Insulin Sensitivity and Secretion in Youth: From Normal to Diabetes Silva A. Arslanian MD Richard L. Day Professor of Pediatrics 1 year Jubilee, The Queen Silvia Children s Hospital Gothenburg, Sweden January 9, 213 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 Nancy Guerra Kristin Porter Sally Foster Resa Stauffer All the GCRC & PCTRC Nurses over the years
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub OB-NGT OB-IFG/IGT T2DM T1DM The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM IS 3% -cell IS 55% lower -cell 2x high IS +/- -cell 5% lower IS 5% lower -cell 75% lower
Hyperinsulinemic-euglycemic clamp Plasma glucose Variable rate glucose IV insulin (4 or 8 mu/m 2 /min) Insulin Sensitivity Insulin Secretion Insulin Secretion High Low Low Insulin resistant subjects Insulin resistant with low -cell function DI = Sensitivity x secretion Insulin Sensitivity Insulin sensitive subjects High
Insulin Sensitivity Insulin Secretion Insulin Secretion High A B DI = Sensitivity x secretion Low Low AB Insulin Sensitivity High Insulin Sensitivity Insulin Secretion High Insulin Secretion BA Low Low B DI = Sensitivity x secretion A Insulin Sensitivity High
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub OB-NGT OB-IFG/IGT T2DM IS 3% -cell IS 55% lower -cell 2x high IS +/- -cell 5% lower IS 5% lower -cell 75% lower Insulin Sensitivity, 1 st -Phase Insulin, DI & FI: Pre Puberty vs. Puberty Insulin Sensitivity (mg/min/kg FFM per ul/l) 2 15 1 5 P<.1 44 84 Pre Pub Puberty 1 st Phase Insulin ( u/ml) 15 1 5 NS 56 44 Pre Pub Puberty DI (mg/min/kg FFM) 2 1 P=.1 44 56 Pre Pub Puberty Fasting Insulin ( u/ml) 25 2 15 1 5 P=.2 84 44 Pre Pub Puberty
Correlates of in vivo Insulin Sensitivity in Healthy Normal Weight Youth r P BMI -.75. BMI % -.63. % Body fat -.73. WC -.73. VAT -.61. The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub OB-NGT OB-IFG/IGT T2DM IS 3% -cell IS 55% lower -cell 2x high IS +/- -cell 5% lower IS 5% lower -cell 75% lower
Puberty & Insulin Resistance N Engl J Med 315: 215, 1986 J Pediatr 11: 481, 1987 J Clin Endocrinol Metab 72: 277, 1991 J Clin Endocrinol Metab 77: 725, 1993 Diabetes 43: 98, 1994 J Clin Endocrinol Metab 8: 172, 1995 Diabetes 48: 239, 1999 Pediatr Res 48: 384, 2 Int J Obesity 1: 1, 25 Pediatr Res 6: 1, 26 Hepatic Glucose Production Fasting Glucose Fasting Insulin 8 p =.48 2 3 p =.23 ns 2 4 mg/dl 1 u/ml 1 Age Pre Post 9.8 15.3 Pre Post 9.8 15.3 Pre Post 9.8 15.3
Pediatr Res 6: 1, 26 Insulin Sensitivity Insulin Secretion DI 25 2 15 1 5 p <.1 u/ml 2 1 p <.5 mg/kg/min 14 12 1 8 6 4 2 ns Age Pre Post 9.8 15.3 Pre Post 9.8 15.3 Pre Post 9.8 15.3 Pediatr Res 6: 1, 26 Adiponectin ( g/ml) 2 1 Pre Post Puberty Age 9.8 15.3 Insulin sensitivity decreased by ~ 5% Insulin secretion doubled The decrease in insulin sensitivity was independent of changes in % BF Adiponectin decreased by ~5%
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub OB-NGT OB-IFG/IGT T2DM IS 3% -cell IS 55% lower -cell 2x high IS +/- -cell 5% lower IS 5% lower -cell 75% lower Insulin Sensitivity in Normal-weight & Overweight Adolescents Bacha F et al. Diabetes Care 27: 547, 24 mg/min/kg FFM per u/ml 16 White Black 14 12 1 8 6 4 2 P <.1 P <.1 NW OW NW OW 2.2 35.2 BMI 21.2 35.7 22.9 43.4 %BF 22.5 43.6
Insulin Sensitivity, 1 st -Phase Insulin, DI & FI: NW vs. Obese Adolescents Insulin Sensitivity (mg/min/kg FFM per ul/l) 15 1 5 7 NW P<.1 53 OB 1 st Phase Insulin ( u/ml) 25 2 15 1 5 P<.1 56 NW 56 OB DI (mg/min/kg FFM) 2 1 P<.1 55 47 Fasting Insulin ( u/ml) 4 3 P<.1 2 61 1 7 NW OB NW OB BMI, Insulin Sensitivity & Fasting Insulin Arslanian S & Danadian K: TEM 9(5): 194, 1998 Glucose Metabolism (mg/kg/min) 25 2 15 1 5 r = -.74 p =.5 1 2 3 4 BMI (kg/m 2 ) Fasting Insulin ( u/ml) 5 4 3 2 1 Yellow: prepubertal, pink: pubertal r =.63 p =.5 1 2 3 4 BMI (kg/m 2 )
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM The role of abdominal adiposity Fat but metabolically fit youth Ethnicity differential in metabolic risk Android vs Gynoid Obesity Apple Pear Vague J: Presse Medicale 3: 339, 1947 Science 28: 1365, 1998
Abdominal Adipose Tissue (CT) Subcutaneous fat Lumbar L4-L5 Visceral fat Insulin Sensitivity in High vs Low-VAT Obese Adolescents Insulin Sensitivity (mg/kg/min per µu/ml) 4 3 2 1 P=.32 High VAT Low VAT BMI 35.2 % BF 43.4 Bacha F et al J Clin Endocrinol Metab 88: 2534, 23
J Pediatr 148: 188, 26 Insulin sensitivity (mg/min/kg FFM per U/ml) Insulin Sensitivity and Fasting Insulin across Waist Circumference percentile Groups 2 15 1 5 P <.1 <75 th 75-9 th >9 th <75 th 75-9 th >9 th Fasting insulin ( U/ml) 5 4 3 2 1 WC % (Fernandez et al. J Pediatr 145: 439, 24) P <.1 WC % J Pediatr 149: 89, 26 Triglycerides (mg/dl) 16 14 12 1 8 6 p<.1 HDL (mg/dl) <75 th 75-9 th <75 th 75-9 th WC% >9 categories th WC% categories >9 th 8 6 4 2 p<.1
Childhood WC Predicts Adult Metabolic Syndrome Sun S et al. J Pediatr Sept. 27 Fels Data Waist Circumference (cm) 15 1 9th 95 Males 9 MS vs. Non-MS 75th 85 8 5th 25t 75 7 1th 65 6 55 5 45 4 2 3 4 5 6 7 8 9 11112131415161718192 Age in Years
Abdominal obesity is used as the sine qua non for the diagnosis of metabolic syndrome in children and adolescents The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM The role of abdominal adiposity Fat but metabolically fit youth
Diabetes Care 29: 1599, 26 OB-MF OB-MUF P Age (yrs) 13. +.4 12.8 +.3 ns BMI (Kg/m 2 ) 32.6 +.8 33.6 +.9 ns % Body fat 42.6 + 1.5 43.8 +.7 ns W/H ratio.86 +.2.91 +.1.26 Visceral fat (cm 2 ) 6.3 + 6.9 78.3 + 6.9.17 VO 2 max 55.2 + 3.5 49.9 + 3.2.45 Adiponectin ( g/ml) 8.6 + 1.2 6.1 +.5.39 HDL (mg/dl) 42.5 + 2.3 38.7 + 1.2.15 17 pair-matched obese teens: OB-LR (MIR), OB-HR (SIR) Not all obese youth have the same risk despite similar BMI! Insulin Sensitivity (μmol/kg/min per pmol/l) 5 2.5 OB-MF P<.1 OB-MUF 1 st Phase Insulin (pmol/l) 2 15 1 5 P=.22 OB-MF OB-MUF DI (mmol/kg/min) 5 2.5 P=.2 OB-MF OB-MUF Bacha et al Diabetes care 29:1599, 26
Conclusion Not all obese youth are the same! The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM What are the metabolic defects in Pre Diabetes? IGT IFG
Pediatr 116: 1122, 25 NHANES 1999-2, n=915, >8 hr fasting Prevalence of youth IGT? IGT (%) T2DM (%) Quasi Population Based NHANES (99-2) (IFG:11)? STOPP-T2D 2 (IFG:4).4 Non Population Based Yale (4-1 yrs) 25 Yale (11-18 yrs) 21 4. Pittsburgh 7 Pittsburgh 2 Italy 4.1.2 Germany 36.3 5.9 U.K..21
Diabetes Care 32: 1, 29 NGT IGT T2DM (8F + 4M) (13F + 6M) (1F + 7M) Age (yrs) 14.2 ±.6 13.8 ±.3 14.7 ±.3 BMI (Kg/m 2 ) 36. ± 1.5 35. ± 1.5 36.3 ± 1.3 % Body Fat 45.4 ± 1.5 44.3 ± 1. 41. ± 1.7 WC 18.5 ± 5.7 14.3 ± 3.5 17.9 ± 2.9 VAT (cm 2 ) 75.8 ± 14.6 72.1 ± 5.6 78.7 ± 6.5 HbA1C (%) 5.2 ±.1 5.3 ±.2 6.8 ±.2* Insulin Sensitivity in NGT vs IGT vs T2DM Insulin-stimulated Rd (mg/kg/min) 7.5 5 2.5 P<.5 NGT IGT T2DM
Insulin (pmol/l) 5 4 3 2 1 NGT IGT T2DM -3-15 15 3 45 6 75 9 15 12 Time (min) DI (mmol/kg/min) 5 2.5 p<.1 NGT IGT T2DM Diabetes Care 32: 1, 29 2 hr glucose (mmol/l) 2 1 r=-.73 p<.1 NGT IGT T2DM 2.5 5 7.5 DI (mmol/kg/min) 1
Conclusion IGT in youth is characterized by -cell dysfunction manifested in impaired 1 st -phase insulin secretion relative to insulin sensitivity, but preservation of 2 nd -phase insulin secretion. Youth with IGT are not more insulin resistant than their NGT peers if matched for body composition and fat topography. The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM What is the metabolic defect(s) in Pre Diabetes? IGT IFG
Diabetes Care: 33, 2225, 21 Insulin Sensitivity (μmol/min/kg FFM per pmol/l) 6 4 2 p=.7 Insulin (pmol/l) NGT IFG IGT IFG+IGT T2DM 36 p<.1 p<.1 24 12 NGT IFG IGT IFG/IGT T2DM -3-15 15 3 45 6 75 9 15 12 Time (min) Diabetes Care: 33, 2225, 21 -cell Function relative to insulin sensitivity (mmol/min/kg FFM) 7 3.5 p<.1 NGT IFG IGT IFG/IGT T2DM
Conclusion All pre diabetes states in obese youth, with similar BMI, % body fat and abdominal adiposity are characterized by reductions in -cell function relative to insulin sensitivity. IFG : greater impairment in both 1 st and 2 nd phase insulin secretion. IGT: impairment in 1 st phase insulin secretion. IFG /IGT: Intermediary phenotype Diabetes Care: 32, 1327, 29
Diabetes Care 34: 2597, 211 Diabetes Care 212
Diabetes Care 212 The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM What is the metabolic defect in T2DM?
Diabetes Care 28: 638, 25 11 yrs old BMI: 4 HTN Study Subjects OBCN T2DM P Age (yrs) 14.6 +.2 15.5 +.3 ns BMI (kg/m2) 37.5 + 1.3 35.9 + 1.8 ns % Body fat 43.5 + 1. 41.3 + 1.5 ns VAT (cm 2 ) 68.2 + 6.2 9.6 + 15. ns HbA1c (%) 5.4 +.1 6.9 +.3 <.1 Gungor N et al. Diabetes Care 28: 638, 25
Insulin (pmol/l) 2 16 12 8 4 T2DM OBC -3-15 15 3 45 6 75 9 15 12 Time (min) 3 2 1 p <.1 OBC T2DM DI (mg/kg/min) 8 6 4 2 p <.1 OBC T2DM Gungor N et al. Diabetes Care 28: 638, 25 Adiponectin in youth T2DM 8 Adiponectin ( g/ml) 6 4 2 p =.1 OBC T2DM Gungor N et al. Diabetes Care 28: 638, 25
Treatment Options for type 2 Diabetes in Adolescents and Youth 15 centers Funded by National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Designed in 22, ended 2/211, results April 212 Question What is the best treatment in preventing loss of glycemic control? Metformin Metformin + Intensive Lifestyle Metformin + Rosiglitazone
Primary Outcome Results Metformin + Rosi Metformin + Lifestyle Overall Failure rate 45.6% Metformin 319/699 Lancet June 25, 211
J Pediatr 144, 656, 24 9% decrease within 6 years 15% decline/year UKPDS 5% decline/year Pediatric Diabetes E Pub 212 After a median of 2 months -cell function declined 2% per year
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM T1DM & Obesity
Diabetes Care 26: 2871, 23 1 8 1979-1989 199-1998 % 6 4 2 Males Females < 11 yrs > 11 yrs Ab + Ab - From the 198s to the 199s the prevalence of overweight at diagnosis of type 1 diabetes has tripled Acta Pediatr 88: 1223, 1999 At age 18, girls with T1DM were 6.5 Kg heavier and had 2.7 kg/m 2 higher BMI than control girls. Diabetic Med 2: 15, 23 Abdominal fat accumulation was associated with Increased insulin requirements & hyperlipidemia
Can you tell what type of diabetes? Is it obese Type 1? Is it Type 2? 11 yrs old BMI: 4 HTN Large Ketonuria Type 1.5 diabetes Hybrid Diabetes Double Diabetes LADA LADY 8.1% ICA+, 3.3% GAD+, 34.8% IAA+ 5% requiring insulin after 1 year Pediatrics 17: e12, 21 J Pediatr Endocrinol Metab 15: 525, 22 29.7% + for one Ab, 1.8% + for GAD, or IA2 or both No difference in treatment related to AB + or - JCEM 89: 2222, 24 74% positive for any Ab, 32% + for 2 Abs, 11% + for 4 Abs
Ab + 36% Ab - Ab + Age (yrs) 13.9 13. BMI z-scores 3.5 3. C-Peptide (>1.5ng/dl) 33% 28% HbA1C (%) 8. 7.5 Glucose (mg/dl) 238 251 Chol. (mg/dl) 183 173 HDL (mg/dl) 42 41 TG (mg/dl) 157 128 Arch Dis Child 91: 473, 26 Can you tell what it is? Rooster Peacock
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub IR-NGT IR-IFG/IGT T2DM What is the metabolic defect in T2DM? What are the metabolic features of Ab + T2DM? Diabetes 58: 738, 29 Ab- Ab+ OBCN P (6m+8f) (1m+14f) (23m+17f) (5B+9W) (12B+12W) (21B+19W) Age (yrs) 14.6 +.5 14.8 +.5 14. +.2 ns BMI (kg/m2) 35.8 + 1.5 33.7 + 1.3 35.8 +.9 ns HbA1c (%) 6.8 +.2 6.5 +.2 5.3 +.1 <.1 DD (months) 4.8 + 1.6 9.4 + 2.3 ns % Body Fat 41.7 + 1.6 41.7 + 1.3 42.3 +.7 ns VAT (cm 2 ) 73.6 + 5.8 74.7 + 8.7 74. + 6.1 ns
Insulin Stimulated Rd (mg/kg/min) 1 8 6 4 2 Diabetes 58: 738, 29 P =.1 P =.3 Ab- Ab+ OBCN Insulin Stimulated Rd (mg/kg/min) 15 1 5 P =.1 P =.3 Diabetes 58: 738, 29 Ab - Ab + OBCN NWCN
Insulin ( u/ml) 5 4 3 2 1 Insulin Secretion OBCN Ab- Ab+ -3-15 15 3 45 6 75 9 15 12 Time (min) mg/kg/min 6 5 4 3 2 1 Disposition Index P =.1 Ab- Ab+ OBCN
HbA1c (%) 1 8 6 r = -.64 p <.1 Ab+ Ab- 4 4 8 12 Disposition Index (IS X CF) (µmol/kg/min) Characteristics at Diagnosis Ab- Ab+ P Glucose (mg/dl) 277 + 47 359 + 36 ns HbA1C (%) 1. +.7 1.9 +.7 ns Ketones 18.8% 53.8%.2 Clinical Symptoms 65% 78.3% ns Insulin use 64.3% 7.8% ns FH of DM 92.9% 91.2% ns
Characteristics at the Present Ab- Ab+ P ALT (u/l) 4.5 + 5. 28.4 + 1.7.3 BP-Sys (mmhg) 122 + 3 113 + 2.6 Insulin use 5% 58% ns Diabetes 58: 738, 29 - Ab negative clinically-diagnosed T2DM youth have the inherent/genetic insulin resistance typical of T2DM. - Ab positive CDx-T2DM youth with severe insulin deficiency are obese individuals with type 1 autoimmune diabetes.
The Spectrum of Glucose Tolerance in Youth Years of Disease Progression??? Pre Pub OB-NGT OB-IFG/IGT T2DM IS 3% -cell IS 55% lower -cell 2x high IS +/- -cell 5% lower IS 5% lower -cell 75% lower Thank You
Acknowledgement Satish Kalhan Allan Drash Jack Gerich David Kelley Dorothy Becker Chittiwat Suprasongsin Kapriel Danandian Vered Lewy Rola Saad Neslihan Gungor Fida Bacha Ingrid Libman So Jung Lee Hala Tfayli NIH (RO1, K24, MO1, UO1) Genentech Foundation Eli-Lilly & Comp. Richard L. Day endowed chair PCTRC Nurses All the volunteer children & their parents