MATERNAL GESTATIONAL DIABETES MELLITUS AND PLACENTAL LIPIDS

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1 Note: for non-commercial purposes only MATERNAL GESTATIONAL DIABETES MELLITUS AND PLACENTAL LIPIDS Olaf Uhl 2 1, 1 0, Log10(p-value) 0-0, -1-1, -2-2, LPC160 PC PC PC PC PC PC PC PC PC PE PE PE PE PE PE PE PE PS PS LPC PE Obese GDM

2 EPIDEMIOLOGICAL OBSERVATIONS Gestational diabetes mellitus (GDM) is the most common form of diabetes in pregnancies Maternal glucose status is linked to higher risk for perinatal mortality [1] and offspring macrosomia [2] Despite of glycemic control in T2DM mothers, infants are still at higher risk for macrosomia [3] and various deviations in the lipid status were observed Macrosomia and dyslipidemia might be induced by other factors than glucose Lipids? Sobrovia,FrontPhys, [1] Balsells, JCEM, 2009 [2] Najafian, ISRN Obstet Gynecol, 2012 [3] Evers, Diabetologia, 2002

3 METABOLISM OF PREGNANT WOMEN First trimester adipose tissue accumulation Lipoprotein lipase activity (LPL) Last trimester enhanced lipolysis FA synthesis of AT LPL activity Lipolytic activity of AT [2] Results of IR? [1] Increasing metabolites: TCA intermediates β-hydroxybutyrate Phospholipids Threonine Decreasing metabolites: BCAA Free carnitine, acyl-carn Lyso-Phospholipids 3 [1] Sivan, Diabetes, 1999 [2] Lindsay, PLoS One, 2016

4 PREOBE STUDY DESIGN Aim To better understand the intrauterine effects of GDM and obesity, separately Study design Pregnant women were recruited at the University of Granada 3 Groups (Median BMI): 31 Healthy controls (22. kg/m2) 29 Obese (31.6 kg/m2) 32 GDM (23.3 kg/m2) GDM were treated with nutrition counselling, antidiabetics or insulin CTR GDM Obese M (IQR) n M (IQR) n p-value M (IQR) n p-value Maternal age [y] 31 (6) () (4) Prepregnancy BMI [kg/m 2 ] 22. (2.) (2.7) (3.3) 17 >0.001 Weight gain (week 34) [kg] 13.3 (3.) (6.6) (.8) 17 >0.001 Placenta weight [g] 480 (100) (17) (148)

5 PREOBE - METHODS Immediately after delivery, placentas were frozen at -80 C Frozen placentas were divided into small pieces Placenta samples were defrosted and washed with saline solution to remove blood Lipids were extracted with chloroform/ methanol Phospholipids were analysed by liquid chromatography coupled to triple quadrupole mass spectrometry [1] H 3 C H 3 C O O O O O - O P O O H 3 C CH 3 N + CH 3 Serine Ethanolamine FA 16:0 FA 18:1 [1] Uhl, J Chrom B, 2011

6 BAYON, LIPIDS, 1993 PC Species Bayon Uhl PE Species Bayon Uhl PS Species Bayon Uhl 6

7 PREOBE - RESULTS Unique PL pattern: highest LC-PUFA concentration of all kinds of tissues DHA was counted to 67.3% in PE AA was counted 66.7% in PC Highest species: PC(16:0/16:0), PC(16:0/20:4), PC(16:0/18:2), PC(16:0/18:1) PC sn-1: 7% palmitic acid (16:0) PS sn-1: 100% oleic acid (18:0) Phospholipid classes PC 72% PE 21% PS 7% Species Comp. [%] Species Comp. [%] LPC(16:0) 0.32 PE(16:0/18:1) 1.03 PC(16:0/14:0) 1.19 PE(16:0/18:2) 0.88 PC(16:0/16:0) 1.69 PE(16:0/20:3) 0. PC(16:0/16:1) 1.72 PE(16:0/20:4) 2.03 PC(16:0/18:1) 8.88 PE(16:0/22:6) 0.4 PC(16:0/18:2) 8.90 PE(18:0/18:1) 0.66 PC(16:0/20:3) 3.29 PE(18:0/18:2) 1.28 PC(16:0/20:4) PE(18:0/20:3) 1.22 PC(16:0/22:6) 0.86 PE(18:0/20:4) 4.73 PC(18:0/16:0) 0.68 PE(18:0/22:6) 1.20 PC(18:0/18:1) 0.4 PE(18:1/18:1) 0.96 PC(18:0/18:2) 1.93 PE(18:1/18:2) 1.04 PC(18:0/20:3) 0.73 PE(18:1/20:3) 0.7 PC(18:0/20:4) 3.13 PE(18:1/20:4) 1.90 PC(18:1/18:1) 1.03 PE(18:1/22:6) 1.41 PC(18:1/18:2) 2.26 PS(18:0/18:1) 2.07 PC(18:1/20:3) 0.83 PS(18:0/18:2) 1.02 PC(18:1/20:4) 3.07 PS(18:0/20:3) 1.64 PC(18:2/18:2) 1.27 PS(18:0/20:4) 2.13 PC(18:2/20:4) 1.98 PS(18:0/22:6) LPC <1%

8 GPL PATTERN OF GDM AND OBESE IN COMPARISON TO CONTROLS 2 1, Obese GDM PE(16:0/22:6) PE(18:0/20:4) P <0.0* 1 Log10(p-value) 0, 0-0, -1-1, -2-2, PC(18:0/20:3) PC(18:1/20:3) PE(18:1/20:3) P <0.0* LPC160 PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PE PE PE PE PE PE PE PE PE PE PE PE PE PE PE PS PS PS PS PS LPC PC PE PS * Mann-Whitney-U test, Significance was accepted at p <0.0 8 Uhl, Diab Res Clin Prac, 201

9 DHA TRANSFER Maternal Circulation LDL HDL VLDL NEFA DHA Membrane Receptor EL MFSD2a FABP/ FATP [2] LPL Membrane 13C-labeled FA before caesarean section Fetal [1] Circulation NEFA NEFA PL/ TAG Preferred transfer of DHA through the placenta PL/ TAG Newborn: AA, DHA [3] Umbilical vein Liver Umbilical artery 9 [1] Larque, Journal of lipid research, 2003 [2] Prieto-Sánchez, Clin Nutr, 2016 [3] Uhl, PLoS One, 2016

10 DHA TRANSFER IN GDM PREGNANCIES Maternal Circulation LDL HDL VLDL NEFA GDM No differences reported [4] Membrane Receptor LPL EL NEFA FABP/ FATP PL/ TAG GDM DHA in PC, PE [1] 10 Membrane Fetal Circulation NEFA GDM: Umbilical DHA (maternal/fetal) vein No difference in (maternal/ placental) [3] [1] Bitsanis, Lipids, 2006 [2] Ortega, Diabetes Care, 2009 [3] Pagan, Am J Physiol Endocrinol Metab, 2013 Liver PL/ TAG Umbilical artery GDM DHA just in artery plasma [2] DIVISION [4] Thomas, OF METABOLIC Eur J Clin Nutr, AND 2004 NUTRITIONAL MEDICINE

11 DGLA TRANSFER IN GDM PREGNANCIES Maternal Circulation LDL HDL VLDL NEFA Pre-pregnancy BMI DGLA [4] Membrane Receptor EL FABP/ FATP GDM/ Obese: DGLA [1] LPL NEFA PL/ TAG GDM: DGLA [3] Membrane Fetal Circulation GDM: DGLA in venous cord plasma [2] NEFA Precursor of prostaglandin E1, TAG a vasorelaxant and anticoagulant mediator. Increase Liver in DGLA from Umbilical pre-term to term placentas labor Umbilical vein induction [6] artery PL/ Birth weigth: LPC(20:3) FA(20:3n-9) [] 11 [1] Uhl, Diab Res Clin Prac, 201 [2] Thomas, PLEFA, 200 [3] Bitsanis, Lipids, 2006 DIVISION [4] Hellmuth, OF METABOLIC Int J Obesity, AND accepted NUTRITIONAL MEDICINE [] Hellmuth, Obes Facts, submitted [6] Bitsanis, J Nutr, 200

12 PLACENTAL STRUCTURE Complex structure with different cells with different function GDM leads to histological changes in the syncytiotrophoblast [1] Lipid Droplets [2]: Intracellular structures Surrounded by phospholipids and proteins Contain triacylglycerols and cholesterol ester Role in placenta? Poster I-4 Antonio Gázquez Placental Lipid Droplet Composition is Associated Zeldovich, with PLoS Maternal Pathog, 2011 Clinical Parameters and Cord Blood Metabolites A. Structure and orientation of fetus and placenta in uterus B. Maternal blood bathes the villous trees. Syncytium (SYN), subsyncytial cytotrophoblasts (sctb), extravillous trophoblasts (EVT). 12 [1] Al-Okail, Endocrine Journal, 1994 [2] Hernandez-Albaladejo, ACTA Obst Gyn, 2014

13 PREOBE - RESULTS PC(16:0/20:4) PE(18:0/20:4) Placental PC(16:0/20:4) in % y = 0,0023x + 11,966 R² = 0, Placental weight in g Placental PE(18:0/20:4) in % 7 6, 6, 4, 4 3, 3 y = 0,0019x + 4,0341 R² = 0, Placental weight in g AA: cell and tissue growth [1] PC(16:0/20:4) PE(18:0/20:4) PE(AA) ~ birth weight [2] Placental PC(16:0/20:4) in % y = 0,61x + 1,98 R² = 0, Fetal plasma AA in % Placental PE(18:0/20:4) in % 7 6, 6, 4, 4 3, 3 y = -0,0089x +,233 R² = 0, Fetal plasma AA in % Plasma TAG(AA) ~ body weight [3] 13 [1] Sellmayer, Lipids, 1999 [2] Crawford, Am J Clin Nutr, 2000 [3] Koletzko, Ann Nutr Metab, 1991

14 SUMMARY Results Elevated levels of AA and DHA in GDM placentas Lower levels of DGLA in GDM Comparable disarrangement of GPL species pattern between obese and GDM PC(AA) Fetal supply PE(AA) Placental development Limitations Dietary bias of GDM patients Complex structure of placental tissue No correction for multiple testing 14

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