Association between Long-term Exposure to PM2.5

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Association between Long-term Exposure to PM _2.5 and Incidence of

Type 2 Diabetes in Taiwan

Chia-Ying Li

¹

, Huey-Jen Su

^1,*

, Chih-Da Wu

²

, Wen-Chi Pan

³

, Yi-Chen Chen

¹

1 Department of Environmental and Occupational Health, Medical College, National Cheng Kung University

2Department of Forestry and Natural Resources, College of Agriculture, National Chiayi University

3Institute of Environmental and Occupational Health Sciences, National Yang-Ming University

*Corresponding author: hjsu@mail.ncku.edu.tw

ISEE-ISES AC2016

June 26-29, 2016, Sapporo, Japan

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Conflict of Interest

I have no financial relationships to disclose.

(3)

PM _2.5 in Taiwan

2006-2012

Characteristic Concentration (µg/m

³

)

Mean (± SD) 32.59 (±8.15)

Maximum 47.20

Minimum 13.31

IQR 12.03

Air pollution such as PM

_2.5

is a big problem in Asia.

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Air quality for PM

_2.5 Concentration limit (µg/m³)

24-hour Annual

WHO 25 10

Japan 35 15

Republic of Korea 50 25

China Class 1 35 15

Class 2 75 35

Taiwan 35 15

(4)

Effects of PM _2.5 on Type 2 Diabetes - Hypothesized Mechanism-

Metabolic abnormali.es

PM _2.5

Insulin

TLRs, NLRs receptors as

sensors

(Weichenthal et al., 2014; Laing et al., 2010; Xu X et al., 2010;

Mills et al., 2005; Sun et al., 2009)

(Brook et al., 2013; Chen Jet al., 2008; Dubowsky et al., 2006;

Xu et al., 2011; Steinvil et al., 2008)

(Laing et al., 2010;

Kampfrath et al., 2011;

Zheng et al., 2012)

Brown adipose .ssue

altera.ons

Endothelial dysfunc.on

Endoplasmic re.culum stress

Inﬂamma.on (visceral adipose .ssue)

Mitochondrial dysfunc.on

Increase makers of inﬂamma.on (CRP, IL-‐6)

(Dominici et al., 2007; Liberda et al., 2010; Li et al., 2011;

Shi et al., 2006; Vandanmagsar et al., 2011)

(Xu et al., 2011; Zhong et al., 2011; Lowell et al., 2005)

(Kampfrath et al., 2011; Zheng et al., 2012; Laing et al., 2010)

(Knight-‐Lozano et al., 2002;

Xu et al., 2011)

(Weichenthal et al., 2014; Dubowsky et al., 2006; Zeka et al., 2006;

Lee et al., 2011; Hoﬀmann et al.,2009)

Type 2 diabetes

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Objectives

•  To investigate the impact of PM _2.5 on the incidence of type 2 diabetes, utilizing retrospective cohort study design.

•  To assess the dose–response relationship between PM _2.5 exposure level and incidence of type 2

diabetes.

5

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Study Design and Frame Work Retrospective Cohort

Statistical Analysis

Cox proportional hazards model

Individual Exposure Concentration National Health Insurance

Research Database

Longitudinal Health Insurance Database 2000 (LHID 2000)

Study Population

Newly diagnosed with diabetes

Nondiabetic adults

Exposure Database

Taiwan Air Quality Monitoring Network

Adjusted Factors

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16/10/17 7

Longitudinal Health Insurance Database 2000 (LHID 2000)

Study Population

(recruited adults without diabetes) 2001 – 2012

n=505,151

Exclude

1.  Subjects with diagnosed diabetes before 2001

2.  Subjects who were < 20 years old

Case subjects: Newly diagnosed with diabetes

•  Concurrent use of antihyperglycemic medications

•  Subjects with diagnosis code 250 three times in a year

Control subjects: without diabetes diagnosis

Selection Criteria

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PM _2.5 Exposure

•  Taiwan Air Quality Monitoring Network

•  Hourly data during 2006-2012 (data was available since 2006)

•  71 stationary sites located around the Main Taiwan Island

•  Individual Exposure Concentration

–  Ordinary Kriging and zonal statistics (ArcGIS 10.2)

–  According to the registered location of medical facilities of each

subject

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Statistical Analysis

•  Cox proportional hazards model

–  Hazard Ratio (95% CI)

•  Adjusted factors

–  Individual-level variables (age, sex, insurance amount, and occupational type)

–  Comorbidities (hypertension and hyperlipidemia)

–  Area-level variables (township urbanization level and county- level income)

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λ（T=t|X=x）= λ

₀

（t）exp（β

₁

X

₁

+ β

₂^T

X

₂₊

β

₃^T

X

₃₊

β

₄^T

X

₄

+

β

₅^T

X

₅

+

β

₆^T

X

₆

+

β

₇^T

X

₇

）

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Baseline characteristics

•  Of the 505,151 eligible participants enrolled in the study, a total of 48,611 newly developed diabetes cases were

identified.

•  The incidence of type 2 diabetes in the study sample was 1.14%

Baseline characteristics Statistics

Age 41.6 ± 15.80 years

Male 48.74%

Female 51.26%

Insurance amount NTD$18,092 ± 15,331.40 (about USD$ 560.97)

Baseline characteristics of study population (n=505,151)

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Long-term PM _2.5 & diabetes incidence

11

The results suggest that per 12.03 µg/m

³

increase of long-term exposure to PM

_2.5

was contributing to a 4.9% increase of the risk for diabetes incidence in Taiwan.

Association between long-term PM

_2.5

exposure and incidence of type 2 diabetes

Model HR (95% CI) per IQR increment of

PM

_2.5^§

P-value

Crude model 1.048 (1.033-1.064) <0.001

Addition of individual-level covariates

^a

1.036 (1.021-1.051) <0.001 Addition of comorbid conditions

^b

1.056 (1.041-1.071) <0.001 Addition of area-level covariate

^c

1.049 (1.033-1.065) <0.001

§Interquartile range (IQR)=12.03 µg/m³

aAdjusted for age group, sex, level of insurance amount and occupational type.

bAlso adjusted for hypertension and hyperlipidemia.

cAlso adjusted for county level income and township level urbanization.

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Sensitivity analysis

Sensitivity analysis for the associations of incident diabetes with quartile of PM

_2.5

Model No. of cases Adjusted HR (95% CI)

^a

P-value

Quartile of PM

_2.5

First 105363 1

Second 180233 0.974 (0.946-1.002) 0.0652

Third 98628 1.042 (1.009-1.077) 0.0126

Forth 120927 1.082 (1.050-1.114) <0.0001

Restricted to participants with

No relocation 267267 1.046 (1.025-1.067) <0.0001

Diabetes diagnosis with using antihyperglycemic

medications

484960 1.095 (1.072-1.118) <0.0001

aModel was adjusted for age group, sex, level of insurance amount, occupational type, hypertension, hyperlipidemia,

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Stratified analysis

13

Stratified analysis for the hazard ratio of incident diabetes and per IQR increment of PM_2.5

Characteristic No. of cases Total number HR (95% CI) P-value Sex^a

male 26,312 246,196 1.063 (1.040-1.086) <0.0001

female 22,299 258,955 1.028 (1.004-1.053) <0.05

Age^b

<65 33519 445,094 1.026 (1.006-1.046) 0.011

≧65 15092 60,057 1.035 (1.006-1.064) 0.016

Insurance amount^c

low 19259 222617 1.071 (1.044-1.098) <0.0001

high 29352 282534 1.037 (1.016-1.058) 0.001

Hypertension^d

no 19751 367009 1.038 (1.012-1.065) 0.004

yes 28860 138142 1.034 (1.013-1.055) 0.016

Hyperlipidemia^d

no 29733 419515 1.027 (1.006-1.048) 0.0107

yes 18878 85636 1.051 (1.024-1.079) <0.001

aModel was adjusted for age group, level of insurance amount, occupational type, hypertension, hyperlipidemia, county, county level income, and township urbanization.

bModel was adjusted for sex, level of insurance amount, occupational type, hypertension, hyperlipidemia, county, county level income, and township urbanization.

cModel used the median amount of the insurance (19200 NTD) as cutoff value and adjusted for age group, sex, occupational type, hypertension, hyperlipidemia, county, county level income, and township urbanization.

dModel was adjusted for sex, age, level of insurance amount, occupational type, county, county level income, and township urbanization.

The study observed stronger associations between diabetes and PM

_2.5

among participants who were males, > 65 years of age, or had lower insurance

amount.

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Dose-response curve

Quartile of PM_2.5 Adjusted HR (95% CI) P-value

First 1

Second 0.974 (0.946-1.002) 0.0652 Third 1.042 (1.009-1.077) 0.0126 Forth 1.082 (1.050-1.114) <0.0001

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Summary of previous findings

Location Subject Air pollution Exposure

Time Result

Taiwan

(This study) 505,151 adults PM_2.5

(IQR=12.03 µg/m³) 12 years HR=1.05 (1.033-1.065) 1.005 for 1 µg/m³

Ruhr,

Germany 1,775 women PM

(IQR=10 µg/m³) 16 years HR=1.15 (1.04–1.27) 1.014 for 1 µg/m³ Los Angeles 3,992 black women

PM_2.5

(10 µg/m³) 10 years IRR=1.63 (0.78–3.44) 1.051 for 1 µg/m³

U.S.

NHS:

74,412 female nurses

HPFS:

15,048 male health

professionals

PM_2.5 PM₁₀ PM_10–2.5

(IQR=4 µg/m³)

12 months

HR=1.03 (0.96–1.10) for PM_2.5 1.007 for 1 µg/m³

Ontario,

Canada 62,012 adults PM_2.5

(10 µg/m³) 6 years HR=1.11 (1.02-1.21) for PM_2.5 1.010 for 1 µg/m³

6 sites, U.S. 6,814 adults PM_2.5

(IQR=2.43 µg/m³) 9 years HR=1.05 (0.87-1.26) 1.020 for 1 µg/m³ Ruhr,

Germany 3,607 adults All PM_2.5

Traffic-related PM_2.5 (1 µg/m³)

5 years

HR=1.03 (0.95–1.12) for all PM_2.5 HR=1.36 (0.97–1.89) for traffic- related PM_2.5

•  Incidence of both hypertension and diabetes is almost twice as high in African American women as in white women.

(Downey et al., 2009)

•  Risk for developing diabetes was increased for Asians, Hispanics, and African Americans compared with whites

(Shai et al., 2006; Iris et al., 2006)

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Strengths

1.  The study represents the general population in Taiwan, and is the largest population-based observational study around the world to evaluate the association between PM

_2.5

exposure and incident diabetes.

(National Health Insurance Research Database 2014)

2.  Assessment of dose-response relationship between PM

_2.5

exposure level and incidence of type 2 diabetes.

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Limitations

1.  Misclassification of exposure

The PM

_2.5

exposure status was based on the concentration derived from the registered location of medical facilities, which may not

representative enough to the real exposure level for each subject.

2.  Individual diabetes risk factors

Fail to consider factors including BMI, smoking status, drinking, diet, physical activity, individual education level, marital status, family history and employment status in data analysis, which may lead to

overestimate the risk in the current finding.

3.  Undiagnosed cases of diabetes

The study could not identify undiagnosed cases of diabetes in the cohort. It may underestimated the true effect of PM

_2.5

exposure.

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Conclusions

1.  Long-term exposure to PM

_2.5

increased the risk of type 2 diabetes in the population of Taiwan.

2.  The study observed stronger associations between diabetes and PM

_2.5

exposure among participants who were < 65 years of age, males, or had lower insurance amount.

3.  A dose-response relationship between PM

_2.5

exposures and

incident diabetes in higher exposure concentration is found.

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Thank You for Your Attentions!

Chia-Ying Li

Email: s76034023@mail.ncku.edu.tw

Acknowledgement

This work was supported by Ministry of Science and Technology, Taiwan, R.O.C.

This study is based in part on data from the National Health Insurance Research Database provided by the National Health Insurance Administration, Ministry of Health and Welfare and managed by National Health Research Institutes.

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Study Design and Frame Work Retrospective Cohort

Statistical Analysis

•  Cox proportional hazards model

Individual Exposure Concentration

•  Ordinary Kriging (ArcGIS 10.2)

•  based on medical treatment locations of subjects

National Health Insurance Research Database

•  Longitudinal Health Insurance Database 2000 (LHID 2000)

•  From 2000 to 2012, retrieving millions of people's medical records

Study Population

2001-2012 N=505,151

Newly diagnosed with diabetes

•  antihyperglycemic medications

•  diagnosis code 250 three times in a year

Nondiabetic adults

Exposure Assessment

Taiwan Air Quality Monitoring Network 2006-2012

Adjusted Factors

•  Individual-level variables

•  Contextual variables

•  Comorbidities

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Summary of previous finding

Location Subject Air pollution Exposure Time Result

Taiwan

(This study) 505,151 adults PM_2.5

(IQR=12.03 µg/m³) 12 years Adjusted HRs:

1.05 (1.033-1.065) Ruhr,

(IQR=10 µg/m³) 16 years Adjusted HRs:

1.15 (1.04–1.27) Los Angeles 3,992 black women

PM_2.5

(10 µg/m³) 12 months Adjusted IRRs:

1.63 (0.78–3.44)

U.S.

NHS:

HPFS:

15,048 male health

professionals

PM_2.5 PM₁₀ PM_10–2.5

(IQR=4 µg/m³)

12 months Adjusted HRs:

1.03 (0.96–1.10) for PM_2.5

Ontario,

(10 µg/m³) 6 years Adjusted HRs:

1.11 (1.02-1.21) for PM_2.5 6 sites, U.S. 6,814 adults PM_2.5

(IQR=2.43 µg/m³) 9 years Adjusted HRs:

1.05 (0.87-1.26)

Ruhr,

Germany 3,607 adults All PM_2.5

Traffic-related PM_2.5 (1 µg/m³)

5 years

Adjusted RRs:

1.03 (0.95–1.12) for all PM_2.5

Adjusted RRs:

1.36 (0.97–1.89) for traffic- related PM_2.5

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Location Subject Air pollution Result

Taiwan

(This study) 505,151 adults PM_2.5

(1 µg/m³) Adjusted HRs: 1.004 Ruhr,

(1 µg/m³) Adjusted HRs: 1.014 Los Angeles 3,992 black women

PM_2.5

(1 µg/m³) Adjusted IRRs: 1.051

U.S.

NHS:

HPFS:

15,048 male health

professionals

PM_2.5 PM₁₀ PM_10–2.5

(IQR=1 µg/m³)

Adjusted HRs:

1.007 for PM_2.5

Ontario,

(1 µg/m³) Adjusted HRs: 1.010 6 sites, U.S. 6,814 adults PM_2.5

(1 µg/m³) Adjusted HR: 1.020

Ruhr, 3,607 adults All PM_2.5

Traffic-related PM

Adjusted RRs:

1.03 (0.95–1.12) for all PM_2.5

•  Incidence of both hypertension and diabetes is almost twice as high in African American women as in white women.

(Downey et al., 2009)

•  Risk for developing diabetes was increased for Asians, Hispanics, and African Americans compared with whites

(Shai et al., 2006; Iris et al., 2006)

Summary of previous finding

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16/10/17

Introduction

23

PM

_2.5

and Type 2 Diabetes

ü  Long-term PM

_2.5

exposure may contribute to elevated incidence of type 2 diabetes, but the results were not always significant.

(Kramer et al., 2010; PueZ et al., 2011; Coogan et al., 2012; Chen et al., 2013)

ü  Empirical research evidence relating PM

_2.5

and diabetes still lack in Asia where the PM

_2.5

concentration is higher and the diabetes burden is greater.

(Ramachandran et al., 2013; Thiering et al., 2015)

PM

_2.5

Increase makers of inflammation

resistance ^Insulin Type 2 diabetes Cumulative adverse

health effect

The Ranking Major Causes of Deaths in Taiwan ^Year

12 7

5 5 5 4 4

5 5 5 4

0 2 4 6 8 10 12 14

1981 1991 2001 2007 2009 2011

Ranking

Association between Long-term Exposure to PM2.5