Fisiopatolgia del GDM e conseguenze per la madre e per il feto Annunziata Lapolla

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1 Fisiopatolgia del GDM e conseguenze per la madre e per il feto Annunziata Lapolla DPT di Medicina Università di Padova

2 Diabete gestazionale importanza della diagnosi Identificare pazienti che necessitano di un intervento terapeutico per prevenire le complicanze maternofetali Identificare pazienti ad elevato rischio per lo sviluppo di diabete tipo 2 ed altre alterazioni metaboliche

3 Glucose homeostasis in pregnancy ENDOCRINE-METABOLIC ADAPTATIONS Impaired insulin sensitivity Increased beta-cell response Moderate increase in blood glucose levels Changes in the levels of circulating FFA, triglycerides, cholesterol and phospolipids These changes represent a necessary adaptation to meet the energy demands of the fetus and to prepare the maternal organism for delivery and lactation

4 Gestational Diabetes Mellitus defect in the regulation of blood glucose Genes Epigenetic Mechanisms Environment Exogenous glucose Glucose production (liver) Blood glucose Insulin Resistance Impaired Insulin Secretion Pancreatic β-cell Insulin secretion Glucose utilization (muscle, fat) Insulin

5 Longitudinal changes in glucose metabolism during pregnancy Insulin µu/ml Insulin µu/ml 1a fase secrezione insulinica durante GTT 2a fase secrezione insulinica durante GTT Glucose mg/min Produzione epatica di glucosio mg/min Glucose mg/kg*ffm/min Produzione epatica di glucosio mg/kg fat free mass/min Catalano P:Am J OG,1999

6 Insulin Sensitivity FASTING QUICKI p< p< p<0.05 DYNAMIC OGIS (mg/min/m 2 ) p< p< p< p< Beta cell function INSULIN RESPONSE AUC I /AUC G µu/mg p< DISPOSITION INDEX OGIS*(AUC I /AUC G ) p< p<0.02 A Lapolla:Am J Physiol Endocrinol Metab,2011

7 IRS-1 e β3-ar in GDM Prevalence of β 3 AR gene polymorphism Prevalence of IRS 1 gene polymorphism Fallucca F,Dalfrà MG,Lapolla A : Metabolism,2006

8 Fisiopatologia Diabete Gestazionale e Diabete tipo 2 Insulin Output Insulin Output DM tipo 2 NTG RTG Tempo: anni Insulin Sensitivity NTG Tempo: mesi Diabete Gestazionale Caratteristiche cliniche comuni del Diabete Gestazionale Insulino-resistenza Riduzione funzione β-cellula Alto rischio sviluppare DM tipo 2 Resistant Insulin Sensitivity Sensitive Mod da Reece,1995

9 Glucose tolerance returns to normal levels after delivery in the majority of GDM women GDM Long Term Consequences? After Delivery 99% NGT

10 β-cell function declines within the first year postpartum in women with recent glucose intolerance in pregnancy Retnakaran R:Diabetes Care 2010

11 Postpartum diabetes risk in GDM women Cumulative post partum diabetes (%) Ab+ Ab- insulin treatment Ab- diet BMI>30 Ab- diet BMI< Follow-up after delivery (yrs) Löbner K:Diabetes,2006

12 Autoimmunity in pregnancy Lapolla A: NMCD,2009

13 LADA e GDM Adult-0nset type 1 diabetes and pregnancy : Three case reports Bonsembiante B, Dalfrà MG, Masin M, Gallo A, Lapolla A Case Reports in Medicine 2013

14 Rischio di diabete tipo 2 dopo GDM Bellamy L:Lancet,2009

15 Risk of development of type 2 diabetes Cumulative Probability (95% CI) Follow-up Years pgdm (5470) Controls (783) ( ) ( ) ( ) ( ) 2 ( ) ( ) 3.9 ( ) Hazard risk 9.6 times greater for pgdm than Controls Lee A,Diabetes Care 2007

16 Predictors of Developing Type 2 Diabetes Covariates Hazard Risk (95% CI) Patients Requiring Insulin 3.5 Asian Race 2.1 Birth Weight Increase (for each 10% centile) 1-h Blood Glucose (for each 1 mmol >10.1mmol) Fasting and 2-h blood glucose were not independent risk factor Lee A,Diabetes Care 2007

17 SINDROME METABOLICA IN DONNE CON PREGRESSO GDM Autore Followup anni Prevalenza SM % (SM Criteri) Verma et al anni % (ATP III) Bo S. et al anni 21% (ATP III) Albareda M. et al anni 11.1% (ATP III) Lauenborg et al anni 38.4% (WHO) Di Cianni et al mesi 9% (ATP III) Kousta et al mesi 37% (IDF)

18 Fattori di Rischio Cardio Vascolari in donne con pregresso GDM Circonferenza addominale Pressione arteriosa HDL TG FPG Sindrome metabolica OR 95%CI 1.54 ( ) 1.67 ( ) 0.98 ( ) 1.15 ( ) 8.46 ( ) 3.18 ( p <0.001 <0.001 Carr DB, Diabetes Care, 2006

19 Alterazioni Vascolari e pregresso Diabete Gestazionale Study pgdm (n.) Method of Assessment Results Hu (1988) 17 Echo tracking of aorta Impaired Anastasiou (1995) Honnemann (2002) Paradisi (2002) Heitritter (2005) 33 Flow-mediated dilation Impaired 17 Flow-mediated dilatation Normal 25 Flow-mediated dilatation Impaired 23 Echo tracking of aorta Reduction of stroke volume Increased Total peripheral resistance Bo (2006) 82 Intimal medial thickness Higher Mod from Banerjee M, Nat Clin Pr Cardiovasc Med, 2006

20 Increased Risk of Cardiovascular Disease in Young Women Following Gestational Diabetes Mellitus Young women with GDM had had a substantially increased risk risk for for CVD compared with women without GDM. Much of of this this increased risk risk was attributable to to subsequent development of of type 2 diabetes. B.R. Shah, Diabetes Care 2008; 31:

21 Mild Glucose Intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. Kaplan-Meier curve GCT+OGTT- GCT- GDM Retnakaran R: CMAJ,2009

22 Sovrappeso e sindrome metabolica nei nati da madri con GDM o DM1 outcomes O-GDM O-noGDM O-DM1 O-BP Overweight Unadjusted Adjusted 2.09 ( ) 1.79 ( ) 1.36 ( ) 1.47 ( ) 2.15 ( ) 2.27 ( ) Ref Ref Metabolic syndrome Unadjusted Adjusted 5.35 ( ) 4.12 ( ) 3.17 ( ) 2.74 ( ) 2.73 ( ) 2.59 ( ) Ref Ref Clausen T :JCEM 2009

23 High prevalence of type 2 diabetes and prediabetes in adult offspring of women with gestational diabetes ore type 1 diabetes O-GDM O- nogdm O-DM1 O-BP p Type 2 DM% IGT% IFG% Type 1 DM% Clausen T Diabetes Care,2008

24 Insulinoresistenza e funzione β cellulare nei nati da madre con GDM o DM1 Kelstrup L:JCEM 2013

25 POGO study offspring

26 Maternal hyperglycemia and hyperinsulinemia and consequently fetal hyperglycemia and hyperinsulinemia alter the function of evey stage of fetal metabolism including the hypothalamus, the pancreas and adipose tissue Vracnis N: Exp diab Res 2012

27 Raccomandazioni per donne con pregdm Jones EJ: JOGNN,2009

28 Pregnancy outcome PRE-LAGB e POST-LAGB Post-LAGB 19 Pre-LAGB 19 Age (yrs) 34.2± ±4.3* Prepregnancy BMI (kg/m2) 35.3± ±6.4 Weight 5.3± ±10.2** GDM(%) Gestational hypertension(%) Preeclampsia (%) CS(%) PTD(%) GW of delivery 39.7± ±2.2 Birthweight (g) 32913± ±473 LGA(%(n )) 11.8(2) 16.7(3) SGA(%(n )) 0(0) 5.6(1) NICU(%(n )) 11.8(2) 5.6(1) Lapolla A,:Obes Surg,2010

29 Grazie per l attenzione l