Mechanistic insights into air pollution and Type 2 diabetes.

HEI Conference April 30, 2018

Sanjay Rajagopalan, MD

58-year-old patient with Type 2 Diabetes Mellitus (T2DM): HbA1c=7.5 and Blood Pressure (BP)=135/80

10-year Cardiovascular (CV) event = 5%

Natural History of T2DM

Defronzo & Felber. Diabetes. 1988; 37: 667-687 and Metabolism. 1990; 39: 1068-75.

LeanNGT

OBNGT

OB-IGT

OB-DIAB

High INS

OB-DIAB

Low INS

140 –-

100 –-

60 –-

20 –

MeanPlasma InsulinDuring OGTT

(µU/ml)

– 300

– 250

– 200

– 150

– 100

Insulin-MediatedGlucoseUptake

(mg/m2·min)

140 –-

100 –-

60 –-

20 –

MeanPlasma Glucose

During OGTT(mg/dl)

5-15 YEARS

OGTT = oral glucose tolerance testOB = obese NGT = no glucose intolerance IGT = initial glucose intolerance INS = insulin resistant

De Fronzo’s Ominous Octet

Multiple defects contribute to the progression of type 2 diabetes mellitus

Adapted from De Fronzo RA. Diabetes. 2009;58:773-95.

Hyperglycaemia

DecreasedInsulin

Secretion

IncreasedGlucagonSecretion

NeurotransmitterDysfunction

DecreasedIncretin Effect

IncreasedHGP Decreased

Glucose Uptake

IncreasedGlucose

Reabsorption

IncreasedLipolysis

Islet-α cell

IF TRADITIONAL RISK FACTORS WERE WORSENED BY AIR POLLUTION… THE GLOBAL RISK POSED WOULD BE EVEN LARGER…

Zone 1Well characterized

health effects of well studied pollutants.

Zone 2Emerging, but still unqualified,

(Hypertension, diabetes, and others)

Zone 3Inadequate characterized health effects

of emerging pollutants.

Number of Pollution Related Deaths = 9 Million

Number of Pollution Related Deaths = ?

Landrigan P et al. The Lancet Commission on pollution and health Lancet. 2017 Oct 17.

If traditional risk factors WERE

WORSENED BY AIR POLLUTION…

the global risk posed would be even

larger…

Number of Pollution Related Deaths = ?

How may Air Pollution Cause Type 2 DM?

Rao X et al. Toxicol Sci. 2015 Feb;143(2):231-41

M = macrophageT = T cell GLUT = glucose transporter

• Chronic low level inflammation represents a convergent pathway for multiple diseases

• Cellular inflammation has emerged as a primary determinant of many components of the metabolic syndromeHotamisligil G et al. Nature 2006; 444; 86-67; Shoelson S et al. JCI 2006; 116; 3015-26; Olefsky et al. Ann Rev Physiol 2010; 72; 1-28

Chronic PM2.5 Ambient Exposures (20 wk) Potentiates Inflammation/Insulin Resistance in Mice

0

0.2

0.4

0.6

0.8

FA PMIn

su

lin

(n

g/m

l)

Sun Q, Yue et al. Circulation 2009; 119(4):538-46.

*

0

5

10

15

Con

cent

ratio

n

FA PM2.5 FA PM2.5TNF-α IL-6pg/ml ng/ml

*

*

FA

PM2.5

F4/80 Cav Topro3 Merge SVF

0

2

4

Rel

ativ

e fo

lds

FAPM2.5

Nos2 TNF-α Itgax IL-6 IL-10 Mgl1 Pparγ

M1 M2

*

*

**

FA = filtered air PM = particulate matter SVF = ??

Chart1

FA0.067976955

PM0.1404268099

Insulin (ng/ml)

0.2051034607

0.5895601396

Sheet1

Insulin Standard

ng/mlOD450OD630B-COD450OD630B-C

6.40.8450.0370.8080.8960.0370.8590.83356.40.8335

3.20.4430.0360.4070.5060.0370.4690.4383.20.438

1.60.2820.0380.2440.2880.0370.2510.24751.60.2475

0.80.160.0360.1240.1710.0370.1340.1290.80.129

0.40.1110.0360.0750.1140.0360.0780.07650.40.0765

0.20.0830.0350.0480.0870.0350.0520.050.20.05

0.10.0750.0370.0380.0740.0350.0390.03850.10.0385

00.0610.0340.0270.0610.0350.0260.026500.0265

SamplesOD450OD630B-CConcentration

FA3-00.1290.0360.0930.5059288538

FA3-300.1410.0370.1040.5928853755

FA3-600.1360.0360.10.5612648221MinFA3FA4FA5FA6AverageSTDSEMP

FA3-900.140.0370.1030.584980237200.50592885380.17391304350.21343873520.22134387350.27865612650.15292918670.0764645934

FA3-1200.1880.0350.1530.9802371542300.59288537550.16600790510.46640316210.11067193680.33399209490.23284401250.1164220063

FA4-00.0860.0350.0510.1739130435600.56126482210.17391304350.53754940710.17391304350.36166007910.21700768640.1085038432

FA4-300.0840.0340.050.1660079051900.58498023720.48221343870.55335968380.15019762850.4426877470.19967321640.0998366082

FA4-600.0860.0350.0510.17391304351200.98023715420.4426877470.63241106720.30039525690.58893280630.29419437260.1470971863

FA4-900.1260.0360.090.4822134387

FA4-1200.1230.0380.0850.442687747PM3PM4PM5PM6

FA5-00.0920.0360.0560.213438735200.40316205530.77470355730.28458498020.38735177870.46245059290.21470371250.10735185630.2126136546

FA5-300.1240.0360.0880.4664031621300.18181818180.19762845850.49802371540.40316205530.32015810280.15564626540.07782313270.9245245882

FA5-600.1320.0350.0970.5375494071600.15019762850.17391304350.50592885380.40316205530.30830039530.17427199750.08713599880.7146128825

FA5-900.1340.0350.0990.5533596838900.22924901190.30039525690.56126482210.50592885380.39920948620.1594801660.0797400830.7452439166

FA5-1200.1440.0350.1090.63241106721200.32411067190.3478260870.50592885380.56916996050.43675889330.11960468210.05980234110.3748980315

FA6-00.0920.0350.0570.2213438735

FA6-300.0790.0360.0430.1106719368FA+LA1FA+LA2FA+LA3FA+LA4

FA6-600.0890.0380.0510.173913043500.22924901190.11857707510.08695652170.32411067190.18972332020.10838979610.054194898

FA6-900.0830.0350.0480.1501976285300.06324110670.14229249010.21343873520.58498023720.25098814230.23095769570.1154788478

FA6-1200.1030.0360.0670.3003952569600.11067193680.17391304350.35573122530.42687747040.2667984190.14892673610.074463368

PM3-00.1150.0350.080.4031620553900.14229249010.23715415020.16600790510.4426877470.24703557310.13652107540.0682605377

PM3-300.0890.0370.0520.18181818181200.46640316210.23715415020.21343873520.48221343870.34980237150.14423718680.0721185934

PM3-600.0850.0370.0480.1501976285

PM3-900.0940.0360.0580.2292490119PM+LA3PM+LA4PM+LA5

PM3-1200.1060.0360.070.324110671900.46640316210.18181818180.18181818180.27667984190.16430521490.0821526075

PM4-00.1650.0380.1270.7747035573300.38735177870.47430830040.16600790510.34255599470.15895684990.0794784249

PM4-300.0890.0350.0540.1976284585600.21343873520.49011857710.22134387350.30830039530.15750876560.0787543828

PM4-600.0860.0350.0510.1739130435900.4426877470.49011857710.13438735180.35573122530.19315085730.0965754286

PM4-900.1020.0350.0670.30039525691200.52964426880.32411067190.35573122530.40316205530.11067193680.0553359684

PM4-1200.1080.0350.0730.347826087

PM5-00.1040.0390.0650.2845849802

PM5-300.1270.0350.0920.4980237154

PM5-600.1290.0360.0930.5059288538

PM5-900.1380.0380.10.5612648221FAPMFA+LAPM+LA

PM5-1200.1280.0350.0930.505928853800.27865612650.46245059290.18972332020.2766798419

PM6-00.1170.0390.0780.3873517787300.33399209490.32015810280.25098814230.3425559947

PM6-300.1160.0360.080.4031620553600.36166007910.30830039530.2667984190.3083003953

PM6-600.1150.0350.080.4031620553900.4426877470.39920948620.24703557310.3557312253

PM6-900.1310.0380.0930.50592885381200.58893280630.43675889330.34980237150.4031620553

PM6-1200.1360.0350.1010.5691699605

FA+LA1-00.0940.0360.0580.2292490119SEM

FA+LA1-300.0740.0370.0370.063241106700.07646459340.10735185630.0541948980.0821526075

FA+LA1-600.080.0370.0430.1106719368300.11642200630.07782313270.11547884780.0794784249

FA+LA1-900.0840.0370.0470.1422924901600.10850384320.08713599880.0744633680.0787543828

FA+LA1-1200.1280.040.0880.4664031621900.09983660820.0797400830.06826053770.0965754286

FA+LA2-00.0790.0350.0440.11857707511200.14709718630.05980234110.07211859340.0553359684

FA+LA2-300.0810.0340.0470.1422924901

FA+LA2-600.0990.0480.0510.1739130435

FA+LA2-900.0970.0380.0590.2371541502

FA+LA2-1200.0960.0370.0590.2371541502

FA+LA3-00.0760.0360.040.0869565217

FA+LA3-300.0920.0360.0560.2134387352

FA+LA3-600.1090.0350.0740.3557312253

FA+LA3-900.0850.0350.050.1660079051

FA+LA3-1200.090.0340.0560.2134387352

FA+LA4-00.1050.0350.070.3241106719

FA+LA4-300.1390.0360.1030.5849802372

FA+LA4-600.120.0370.0830.4268774704

FA+LA4-900.1210.0360.0850.442687747

FA+LA4-1200.1260.0360.090.4822134387

PM+LA3-00.1230.0350.0880.4664031621

PM+LA3-300.1140.0360.0780.3873517787

PM+LA3-600.1130.0570.0560.2134387352

PM+LA3-900.1210.0360.0850.442687747

PM+LA3-1200.1310.0350.0960.5296442688

PM+LA4-00.0890.0370.0520.1818181818

PM+LA4-300.1250.0360.0890.4743083004

PM+LA4-600.1270.0360.0910.4901185771

PM+LA4-900.1260.0350.0910.4901185771

PM+LA4-1200.1050.0350.070.3241106719

PM+LA5-00.090.0380.0520.1818181818

PM+LA5-300.0850.0350.050.1660079051

PM+LA5-600.0940.0370.0570.2213438735

PM+LA5-900.0820.0360.0460.1343873518

PM+LA5-1200.1150.0410.0740.3557312253

Insulin Standard

ng/mlOD450OD630B-COD450OD630B-C

6.40.7220.0440.6780.7550.0460.7090.69356.40.6935

3.20.4340.040.3940.4540.0380.4160.4053.20.405

1.60.2310.0380.1930.250.0410.2090.2011.60.201

0.80.1470.0390.1080.1580.0380.120.1140.80.114

0.40.1020.0370.0650.1070.0410.0660.06550.40.0655

0.20.0790.0360.0430.0790.0360.0430.0430.20.043

0.10.070.0370.0330.0680.0360.0320.03250.10.0325

00.060.0380.0220.0570.0360.0210.021500.0215

SamplesOD450OD630B-CConcentration

FA1-00.070.0410.0290.0159027128

FA1-300.110.0390.0710.4087932647

FA1-600.1070.040.0670.3713751169

FA1-900.1220.0370.0850.539756782

FA1-1200.1220.0350.0870.5584658559

FA2-00.0730.0350.0380.1000935454

FA2-300.0770.0370.040.1188026193

FA2-600.1030.0390.0640.3433115061

FA2-900.1140.0370.0770.4649204864

FA2-1200.1380.0360.1020.6987839102

PM1-00.1930.0370.1561.2039289055

PM1-300.1440.0390.1050.726847521

PM1-600.1620.0360.1260.923292797

PM1-900.1380.0360.1020.6987839102

PM1-1200.1460.0350.1110.7829747428

PM2-00.1180.0390.0790.4836295603

PM2-300.0850.0360.0490.2029934518

PM2-600.1070.0370.070.3994387278

PM2-900.1160.0360.080.4929840973

PM2-1200.1570.0370.120.8671655753

PM+LA1-00.0910.0370.0540.2497661366

PM+LA1-300.0850.0360.0490.2029934518

PM+LA1-600.0790.0350.0440.1562207671

PM+LA1-900.0880.0380.050.2123479888

PM+LA1-1200.0870.0350.0520.2310570627

PM+LA2-00.1090.0350.0740.4368568756

PM+LA2-300.1110.0380.0730.4275023386

PM+LA2-600.1310.0380.0930.6145930776

PM+LA2-900.1370.0360.1010.6894293732

PM+LA2-1200.1110.0360.0750.4462114125

MinFA3FA4FA5FA6FA1FA2AverageSTDSEMP

00.50592885380.17391304350.21343873520.22134387350.01590271280.10009354540.20510346070.1665088540.067976955

300.59288537550.16600790510.46640316210.11067193680.40879326470.11880261930.31059404390.20555579060.0839178001FAPMFA+LAPM+LA

600.56126482210.17391304350.53754940710.17391304350.37137511690.34331150610.36022115650.16834229240.068725453100.20510346070.58956013960.18972332020.3033325076

900.58498023720.48221343870.55335968380.15019762850.5397567820.46492048640.46257137610.15946957080.0651031797300.31059404390.36841223070.25098814230.3316327549

1200.98023715420.4426877470.63241106720.30039525690.55846585590.69878391020.60216349860.23306487480.0951483367600.36022115650.4259888510.2667984190.3391430061

900.46257137610.46476765870.24703557310.3937942076

PM3PM4PM5PM6PM1PM2AverageSTDSEM1200.60216349860.56619598190.34980237150.3773509282

00.40316205530.77470355730.28458498020.38735177871.20392890550.48362956030.58956013960.34397403050.14042680990.0334331964

300.18181818180.19762845850.49802371540.40316205530.7268475210.20299345180.36841223070.21809647080.08903751140.646672766SEM

600.15019762850.17391304350.50592885380.40316205530.9232927970.39943872780.4259888510.28090233230.1146778970.633391276400.0679769550.14042680990.0541948980.0619764528

900.22924901190.30039525690.56126482210.50592885380.69878391020.49298409730.46476765870.17265748720.0704871240.982188875300.08391780010.08903751140.11547884780.0618997412

1200.32411067190.3478260870.50592885380.56916996050.78297474280.86716557530.56619598190.22248928370.09083086970.7900878385600.06872545310.1146778970.0744633680.0899458476

900.06510317970.0704871240.06826053770.0998207796

FA+LA1FA+LA2FA+LA3FA+LA4AverageSTDSEM1200.09514833670.09083086970.07211859340.0513024655

00.22924901190.11857707510.08695652170.32411067190.18972332020.10838979610.0541948980.8756116993

300.06324110670.14229249010.21343873520.58498023720.25098814230.23095769570.11547884780.679499827

600.11067193680.17391304350.35573122530.42687747040.2667984190.14892673610.0744633680.3958723734

900.14229249010.23715415020.16600790510.4426877470.24703557310.13652107540.06826053770.0583242794

1200.46640316210.23715415020.21343873520.48221343870.34980237150.14423718680.07211859340.0920550029

PM+LA3PM+LA4PM+LA5PM+LA1PM+LA2AverageSTDSEM

00.46640316210.18181818180.18181818180.24976613660.43685687560.30333250760.13858356150.06197645280.1168561173

300.38735177870.47430830040.16600790510.20299345180.42750233860.33163275490.1384120290.06189974120.7526504179

600.21343873520.49011857710.22134387350.15622076710.61459307760.33914300610.20112502940.08994584760.5781788545

900.4426877470.49011857710.13438735180.21234798880.68942937320.39379420760.22320604870.09982077960.5660051605

1200.52964426880.32411067190.35573122530.23105706270.44621141250.37735092820.11471580040.05130246550.1218610944

FAPMFA+LAPM+LA

Fasting insulin level0.20510346070.58956013960.18972332020.3033325076

FAPM

SEMFasting insulin level0.20510346070.5895601396

0.0679769550.14042680990.0541948980.0619764528SEM0.0679769550.1404268099

Fasting blood Insulin (ng/ml)

FA0.20±0.07

PM2.50.59±0.14

Sheet1

Sheet2

0.07646459340.07646459340.10735185630.10735185630.0541948980.0541948980.08215260750.0821526075

0.11642200630.11642200630.07782313270.07782313270.11547884780.11547884780.07947842490.0794784249

0.10850384320.10850384320.08713599880.08713599880.0744633680.0744633680.07875438280.0787543828

0.09983660820.09983660820.0797400830.0797400830.06826053770.06826053770.09657542860.0965754286

0.14709718630.14709718630.05980234110.05980234110.07211859340.07211859340.05533596840.0553359684

FA

PM

FA+LA

PM+LA

Time after glucose injection (min)

Insulin (ng/ml)

PM Exposed C57BL/6 mice fed with HFC

Sheet3

0.0764645934

0.1073518563

0.054194898

0.0821526075

Insulin (ng/ml)

Baseline Insulin Level

0.0679769550.0679769550.14042680990.14042680990.0541948980.0541948980.06197645280.0619764528

0.08391780010.08391780010.08903751140.08903751140.11547884780.11547884780.06189974120.0618997412

0.06872545310.06872545310.1146778970.1146778970.0744633680.0744633680.08994584760.0899458476

0.06510317970.06510317970.0704871240.0704871240.06826053770.06826053770.09982077960.0998207796

0.09514833670.09514833670.09083086970.09083086970.07211859340.07211859340.05130246550.0513024655

FA

PM

FA+LA

PM+LA

Time (min)

Insulin (ng/ml)

PM exposed mice fed with HFC

0.067976955

0.1404268099

0.054194898

0.0619764528

*

Insulin (ng/ml)

Fasted Insulin Level

0.067976955

0.1404268099

Insulin (ng/ml)

*

Toxicol Pathol. 2013 Feb;41(2):361-73. doi: 10.1177/0192623312464531 TOXICOLOGICAL SCIENCES 124(1), 88–98 (2011)

WAT

= w

hite

adi

pose

tiss

ue

BAT

= br

own

adip

ose

tisse

FA = filtered airPM = particulate matter

Hypothetical Model of PM2.5 Mediated Hepatic Insulin Resistance (IR) and Steatosis

Zheng et al. J Hepatol. 2013 Jan;58(1):148-54.

Does Air Pollution Induce Metabolic Changes and Shift in Thermogenesis?

Does Air Pollution Alter Brown Adipose Structure and Function?

Baby Fat May Help You Lose Weight

http://online.wsj.com/article/SB10001424052702304506904575180053884870776.html?mod=WSJ_LifeStyle_LeadStoryNA

Long Term PM2.5 Exposure (40 weeks): Impact on Mitochondrial Structure

Tox Sciences 2011; 124; 88-98FA = filtered air PM = particulate matterWAT = white adipose tissue BAT = brown adipose tissue

PM2.5 Mediated Changes in Whole Body Metabolism and Thermogenesis

Liu et al. Part Fibre Toxicol. 2014 May 30;11:27

Are Central Nervous System Pathways Responsible for Metabolic Control

Involved?

Hypothalamic Inflammation with Long-Term Exposures in C57/Bl6 mice

Environ Health Perspect. 2014 Jan;122(1):79-86

Intracerebroventricular (ICV) infusion of IKKβ Inhibitor (IMD-0354) Inhibits PM2.5 Effects

• O2 consumption (A), CO2 production (B), respiratory exchange ratio (C) and heat production (D) of mice measured by indirect calorimetry over a 24 hrs period (from 10:00 am to 10:00 am the next day) after 4 wks of PM2.5 exposure and IKKβ inhibitor treatment. *P

Regression associations between cumulative averages of daily PM2.5 and metabolic outcomes

over 0–90 days prior to FSIGT

Zhanghua Chen et al. Dia Care 2016;39:547-554© FSIGT = frequently sampled intravenous glucose tolerance

1-SD (5.1 μg/m3) increase in 0–40 days’ PM2.5 was significantly associated with a 4.9% decrease in SI. Effect size similar to 1% increase in body fat.

ASPIRE: AIR POLLUTION: STRATEGIES FOR PERSONALIZED

INTERVENTION TOREDUCE EXPOSURE

SPONSOR: National Institutes of Health (NIH)Location: Beijing ChinaCollaborators: Peking University, Peking Union Medical College. Fuwai HospitalPrincipal Investigator(s): Sanjay Rajagopalan, Robert D. BrookCo-Investigators: Wei Huang (Peking University)

Dong Feng Gu (Fuwai Hospital)Zhongjie Fan (PUMC)

Case Western Reserve/OSU

Andrew MaiseyeuJeffrey DeiulisPalanivel RangasamyXiaoquan RaoJixin ZhongQinghua Sun

Technischen Universität Dresden Henning Morawietz

University of MichiganRobert BrookBhramar MukherjeeZhichao SunMasako MorishitaTimothy Dvonch

New York UniversityLung-Chi ChenTerry Gordon

JHU Bloomberg School of Public Health

Shyam BiswalThomas Sussan

Michigan State UniversityJack Harkema

EPARobert DevlinWayne CascioDan Costa

Peking Union Medical College/Fuwai HospitalZhongjie FanDong Feng Gu

Tsinghua UniversityFumo Yang

University of TorontoHealth CanadaJeffrey Brook

University of MainzThomas Muenzel

Peking UniversityWei Huang

Slide Number 158-year-old patient with Type 2 Diabetes Mellitus (T2DM): HbA1c=7.5 and Blood Pressure (BP)=135/80Natural History of T2DMDe Fronzo’s Ominous Octet If traditional risk factors WERE WORSENED BY AIR POLLUTION… the global risk posed would be even larger…Slide Number 6How may Air Pollution Cause Type 2 DM?Slide Number 8Chronic PM2.5 Ambient Exposures (20 wk) Potentiates Inflammation/Insulin Resistance in MiceSlide Number 10Slide Number 11Hypothetical Model of PM2.5 Mediated Hepatic Insulin Resistance (IR) and SteatosisDoes Air Pollution Induce Metabolic Changes and Shift in Thermogenesis?Does Air Pollution Alter Brown Adipose Structure and Function?Long Term PM2.5 Exposure (40 weeks): Impact on Mitochondrial StructurePM2.5 Mediated Changes in Whole Body Metabolism and ThermogenesisAre Central Nervous System Pathways Responsible for Metabolic Control Involved?Hypothalamic Inflammation with Long-Term Exposures in C57/Bl6 miceIntracerebroventricular (ICV) infusion of IKKb Inhibitor (IMD-0354) Inhibits PM2.5 Effects �Slide Number 20Slide Number 21ASPIRE: Air Pollution: Strategies for Personalized Intervention to�Reduce Exposure�Slide Number 23