

Prevention for getting severe

Prevention of relapsing

Accurate foresight

Delayed onset

Stop progression

Recovery

Personalized medicine

Personalized prevention

Medical checkups

information

Genome

information

Differential functions of small and large intestine

in relation to microbial density

Diabetes Care 38:159–165, 2015

Jejunum

-FFAs -Calcium/Vit D -Vit ADEK

Ileum

-Vit B12 -Bile acids

Colon

-Water -SCFAs

Lactobacillus Streptococcus

Enterobacteriaceae

Bacteroids Bifidobacterium Clostridium Eubacterium Ruminococcus

GUT SEGMENT FUNCTION COMPOSITION pH

4-5

5-6

6-7

Density

101-103

104-107

1010-1013

Duodenum

-Proteins -Monosaccharide -SCFAs -Immunomodulation

9

Intestinal bacterial species associated with and/or

predictive of insulin resistance/T2DM development as

future potential clinical diagnostic markers of T2DM

Diabetes Care 38:159–165, 2015

Increase in T2DM

x

Decrease in T2DM

x

Intestinal bacterial phyla

Firmicutes

Bacteroidetes

Intestinal bacterial species

Roseburia

Eubacterium halii

Faecalibacterium prauznitzii

Lactobacillus gasseri

Streptococcus mutans

E. coli

Increase in T2DM

x

x

x

Decrease in T2DM

x

x

x

Gut microbiota–produced SCFAs in obese/T2DM

Diabetes Care

38:159–165, 2015

COLON

SYSTEMIC

Obesuty

/T2DM Lean

The further promotion of diabetes research

The elucidation of the physiological and pathophysiological action

of the diet (nutrient) and exercise effecting on the homeostasis of the body

Exercise

Diet/Nutrient

Intestinal flora

Fat

Protein

Carbohydrate

Sugar

Alcohol

Dietary fiber

Salt

Energ

y

Dyslipidemia

Obesity

High blood sugar

High blood pressure

Sarcopenia

The promotion of research which become the theoretical foundation

of the diet and exercise therapy

10

Liraglutide and Body Weight

Shows the mean body weight for patients in the full-analysis set who

completed each scheduled visit, according to presence or absence

of prediabetes at screening.

0

-2.8±6.5kg

-8.4±7.3kg

Ch

an

ge in

Bo

dy W

eig

ht

(%)

weeks

-2

-4

-6

-8

-10

-12 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

LOCF

LOCF

Normoglycemia Prediabetes

Liraglutide Liraglutide

Placebo Placebo

N. Engl. J. Med. 373: 11-22, 2015

Liraglutide group was associated with a lower incidence

of developing type 2 diabetes

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Pa

tie

nts

Re

ce

ivin

g

a D

iag

no

sis

of

Dia

be

tes

(%

)

0 8 16 24 32 40 48 56

Cumulative No. of Patients Receiving a Diagnosis of Diabetes over 56 Weeks (NO. at Risk)

Week

Placebo 1(1225) 2(1210) 3(1204) 4(1096) 5(1035) 8(984) 9(911) 10(908) 11(818) 12(817) 13(816) 14(813)

Liraglutide 1(2219) 2(2210) 3(2137) 4(2130)

1

Liaglutide Placebo

P<0.001

3 2

4 5

8 10

9

13 11

14

12

1 2 3 4

N. Engl. J. Med. 373: 11-22, 2015

11

Effects of adiponectin is

decreased by decreased

expression of AdipoR1

Hypoadiponectinemia

Dicreased Adiponectin secretion,

Decreased Adiponectin receptor expression

（Decreased Adiponectin effect） and Relation to pathophysiology （Hypothesis）

Cancer cell Nerve cell Liver cell Skeletal muscle

Cell

Vascular endothelial cell

Adipo

R1

Macrophage

Type 2

diabetes Atherosclerosis Cancer

Alzheimer

disease

Effects of adiponectin is

decreased mainly by decreased

expression of AdipoR1/2

Adipo

R1

Adipo

R1

Adipo

R1

Adipo

R2

Adipo

R2

Adipo

R2

Obesity

Inflammation

Atherosclerosis

Effects of adiponectin is

decreased by decreased

expression of AdipoR1/2

Adipo

R1

Adipo

R2

Liver cell

Fatty liver

（Yamauchi T. & Kadowaki T.

Cell Metabolism 17:185-196, 2013）

Endothelial dysfunction

Development of orally-administrable type 2 diabetes medicine, calorie restriction/exercise mimic drugs, or life extension drug

targeting AdipoR

Exercise

SIRT1

Extension of life expectancy Inhibition of Diabetes, Cardiovascular

diseases, NASH, and Cancer

Life-expectancy related organ

Metabolism-related organ

Calorie restriction

AMPK

PGC-1α

SIRT1

Adiponectin/ AdipoR AdipoR

agonist

（Orally-administrable）

PPAR

(Nature Medicine 2001, Nature Medicine 2002, Nature 2003,

Nature Medicine 2007, Nature2010, Nature2013)

First in Class

⇒Adiponectin Receptor Agonist : AdipoRon

AdipoRon

Bind to AdipoR1・AdipoR2

Improve insulin resistance, glucose metabolism

in type 2 diabetes model mouse

100

50

0

Ins

ulin

res

ista

nc

e (

%)

* n.s.

AdipoRon (p.o.)

－ ＋ － ＋ Mouse fed

with high-fat diet R1・R2 deficient mouse fed with

high-fat diet

Improve exercise tolerance (muscle endurance)

in type 2 diabetes model mouse

**

2.0

1.0

0

Mu

sc

le

en

du

ran

ce

(min

/tim

e)

n.s.

－ ＋ － ＋ Mouse fed with

high-fat diet

R1・R2 deficient mouse fed with

high-fat diet

AdipoRon (p.o.)

Bind to AdipoR1 Bind to AdipoR2

AdipoRon

(Iwabu-Okada M et al. Nature 503:493-499, 2013)

AdipoRon

Increase the amount of mitochondria

2.0

1.0

0 Mit

och

on

dri

al

RN

A

am

ou

nt

(ra

tio

) **

Control Adiponectin

**

AdipoRon

AdipoRon binds to AdipoR1・R2 and improves insulin resistance,

glucose metabolism and muscle endurance via AdipoR1・R2.

12

生存率

Time (day)

Kaplan–Meier survival curves

Oral administration of AdipoRon improved lifespan

shortened by high-calorie, high-fat diet

0.0

0.2

0.4

0.6

0.8

1.0

1.2

0 20 40 60 80 100 120

High-calorie, high-fat diet+AdipoRon

（p < 0.05）

High-calorie, high-fat diet（p < 0.01）

Healthy diet

High-calorie, high-fat diet

High-calorie, high-fat diet + AdipoRon

Healthy diet

Nature 503: 493-499, 2013

Adiponectin receptor activation small molecule compound

AdipoR1/R2 agonist (AdipoRon)

fatty acid

combustion ↑

Gluconeogenesis ↓

Fatty liver ↓

Inflammation ↓

Oxidative stress ↓

Liver Skeletal muscle Adipocytes, macrophage

Mitochondrial function ↑

Fatty acid combustion ↑

Exercise endurance ↑

Neutral lipid content ↓

Oxidative stress ↓

Vascular endothelium

function ↑

Inflammatory intimal

thickening ↓

Nature, 503, 493-499, 2013, unpublished data

Vascular endothelial cell

Inflammation ↓

Macrophage

（M1:Bad MΦ） ↓

Oxidative stress ↓

Improvement of insulin resistance, glucose and lipid metabolism

Improvement of inflammation and vascular endothelium function

Extension of life expectancy

13

Clarified a tertiary structure of AdipoR

AdipoR2・Fv complex

AdipoR2

Fv domain

of the

antibody for

AdipoR2

C-terminal extracellular domain

N-terminal intracellular domain

8 April 2015 Nature electric edition

Optimization of the compound based on tertiary structure analysis of Adiponectin

receptor activation small molecule compound（AdipoRon）and AdipoR

－ Aiming to development of molecula target medicine for type 2 diabetes, lifestyle

diseases and for healthy longevity medicine －

Innovative drug development of the lifestyle diseases

Identification of the convincing target

Identified Adiponectin receptor ahead of the

world

Analysis of the tertiary structure of the Adiponectin

receptor

AdipoR

AdipoR

Succeeded in Tertiary structure decision

Development of a small molecule compound activating

Adiponectin receptor

AdipoRon

Identification of Small-molecule compound

Proof of Concept Elucidation of the tertiary

structure

Optimization of the Adiponectin receptor

agonist based on a tertiary structure

Lifestyle diseases molecular target medicine・

Development of healthy longevity medicine

Optimization of the compound based on the tertiary structure

analysis First in Human

Collaborative research with Dr. Shigeyuki Yokoyama of RIKEN

Molecular target identification of the innovative drug development

Functional analysis

Nature2003

Nature Medicine2007

Nature2010 Nature2013

Nature2015

The further promotion of diabetes research

Promotion of translational researches from fundamental research as a

frontier medical science to the clinical field

Regeneration or

reconstruction of organ

function lost by diabetes

Establishment of the

differentiation methods

for functional cells

Mass cultivation ・tissue construction

Stem cell research

such as iPS cell

Islet transplantation

Pancreatic

transplantation Gene therapy

14

Aiming the definitive treatment of diabetes and its complications

It can be applied to pancreatic

reproduction for type I

diabetes mellitus and organ

reproduction for diabetes

complications

gene

transfer

患者

膵β細胞 血管 肝細胞

拒絶のない移植

iPS cell

体細胞

心筋細胞 神経細胞

１０

Nobel Prize winner

Dr. Shinya Yamanaka

(Prof. of Kyoto University)

2013.2.1

New roadmap for iPS

cell research Start Clinical study in

retina：2013

myocardium：2015-2016

nerve：2016-2017

pancreatic β cell：2016-2017

Pancreatic β cell

・Establishment the

differentiation methods from iPS cell 【almost done】

・ Preclinical study by model

animals 【has been already

started】

・ Initiation of clinical trials

【no less than 5 years】

2014.9.12

The first clinical application using iPS cell

Retina an ARMD

Dr. Masayo Takahashi, PhD, Riken

Regenerative medicine using iPS cell（induced pluripotent stem cell)

Promotion of the international cooperation

aiming at diabetes conquest

The Japan Diabetes Society

15

Evidence-based diabetic medicine

（EBM）

Lower patient’s burden and safety medical care

for diabetes

HOPE and Challenge

The Japan Diabetes Society Action Plan (DREAMS)

Radical treatment of diabetes

（ Regeneration medicine ）

Individuated diabetic medical care

and prevention （Initiative medical care）

Further realization

build upon the outcomes of

DREAMS

The Japan Diabetes Society’s action plan (DREAMS) makes a dream “advance from Control・Care to prevention & radical Cure of diabetes” come true.