insulin resistance in youth vs. adults: from physiology to … · 2019. 3. 29. · insulin...

Silva Arslanian M.D.

Richard L. Day Professor of Pediatrics

Insulin Resistance in

Youth vs. Adults:

From Physiology to Pathophysiology

Is the Glass Half Empty or Half Full?

Swedish Society for Diabetology 2019

Nesli Fida SoJung Rola Julia Tami Hala Ingrid

Gungor Bacha Lee Saad Warren Hannon Tfayli Libman

Nancy

Guerra

Resa

StaufferKristin

Porter

Sally

Foster

Sara Michaliszyn

Lindsey George

Javier de La Heras

Elisa Andreatta

Kathy

Brown

Denise

Shearer

Steve

BurnsJoon

Kim

NIH (R01, K24, T32, K12, M01, U01), DOD

PCTRC Nurses

Insulin Sensitivity in Man

Sensitive Resistant

A state in which a given amount of insulin,

exogenous or endogenous, produces a subnormal

biological response:

- CHO

- Lipid

- Protein

Insulin Resistance in Youth

Risk factors: Modifiable and Unmodifiable

Induction of Insulin Resistance

Alleviation of Insulin Resistance

Youth-Adult Contrast in Insulin Sensitivity

Risk Factors for


Race

GeneticsPCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

Risk Factors for


GeneticsPCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

0

5

10

15

20

25

p < 0.001

Pre Post9.8 15.3

0

100

200

p < 0.005

Insulin Sensitivity Insulin Secretion Fasting Insulin

mu/

ml

Age (yrs) Pre Post9.8 15.3

Pre Post9.8 15.3

0

10

20

30

mu/

ml

Pediatr Res 60: 1, 2006

p = 0.023

0

10

20

Adip

onectin (m

g/m

l)

Pre Post

Age (yrs.) 9.8 15.3

Insulin sensitivity by ~ 50%

Insulin secretion doubled

The in insulin sensitivity was independent

of changes in % BF

Adiponectin by ~50%

The ratio of Leptin/adiponectin 5 fold.


1997

2001

2007

1996

1994

Pubertal insulin resistance involves protein and fat metabolism.

Pubertal IR is driven by GH and not gonadal sex steroids.

The in GH secretion during puberty leads to lipolysis and

FFA to insulin resistance through the Randle cycle.

Pubertal IR and its compensatory hyperinsulinemia may serve

to enhance growth and mass accretion.

Insulin Resistance of Puberty

Risk Factors for


Race

PCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

0

5

10

15

20

25

0

5

10

15

20

25

Insulin Sensitivity Insulin Clearance

ml/

min

/Kg

FF

M

mm

ol/

min

/Kg F

FM

P= 0.021P= 0.011

W B W B

Diabetes 51:3014, 2002

0

250

500

750

1000

1250

1500

-30 -15 0 15 30 45 60 75 90 105 120

AW AA

Time (min)

Insu

lin

(p

mo

l/l)

0

5

10

15

20

AW AA

Dis

po

siti

on I

ndex

(mm

ol/

min

/kg

FF

M)

p=0.019

Arslanian S et al:Diabetes 51:3014, 2002

2001

2006

2008

2006

2011

2003

Adiponectin is in black youth.

Ghrelin (hunger hormone) suppression is in black youth.

PYY (satiety hormone) is in black youth.

Fat oxidation is in black female youth.

Visceral fat is in black youth despite similar BMI or total body fat.

Fat/CHO intake is in black youth’s diet, with inverse correlation to IS.

Diabetogenic risk is worse in black you while atherogenic risk is worse

in white youth.

Insulin Resistance: Race/Ethnicity

Risk Factors for


Race

GeneticsPCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

0

4

8

12

16FH(-)

FH(+)

Total Oxidative Nonoxidative

Insu

lin-s

tim

ula

ted g

luco

se

dis

po

sa

l

(mg

/kg/m

in)

P=0.035

P=0.015 Healthy prepubertal black youth with

+FH of T2DM have ~ 20% insulin

sensitivity in the first decade of life.

1999

0

5

10

15

0

50

100

150

200

0

200

400

600

800

1000

1st

ph

ase

insu

lin

(m

u/m

l)

P=0.011ns

Insu

lin

Sen

siti

vit

y

(mg

/kg

/min

per

mu

l/m

l)

FH (-) FH (+)

0

10

20

30

40

P=0.01

DI

(mg/k

g/m

in)

P=0.008

FH (-) FH (+) FH (-) FH (+)

FH (-) FH (+)

Pro

insu

lin (

pm

ol/

L)

Family History of T2DM: Impaired Insulin Sensitivity

& b-cell Dysfunction in White Youth

2005

Risk Factors for


Race

GeneticsPCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

Risk Factors for


Race

PCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

Insulin Sensitivity in Normal-weight &

Obese Adolescents

0

2

4

6

8

10

12

14

16

White Black

NW OB NW OBmg

/min

/Kg F

FM

pe

r m

u/m

l

P <0.001 P <0.001

20.2 35.2 BMI 21.2 35.7

22.9 43.4 %BF 22.5 43.6

Relationship of BMI and % Body Fat

to Insulin Sensitivity & Fasting Insulin

0

5

10

15

20

25

10 20 30 40

r = -0.74

p = .0005

BMI (kg/m2)

Arslanian S, 1998

Insulin Sensitivity

Yellow: prepubertal, pink: pubertal

Fasting Insulin

0

10

20

30

40

50

10 20 30 40

r = 0.63

p = .0005

BMI (kg/m2)

(mu

/ml)

(mg

/kg

/min

)

0

10

20

30

40

50

0 20 40 60

Body fat (%)

r = 0.70

p =.0005

Fasting Insulin

PearApple

Science 280: 1372, 1998

Do ‘Apples’ Fare Worse Than ‘Pears’ in Youth?

Android Gynoid

Abdominal Adipose Tissue (CT)

Lumbar L4-L5

Visceral fat

Subcutaneous fat

Insulin Sensitivity & Adiponectin in

High vs. Low-VAT Obese Adolescents

High Low

VAT VAT

Insu

lin S

en

sitiv

ity

(mg

/kg

/min

pe

r µu

/ml)

0

1

2

3

4

P=0.032

BMI 35.2% BF 43.4

JCEM 88: 2534, 2003

Diabetes Care 2004

0

4

8

12

Ad

iponectin

(μg/m

l)

High Low

VAT VAT

P= 0.05

0

10

20

30

0 100 200 300 400

Slope p<0.05

Cm2

Glu

co

se

Dis

po

sa

l (m

g/k

g/m

in)

Correlation of VAT & SAT to Insulin

Sensitivity & Fasting Insulin

0

10

20

30

40

50

0 100 200 300 400

Slope p<0.05

Cm2F

astin

g In

su

lin (m

U/m

l)

SAT

VAT

SATVAT

0

20

40

60

80

100

Pre

vale

nce (

%)

High TGLow HDL

Large WC

High BPIFG + IGT

Diabetes Care 30: 2091, 2007

<25th 25-<50th 50-<75th >75th

Insulin Sensitivity Quartiles

0

5

10

15

20

<25th 25-<50th 50-<75th >75th

Adiponectin

P < 0.01

(mg/m

l)


Insulin Sensitivity Quartiles &

Biomarkers of Endothelial Dysfunction

0

100

200

300

400

0

20

40

60

80

100

ICAM E-Selectin

P < 0.01 P < 0.01

(ng/m

l)

(ng/m

l)

<25th 25-<50th 50-<75th >75th

Insulin Sensitivity QuartilesInsulin Sensitivity Quartiles

<25th 25-<50th 50-<75th >75th0

1

2

3

<25th 25-<50th 50-<75th >75th


IL-6

P < 0.01

Question

Are all obese youth the same or have similar risk for T2DM or CVD?

http://www.10eastern.com/images/FoundPhotos/archives/archive99/fat_mikey2.jpg

Metabolically Healthy vs. Unhealthy Obese Youth

Fat metabolically fit obese youth

AGE: 13.2 yr

BMI: 32.6 kg/m2

% Body Fat: 42.6%

W/H ratio: 0.86

VAT: 60.0 cm2

Insulin Sensitivity: 4.5 L

AGE: 12.8 yr

BMI: 33.2 kg/m2

% Body Fat: 43.8%

W/H ratio: 0.93

VAT: 93.9 cm2

Insulin Sensitivity: 1.7 Fat metabolically unfit obese youth

0

10

20

30

40

50

60

P=NS

MHO MUHO

(cm

2)

(mg/d

l)

0

50

100P=0.016

MHO MUHO

% Body FatFat Mass Visceral Adipose Tissue

Whole Body, Visceral Adiposity, and Liver Fat in


0

10

20

30

40

50

60

P=NS

(Kg)

MHO MUHO0

2.5

5

Liver Fat

(%)

P=0.055

MHO MUHO

2006

2016

2019

0

5

10

15

P<0.004

MHO MUHO0

0.5

1

1.5

2

2.5

3

3.5

(mg/d

l)

P<0.013

MHO MUHO

hs-C-Reactive

Protein

Leptin/Adiponectin

Ratio

Adipokines & Inflammatory Markers in


0

5

10

15

20

25

30P<0.0001

(mg

/kg

/min

per

mu

l/m

l)-1

MHO MUHO

(mg/k

g/m

in)

Type 2 Diabetes Risk in


0

0.5

1

1.5

2

2.5

3

3.5

(mg/k

g/m

in p

er

mu

l/m

l) P<0.0001

0

100

200

300

400

500P=0.021

MHO MUHO MHO MUHO

Peripheral

Insulin Sensitivity

Hepatic

Insulin Sensitivityb-cell Function

Relative to IS

0

100

200

300

400

500

600

P=0.035

nm

ol/

L

MHO MUHO

Atherogenic Lipoprotein Concentrations in


0

5

10

15

20

P=0.021

0

1

2

3

4

5

P=0.021

MHO MUHO MHO MUHO

Small HDLVery Small LDL Large VLDL

nm

ol/

L

nm

ol/

L

Take Home Message

Not all obese youth are the same

Metabolically healthy obese youth have more

favorable risk profile than metabolically unhealthy

youth despite similar BMI and total body fat.

Risk Factors for


Race

GeneticsPCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

0

2

4

6

8

10

Control

PCOS

Glu

co

se D

isp

osa

l (m

g/k

g/m

in)

Total OXGD NOXGD

P=0.002

P=0.04

P=0.003

Insulin Sensitivity in Adolescents with PCOS

PCOS Control

Age (yrs) 12.0 ± 0.7 12.1 ± 0.6

Free T. (pg/ml) 7.2 ± 1.4 3.4 ± 1.0

BMI (kg/m2) 33.1 ± 1.8 31.4 ±1.3

% Body Fat 43.2 ± 1.4 45.6 ± 1.1

FM (kg) 34.8 ±2.9 34.0 ± 2.2

TAF (cm2) 546 ± 49 484 ± 44

J Pediatr 138: 38, 2001

Risk Factors for


Race

GeneticsPCOS

T2DM

NAFLD, IUI, etc.

Insulin

Resistance

Puberty

Obesity

0

200

400

600

800

OBC T2DM

DI (m

g/k

g/m

in)

Diabetes Care 28: 638, 2005

0

400

800

1200

1600

2000

-30 -15 0 15 30 45 60 75 90 105 120

T2DM

OBC

Time

0

1

2

3P<0.001

OBC T2DM

0

5

10

15

20 P=0.002

OBC T2DM

Liver

P<0.001

0

3

6

9A

dip

one

ctin m

g/m

l

OBC T2DM

P=0.001

Ominous OctetDiabetes 58: 773, 2009

2005

2014

2017

Fat Induced Insulin Resistance Model

Our objective was to create an acute model of

lipotoxicity, and assess how quickly we can induce

insulin resistance and ectopic fat deposition in youth.

Am J Physiol Endocrinol metab 265: E1009, 2008

Diabetes 62: 2917, 2012

Paired experiments of NS vs. 20% IL infusion for 3 hrs. followed by a 2hr. hyerglycemic clamp

FFA: from ~ 0.21 to 0.61 mmol/L

~35% decline

Insulin Sensitivity in Response to FFA Elevation

in Prepubertal Youth

Hepatic Insulin Sensitivity

0

5

10

15

20

25

Peripheral Insulin Sensitivity

0

2

4

6

8

10

12

14

16

P< 0.01

Effect of Intralipid Infusion on Hepatic & Peripheral Insulin

Sensitivity in Healthy Normal-Weight Adolescents

NS Intralipid

P< 0.01

NS Intralipid

30% 39%

(mg/k

g/m

in p

er

μU

/ml)

(mg/k

g/m

in p

er

μU

/ml)

-1

(2013)

(mg/d

l)

90

92

94

96

98

100

Fasting Insulin

0

5

10

15

20

25

30

NS Intralipid NS Intralipid

P=0.01

Effect of Intralipid Infusion on Fasting Glucose & Insulin

in Healthy Normal-Weight Adolescents

P=0.01

57% 4%

(μU

/ml)

Fasting Glucose

(mm

ol/kg w

et

weig

ht)

0

1

2

3

4

5

6

7

P< 0.01

Effect of Intralipid Infusion on Intramyocellular Lipid (IMCL)

in Healthy Normal-Weight Adolescents

NS Intralipid

85%

Intramyocellular Lipid by 1H-MR Spectroscopy

Lipid Overflow Theory

Physiol Rev 93: 359, 2013

Diabetes 61: 1-9, 2012

27%

(13) (16) (16)

3 m. exercise training

3x/week, 60 min/session

no calorie restriction

Average Wt. 100 Kg

Diabetes 61: 1-9, 2012

Treatment Options for type 2 Diabetes in

Adolescents and Youth

Designed in 2002, ended 2/2011, results April 2012

http://www.niddk.nih.gov/resources/nihlogo.htm

Metformin failure Rate in T2DM

Adults vs. Youth

1 yr 2 yrs 5 yrs

% F

aili

ng

Me

tfo

rmin

Rx

Kahn et al for ADOPT study, NEJM 2006

Zeitler et al for TODAY study, NEJM 2012

Failure Definition

TODAY: HbA1c >8% x 6m

ADOPT : FG > 180 mg/dl x 2.

AdultT2DM

Metformin + Rosi Failure Rate in T2DM

Adults vs. Youth

% F

aili

ng

Tre

atm

ent

Rascati et al Diabetes, Obesity & Metabolism 2013

Zeitler et al for TODAY study, NEJM 2012

Failure Definition

TODAY: HbA1c >8% x 6m

DOD: Start of Insulin

Adults Youth

AdultT2DM

~60-90% lower

Lancet June 25, 2011

Natural History of Type 2 Diabetes

Youth Type 2 Diabetes

Starts decades earlier than adults.

Response to insulin sensitizing agents is less than adults.

b-cell function deteriorates faster than adults.

The disease appears to be more aggressive in youth

than adults.

One or more of the pathophysiological

mechanisms of type 2 diabetes is worse in

youth compared with adults.

0

1

2

3

4

5

6

7

8

9

Youth Adults

(mg/k

gF

FM

/min

per

µU

/mL

)

P<0.0001

10

20

30

40

50

60

Youth Adults

(µU

/mL

)

P<0.0001

Pediatric Diabetes 2017

Insulin Sensitivity Fasting Insulin

1

2

3

4

5

Youth Adults

(mg/k

gF

FM

/min

) P<0.0001

0

5

10

15

20

Youth Adults

(mg/k

gF

FM/m

in∙µU/m

L)-

1

P=0.002

Pediatric Diabetes 2017

Hepatic Glucose Production Hepatic Insulin Sensitivity

Pittsburgh

insulin resistance in youth vs. adults: from physiology to … · 2019. 3. 29. · insulin...

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