Type 2 diabetes via ®²-cell dysfunction in East Asian people 2017. 1. 7.¢  Type 2...

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Transcript of Type 2 diabetes via ®²-cell dysfunction in East Asian people 2017. 1. 7.¢  Type 2...

  • Type 2 diabetes via β-cell

    dysfunction

    in East Asian people

    Jeong Hyun Park, M.D., Ph.D.

    Department of Internal Medicine, Busan Paik Hospital, College of Medicine, Inje University, Busan, Korea

  • The pathophysiology of type 2 diabetes mellitus

  • Blood glucose levels are the result of the balance between β-cell function and insulin resistance

  • Transition from NGT to Diabetes

    Adapted from Festa A et al. Diabetes 2006:55;1116

  • Adapted from ADA GENNID Study Group. Diabetes 2002:51;2170-2178

    β-cell Function is a Major Contributor to Glucose Tolerance in Four Ethnic Groups in US

    NGT DMIFG/IGT

  • Insulin Secretory Dysfunction and Insulin Resistance in the Pathogenesis of Korean Diabetes Mellitus

    Insulinogenic index HOMA-IR

    Dong J. Kim et al , Metabolism 2001:50(5);590-593

  • Standardized β-cell Function Decline over Insulin Resistance in Korean Diabetes

    Dong J. Kim et al , Metabolism 2001:50(5);590-593

    Insulinogenic index / HOMA-IR

  • The differences between Asians & Caucacians

  • Age-adjusted ethnic prevalence of diabetes mellitus in Hawaii in 1958–1959

    Sloan NR. Ethnic distribution of diabetes mellitus in Hawaii. JAMA 1963; 183: 419–424

  • Difference of Prevalence of Diabetes by Ethnicity

    5-

    20 -

    25 -

    0 -

    15 -

    30 -

    18

    35-

    10 -

    19 20 21 22 23 24 25 26 27 28 29 30 31 32

    40-

    South Asian 22.0

    Chinese 24.0

    Black 26.0

    White 30.0

    Body Mass Index (kg/m2) Body Mass Index (kg/m2)

    5-

    20 -

    25 -

    0 -

    15 -

    30 -

    18

    35-

    10 -

    19 20 21 22 23 24 25 26 27 28 29 30 31

    40-

    South Asian 21.6

    Chinese /Black 26.0

    White

    30.0 D

    ia b e te

    s P re

    va le

    n ce

    ( %

    )

    D ia

    b e te

    s P re

    va le

    n ce

    ( %

    )

    Ntuk UE, et al. Diabetes Care 2014;37:2500-7

    Study design: UK Biobank recruited 502,682 U.K. residents aged 40–69 years. Researchers used baseline data on the 490,288 participants from the four largest ethnic subgroups: 471,174 (96.1%) white, 9,631 (2.0%) South Asian, 7,949 (1.6%) black, and 1,534 (0.3%) Chinese.

     Age-adjusted associations between diabetes prevalence and adiposity (body mass index, BMI)

     A BMI of 24 for Chinese women and a BMI of 26 for Chinese men are equivalent to a BMI of 30 for Caucasians.

  • β-cell function and insulin resistance in four racial groups according to glucose metabolism status

    ADA GENNID Study Group. Diabetes 2002; 51: 2170–2178

  • Ethnic Differences in Insulin Sensitivity & Insulin Secretion

    Kodama K et al. Diabetes Care 2013;36:1789-96

    Study design: Researchers identified studies that measured the insulin sensitivity index (SI) and acute insulin response to glucose (AIRg) in three major ethnic groups: Africans, Caucasians, and East Asians. Researchers identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian). Researchers calculated the hyperbolic relationship using the mean values of SI and AIRg in the healthy cohorts with normal glucose tolerance.

    200 -

    1000 -

    1400 -

    0 -

    800 -

    0

    600 -

    5 15 20 25 30

    1800 -

    A IR

    g (p

    m o l/ L)

    Insulin Sensitivity Index (10-5 min-1 per pmol/L)

    400 -

    1200 -

    1600 -

    10

    African

    Caucasian

    East Asian

  • Reduced early-phase insulin secretion in East Asian compared with Caucasian individuals

    Seino Y et al. J Diabetes Investig. 2016;7:102–109

  • Decreased Insulin Secretion in Japanese

    Møller JB, et al. Diabetes Care 2014;37:796-804, Supplementary data

    Compensatory insulin secretion is lower in Japanese subjects with IGT or T2DM relative to Caucasian counterparts.

    100 -

    400 -

    500 -

    300 -

    200 -

    600 -

    Time (min)

    In su

    lin ( p m

    o l/ L)

    0 -

    0 20 60 90 120 150 180 240 300

    IGT T2DNGT

    Time (min)

    In su

    lin ( p m

    o l/ L)

    0 20 60 90 120 150 180 240 300

    100 -

    400 -

    500 -

    0 -

    300 -

    200 -

    600 - IGT T2DNGT

    Study design: A total of 120 Japanese and 150 Caucasians were enrolled to obtain comparable distributions of high/low BMI values across glucose tolerance states (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes), which were assessed by oral glucose tolerance tests. BMI in the two cohorts was distributed around the two regional cutoff values for obesity.

  • Body Composition Is the Main Determinant for the Difference in Type 2

    Diabetes Pathophysiology Between Japanese and Caucasians

    Jonas B. Møller, Takashi Kadowaki et al. Diabetes Care Volume 37, March 2014

    Caucacian

    Japanese

  • Long-term prospective observational cohort studies, UK & South Korea

  • Long-term (10 years) prospective cohort studies investigating the trajectories of NGT to T2DM

    • South Korea - initial decreased β-cell function

    • United Kingdom - initial decreased insulin sensitivity

    are prerequisites for the development of T2DM

    Β-cell Dysfunction in East Asian type 2 Diabetes Mellitus

    Ohn JH, Kwak SH, Cho YM, et al. Lancet Diabet Endocrinol 2016; 4: 27–34 Tabak AG, Jokela M, Akbaraly TN, et al. Lancet 2009; 373: 2215–2221

  • Baseline characteristics of incident diabetes and non-diabetics cases - analysis from the Whitehall II study in UK

    Tabak AG, Jokela M, Akbaraly TN, et al. Lancet 2009; 373: 2215–2221

  • β-cell function and insulin sensitivity in the development of type 2

    diabetes

    - a community-based 10 years prospective cohort study in South

    Korea

    Ohn JH, Kwak SH, Cho YM, et al. Lancet Diabet Endocrinol 2016; 4: 27–34

    ISI IGI60

  • East Asians might have reduced β-cell reserve capacity that makes them readily susceptible

    to a minor decline of insulin sensitivity

    Daisuke Yabe et al. J Diabetes Investig 2016;7:102-109

  • Genetic Factors by Ethnicity in T2DM

    1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2

    NOTCH2

    PROX1

    GCKR

    THADA

    BCL11A

    RBMS1

    IRS1

    PPARG

    UBE2E2*

    ADAMST9

    ADCY5

    IGFBP2

    PSMD6*

    WFS1

    MAEA*

    ZBED3

    CDKAL1

    ZFAND3*

    KCNK16*

    DGKB

    JAZF1

    GCK

    KLF14

    GCC1-PAX4*

    TP53INP1

    SLC30A8

    ANK1*

    CDKN2A/B

    CHCHD9

    GLIS3*

    CDC123/CAMK1D

    HHEX/IDE

    TCF7L2

    KCNQ1

    KCNQ1*

    KCNJ11

    CENTD2

    MTNR18

    HMGA2

    TSPAN8/LGRS

    SPRY2*

    C2CD4A-C2CD4B*

    ZFAND6

    PRC1

    FTO

    HNF1B (TCF2)

    PEPD*

    FITM2-R3HDML-HNF4A*

    PTPRD*

    SRR*

    INS/IGF #

    HNF1A

    DUSP9

    1.4 1.6

    Europeans East Asians

    Comparison of effect sizes of type 2 diabetes risk in East Asians and Europeans for 53 confirmed single

    nucleotide polymorphisms

     A recent meta-analysis of East Asian studies has discovered eight novel loci for T2D, several of which showed suggestive associations in European populations.

     Most of these variants are predicted to influence the risk of T2D by affecting insulin secretion.

     The majority of loci reported to be associated with T2D show similar effect sizes in East Asian and European populations.

    Ma RC and Chan JC. Ann N U Y Acad Sci 2013;1281:64-91

  • Comparing Asian and Caucacian people with type 2 diabetes Asian patients would be characterized by

    Characteristics of T2DM in East Asians

    Kim YG et al. Diabetologia 2013;56:696-708

     Lower BMI

     Higher amounts of visceral fat with a given BMI, waist circumference

     Predominant insulin secretory defect that might be explained by

    - Lower β-cell mass & function

    - Genetic difference

  • Lancet 2004:363;163

    BMI is not useful for comparison across ethnicity

  • Indian Diabetes is different from Diabetes in UK

    Yajnik CS et al. J Nutr. 2004 Jan;134(1):205-10

  • The physical phenotype of US type 2 diabetes in 200 years ago was nearly similar with the phenotype of East Asian type 2 diabetes

    nowadays.

    The fundamental pathophysiologies of type 2 diabetes are nearly the same.

    The delicate differences observed between these races would be the temporary, transient phenomenon.

    Dr. Peter H. Bennett, via personal communications 1996

  • Summary & Conclusion

    On regarding the East Asian T2DM patients,

    1. East Asians might have reduced β-cell reserve capacity

    2. β-cell dysfunction, as the primary defect in T2DM development

    3. Fundamental pathophysiologic mechanism of