Insulin Resistance in Youth vs. Adults: From Physiology to Pathophysiology Is the Glass Half Empty or Half Full? Silva Arslanian M.D. Richard L. Day Professor of Pediatrics Swedish Society for Diabetology 2019
Nesli Fida SoJung Rola Julia Tami Hala Ingrid Gungor Bacha Lee Saad Warren Hannon Tfayli Libman Sara Michaliszyn Lindsey George Javier de La Heras Elisa Andreatta NIH (R01, K24, T32, Resa Sally Nancy Kristin K12, M01, U01), DOD Stauffer Foster Guerra Porter PCTRC Steve Kathy Denise Joon Nurses Burns Brown Shearer Kim
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 NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Genetics Obesity
Risk Factors for Insulin Resistance in Youth NAFLD, IUI, etc. Puberty Insulin T2DM Resistance PCOS Genetics Obesity
Pediatr Res 60: 1, 2006 Insulin Sensitivity Insulin Secretion Fasting Insulin 25 200 30 p < 0.001 p < 0.005 p = 0.023 20 20 15 m u/ml m u/ml 100 10 10 5 0 0 0 Pre Post Pre Post Pre Post Age (yrs) 9.8 15.3 9.8 15.3 9.8 15.3
Pediatr Res 60: 1, 2006 20 Adiponectin ( m g /ml) Insulin sensitivity by ~ 50% Insulin secretion doubled The in insulin sensitivity was independent 10 of changes in % BF Adiponectin by ~50% The ratio of Leptin/adiponectin 5 fold. 0 Pre Post Age (yrs.) 9.8 15.3
Pediatr Res 60: 1, 2006
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Insulin Resistance of Puberty 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.
Risk Factors for Insulin Resistance in Youth NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Obesity
Diabetes 51:3014, 2002 Insulin Sensitivity Insulin Clearance 25 25 P= 0.011 P= 0.021 20 20 m mol/min/Kg FFM ml/min/Kg FFM 15 15 10 10 5 5 0 0 W B W B
1500 Insulin (pmol/l) AW AA 1250 1000 750 500 250 0 -30 -15 0 15 30 45 60 75 90 105 120 Time (min) 20 (mmol/min/kgFFM) Disposition Index p=0.019 15 10 5 Arslanian S et al: Diabetes 51:3014, 2002 0 AW AA
2006 2006 2001 2008 2003 2011
Insulin Resistance: Race/Ethnicity 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.
Risk Factors for Insulin Resistance in Youth NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Genetics Obesity
1999 Insulin-stimulated glucose disposal 16 FH(-) P=0.035 FH(+) 12 (mg/kg/min) P=0.015 Healthy prepubertal black youth with +FH of T2DM have ~ 20% insulin 8 sensitivity in the first decade of life. 4 0 Total Oxidative Nonoxidative
Family History of T2DM: Impaired Insulin Sensitivity & b -cell Dysfunction in White Youth 15 200 (mg/kg/min per m ul/ml) 1 st phase insulin ( m u/ml) 1000 Insulin Sensitivity ns DI (mg/kg/min) P=0.011 P=0.008 800 150 10 600 100 400 5 50 200 0 0 0 FH (-) FH (+) FH (-) FH (+) FH (-) FH (+) 40 Proinsulin (pmol/L) P=0.01 30 20 10 2005 0 FH (-) FH (+)
Risk Factors for Insulin Resistance in Youth NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Genetics Obesity
Risk Factors for Insulin Resistance in Youth NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Obesity
Insulin Sensitivity in Normal-weight & Obese Adolescents 16 mg/min/Kg FFM per m u/ ml White Black 14 12 10 P <0.001 P <0.001 8 6 4 2 0 NW OB NW OB 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 Insulin Sensitivity Fasting Insulin Fasting Insulin 50 25 50 40 (mg/kg/min) 20 40 15 ( m u/ml) 30 r = -0.74 30 r = 0.63 r = 0.70 10 p = .0005 20 p = .0005 p =.0005 20 5 10 10 0 0 0 10 20 30 40 10 20 30 40 0 20 40 60 BMI (kg/m 2 ) BMI (kg/m 2 ) Body fat (%) Yellow: prepubertal, pink : pubertal Arslanian S, 1998
Do ‘Apples’ Fare Worse Than ‘Pears’ in Youth? Apple Pear Android Gynoid Science 280: 1372, 1998
Abdominal Adipose Tissue (CT) Subcutaneous fat Lumbar L4-L5 Visceral fat
Insulin Sensitivity & Adiponectin in High vs. Low-VAT Obese Adolescents 12 BMI 35.2 4 Adiponectin ( μ g/ ml) (mg/kg/min per µu/ ml) % BF 43.4 Insulin Sensitivity P= 0.05 P=0.032 3 8 2 4 1 0 0 High Low High Low VAT VAT JCEM 88: 2534, 2003 VAT VAT Diabetes Care 2004
Correlation of VAT & SAT to Insulin Sensitivity & Fasting Insulin VAT 30 50 Glucose Disposal (mg/kg/min) Fasting Insulin ( m U/ml) Slope p<0.05 Slope p<0.05 40 SAT 20 30 20 10 SAT 10 VAT 0 0 0 100 200 300 400 0 100 200 300 400 Cm 2 Cm 2
Diabetes Care 30: 2091, 2007 100 Large WC High TG Adiponectin Low HDL Prevalence (%) 80 High BP 20 IFG + IGT 60 P < 0.01 15 ( m g /ml) 40 10 20 5 0 0 25-<50 th 50-<75 th <25 th >75 th 25-<50 th 50-<75 th <25 th >75 th Insulin Sensitivity Quartiles Insulin Sensitivity Quartiles
Insulin Sensitivity Quartiles & Biomarkers of Endothelial Dysfunction IL-6 ICAM E-Selectin 3 100 400 P < 0.01 P < 0.01 P < 0.01 80 300 2 (ng/ml) ( ng/ml ) 60 200 40 1 100 20 0 0 0 25-<50 th 50-<75 th >75 th 25-<50 th 50-<75 th >75 th 25-<50 th 50-<75 th >75 th <25 th <25 th <25 th Insulin Sensitivity Quartiles Insulin Sensitivity Quartiles Insulin Sensitivity Quartiles
Question Are all obese youth the same or have similar risk for T2DM or CVD?
Metabolically Healthy vs. Unhealthy Obese Youth AGE: 13.2 yr BMI: 32.6 kg/m 2 % Body Fat: 42.6% W/H ratio: 0.86 VAT: 60.0 cm 2 Insulin Sensitivity: 4.5 L Fat metabolically fit obese youth AGE: 12.8 yr BMI: 33.2 kg/m 2 % Body Fat: 43.8% W/H ratio: 0.93 VAT: 93.9 cm 2 Insulin Sensitivity: 1.7 Fat metabolically unfit obese youth
Whole Body, Visceral Adiposity, and Liver Fat in 2006 2016 Metabolically Healthy vs. Unhealthy Obese Youth 2019 Fat Mass Liver Fat Visceral Adipose Tissue % Body Fat 60 60 P=NS 100 5 P=0.055 P=NS P=0.016 50 50 40 (Kg) 40 (mg/dl) (cm 2 ) (%) 30 30 50 2.5 20 20 10 10 0 0 0 0 MHO MUHO MHO MUHO MHO MUHO MHO MUHO
Adipokines & Inflammatory Markers in Metabolically Healthy vs. Unhealthy Obese Youth Leptin/Adiponectin hs-C-Reactive Ratio Protein 15 3.5 P<0.004 P<0.013 3 2.5 10 (mg/dl) 2 1.5 5 1 0.5 0 0 MHO MUHO MHO MUHO
Type 2 Diabetes Risk in Metabolically Healthy vs. Unhealthy Obese Youth b -cell Function Hepatic Peripheral Insulin Sensitivity Insulin Sensitivity Relative to IS 500 30 3.5 P<0.0001 P<0.0001 P=0.021 (mg/kg/min per m ul/ml) -1 (mg/kg/min per mul/ml) 3 25 400 2.5 20 (mg/kg/min) 300 2 15 1.5 200 10 1 100 5 0.5 0 0 0 MHO MUHO MHO MUHO MHO MUHO
Atherogenic Lipoprotein Concentrations in Metabolically Healthy vs. Unhealthy Obese Youth Very Small LDL Small HDL Large VLDL 600 20 5 P=0.035 P=0.021 P=0.021 500 4 15 400 nmol/L nmol/L 3 nmol/L 300 10 2 200 5 100 1 0 0 0 MHO MUHO MHO MUHO MHO MUHO
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 NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Genetics Obesity
Insulin Sensitivity in Adolescents with PCOS J Pediatr 138: 38, 2001 10 Glucose Disposal (mg/kg/min) P=0.002 Control 8 PCOS Control PCOS Age (yrs) 12.0 ± 0.7 12.1 ± 0.6 P=0.003 6 7.2 ± 1.4 3.4 ± 1.0 Free T. (pg/ml) P=0.04 33.1 ± 1.8 31.4 ± 1.3 BMI (kg/m 2 ) 4 % Body Fat 43.2 ± 1.4 45.6 ± 1.1 FM (kg) 34.8 ± 2.9 34.0 ± 2.2 2 TAF (cm 2 ) 546 ± 49 484 ± 44 0 Total OXGD NOXGD
Risk Factors for Insulin Resistance in Youth NAFLD, IUI, etc. Puberty Insulin T2DM Race Resistance PCOS Genetics Obesity
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