Youth vs. Adults: From Physiology to Pathophysiology Is the Glass - - PowerPoint PPT Presentation

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 Stauffer Kristin Porter Sally Foster

Sara Michaliszyn Lindsey George Javier de La Heras Elisa Andreatta

Kathy Brown Denise Shearer Steve Burns Joon 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 Insulin Resistance in Youth

Race Genetics PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

Risk Factors for Insulin Resistance in Youth

Genetics PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

5 10 15 20 25

p < 0.001

Pre Post

9.8 15.3

100 200

p < 0.005

Insulin Sensitivity Insulin Secretion Fasting Insulin

mu/ml

Age (yrs)

Pre Post

9.8 15.3

Pre Post

9.8 15.3

10 20 30

mu/ml

Pediatr Res 60: 1, 2006

p = 0.023

10 20

Adiponectin (mg/ml) Pre Post

Age (yrs.) 9.8 15.3

• Insulin sensitivity  by ~ 50%
• Insulin secretion doubled
• The  in insulin sensitivity was independent
• f changes in % BF
• Adiponectin  by ~50%
• The ratio of Leptin/adiponectin  5 fold.

Pediatr Res 60: 1, 2006

Pediatr Res 60: 1, 2006

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 Insulin Resistance in Youth

Race PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity



5 10 15 20 25 5 10 15 20 25

Insulin Sensitivity Insulin Clearance

ml/min/Kg FFM mmol/min/Kg FFM

P= 0.021 P= 0.011

W B W B

Diabetes 51:3014, 2002

250 500 750 1000 1250 1500

• 30
• 15

15 30 45 60 75 90 105 120

AW AA

Time (min)

Insulin (pmol/l)

5 10 15 20

AW AA Disposition Index (mmol/min/kgFFM)

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 Insulin Resistance in Youth

Race Genetics PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

 

4 8 12 16

FH(-) FH(+)

Total Oxidative Nonoxidative Insulin-stimulated glucose disposal (mg/kg/min)

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

5 10 15

50 100 150 200

200 400 600 800 1000

1st phase insulin (mu/ml) P=0.011 ns Insulin Sensitivity (mg/kg/min per mul/ml) FH (-) FH (+)

10 20 30 40 P=0.01 DI (mg/kg/min)

P=0.008 FH (-) FH (+) FH (-) FH (+) FH (-) FH (+) Proinsulin (pmol/L)

Family History of T2DM: Impaired Insulin Sensitivity & b-cell Dysfunction in White Youth

2005

Risk Factors for Insulin Resistance in Youth

Race Genetics PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

  

Risk Factors for Insulin Resistance in Youth

Race PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

 

Insulin Sensitivity in Normal-weight & Obese Adolescents

2 4 6 8 10 12 14 16

White Black

NW OB NW OB

mg/min/Kg FFM per mu/ml

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

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

10 20 30 40 50 10 20 30 40

r = 0.63 p = .0005

BMI (kg/m2) (mu/ml) (mg/kg/min)

10 20 30 40 50 20 40 60

Body fat (%)

r = 0.70 p =.0005

Fasting Insulin

Pear Apple

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

Insulin Sensitivity (mg/kg/min per µu/ml)

1 2 3 4

P=0.032

BMI 35.2 % BF 43.4

JCEM 88: 2534, 2003 Diabetes Care 2004

4 8 12

Adiponectin (μg/ml)

High Low VAT VAT

P= 0.05

10 20 30 100 200 300 400

Slope p<0.05

Cm2

Glucose Disposal (mg/kg/min)

Correlation of VAT & SAT to Insulin Sensitivity & Fasting Insulin

10 20 30 40 50 100 200 300 400

Slope p<0.05

Cm2

Fasting Insulin (mU/ml)

SAT VAT SAT VAT

20 40 60 80 100

Prevalence (%)

High TG Low HDL Large WC High BP IFG + IGT Diabetes Care 30: 2091, 2007

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

Insulin Sensitivity Quartiles

5 10 15 20

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

Adiponectin

P < 0.01 (mg/ml)

Insulin Sensitivity Quartiles

Insulin Sensitivity Quartiles & Biomarkers of Endothelial Dysfunction

100 200 300 400 20 40 60 80 100

ICAM E-Selectin

P < 0.01 P < 0.01 (ng/ml)

(ng/ml)

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

Insulin Sensitivity Quartiles Insulin Sensitivity Quartiles

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

1 2 3

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

Insulin Sensitivity Quartiles

IL-6

P < 0.01

Question

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

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

10 20 30 40 50 60

P=NS MHO MUHO

(cm2) (mg/dl)

50 100 P=0.016 MHO MUHO

% Body Fat Fat Mass Visceral Adipose Tissue

Whole Body, Visceral Adiposity, and Liver Fat in Metabolically Healthy vs. Unhealthy Obese Youth

10 20 30 40 50 60

P=NS

(Kg)

MHO MUHO 2.5 5

Liver Fat (%)

P=0.055 MHO MUHO

2006 2016 2019

5 10 15

P<0.004

MHO MUHO 0.5 1 1.5 2 2.5 3 3.5

(mg/dl)

P<0.013

MHO MUHO

hs-C-Reactive Protein Leptin/Adiponectin Ratio

Adipokines & Inflammatory Markers in Metabolically Healthy vs. Unhealthy Obese Youth

5 10 15 20 25 30 P<0.0001

(mg/kg/min per mul/ml)-1

MHO MUHO (mg/kg/min)

Type 2 Diabetes Risk in Metabolically Healthy vs. Unhealthy Obese Youth

0.5 1 1.5 2 2.5 3 3.5 (mg/kg/min per mul/ml) P<0.0001 100 200 300 400 500 P=0.021 MHO MUHO MHO MUHO

Peripheral Insulin Sensitivity Hepatic Insulin Sensitivity b-cell Function Relative to IS

100 200 300 400 500 600

P=0.035

nmol/L

MHO MUHO

Atherogenic Lipoprotein Concentrations in Metabolically Healthy vs. Unhealthy Obese Youth

5 10 15 20

P=0.021

1 2 3 4 5

P=0.021 MHO MUHO MHO MUHO

Small HDL Very Small LDL Large VLDL nmol/L nmol/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 Insulin Resistance in Youth

Race Genetics PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

   

2 4 6 8 10

Control PCOS

Glucose Disposal (mg/kg/min)

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 Insulin Resistance in Youth

Race Genetics PCOS T2DM NAFLD, IUI, etc.

Insulin Resistance

Puberty Obesity

    

200 400 600 800 OBC T2DM DI (mg/kg/min)

Diabetes Care 28: 638, 2005

400 800 1200 1600 2000

• 30
• 15

15 30 45 60 75 90 105 120 T2DM OBC

Time

1 2 3 P<0.001 OBC T2DM

5 10 15 20

P=0.002

OBC T2DM Liver

P<0.001

3 6 9

Adiponectin mg/ml OBC T2DM P=0.001

Ominous Octet

Diabetes 58: 773, 2009

2005 2014 2017

Insulin Resistance in Youth

Risk factors: Modifiable and Unmodifiable Induction of Insulin Resistance Alleviation of Insulin Resistance Youth-Adult Contrast in Insulin Sensitivity

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

5 10 15 20 25

Peripheral Insulin Sensitivity

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/kg/min per μU/ml) (mg/kg/min per μU/ml)-1

(2013)

(mg/dl)

90 92 94 96 98 100

Fasting Insulin

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

(mmol/kg wet weight)

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

Insulin Resistance in Youth

Risk factors: Modifiable and Unmodifiable Induction of Insulin Resistance Alleviation of Insulin Resistance Youth-Adult Contrast in Insulin Sensitivity

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

Insulin Resistance in Youth

Risk factors: Modifiable and Unmodifiable Induction of Insulin Resistance Alleviation of Insulin Resistance Youth-Adult Contrast in Insulin Sensitivity

Treatment Options for type 2 Diabetes in Adolescents and Youth

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

Metformin failure Rate in T2DM Adults vs. Youth

1 yr 2 yrs 5 yrs

% Failing Metformin 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.

Adult T2DM

Metformin + Rosi Failure Rate in T2DM

Adults vs. Youth

% Failing Treatment

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

Adult T2DM

~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.

1 2 3 4 5 6 7 8 9

Youth Adults

(mg/kgFFM/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/kgFFM/min)

P<0.0001

5 10 15 20

Youth Adults

(mg/kgFFM/min∙µU/mL)-1

P=0.002 Pediatric Diabetes 2017

Hepatic Glucose Production Hepatic Insulin Sensitivity

Tack

Pittsburgh