Maternal malnutrition programmes a prediabetic phenotype in the progeny

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Reusens Institut des Sciences de la vie, Université catholique de

1 Note: for non-commercial purposes only Maternal malnutrition programmes a prediabetic phenotype in the progeny Brigitte Reusens Institut des Sciences de la vie, Université catholique de Louvain, Louvain-la-Neuve, Belgium The Power of Programming Munich, 5-8 Mai 21

University of Louvain Dept of Clinical Biochemistry

Vanesa Bol Samira Boujendar Hanane Cherif Saloua Dahri

Merezak Pierre Romanus Anne Snoeck Nicolas Theys Claude

Nivoit INSERM U457, Paris Bernadette Bréant Lawson Institute,

2 University of Louvain Dept of Clinical Biochemistry University of Cambridge, UK Suzan Ozanne Florence Bieswal Vanesa Bol Samira Boujendar Hanane Cherif Saloua Dahri Olivier Dumortier Ilham El Khattabi Kevin Goosse Siham Merezak Pierre Romanus Anne Snoeck Nicolas Theys Claude Remacle Thomas Bouckenooghe Luise Kalbe Céline Morrens Pierre Nivoit INSERM U457, Paris Bernadette Bréant Lawson Institute, London, Ontario David Hill Edith Arany Steno Institute, Copenhagen,, DK Jorn Nerup Tomas Sparre

3 Impaired insulin secretion versus sensitivity: cause and effect? Brigitte Reusens Early Nutrition Programming & Health Outcomes in Later Life: Obesity & Beyond BUDAPEST, HUNGARY Budapest, April 2-21, 27

4 What is first programmed? The beta cells or the insulin-sensitive target tissues

5 Sequence of the key pathological features of type 2 diabetes Leahy JL, 25 Aquired organ abnormalities

6 Animal models of early food manipulation Protein Restriction Calorie Restriction Uterine Artery Ligation Gestational Diabetes High Fat / (High saccharide) Diet Maternal Obesity Other specific dietary manipulation

7 Glucagon Insulin Intrauterine Programming of the foetal endocrine pancreas?

8 Mass of β cells Apoptosis or necrosis Neogenesis from precursors (Ngn3, Pdx1= differentiation) Proliferation of differentiated β cells

9 Low Calorie and Low Protein Diets Gestation C 2% protein LCL LC LPL LP 2% protein 2% protein 8% protein 8% protein 5% cal. 5% cal. F15 F21 Dumortier et al., 27

10 Beta cell mass and proliferation F 21.5 β cell mass (mg) * ** ** * 1 Image analysis C LCL LC Proliferation (%) LPL LP 12 *** *** Dumortier et al., BrdU labelling C LCL LC LPL LP

11 Differentiation of the endocrine pancreas Cell differentiation NGN3 1th -15th day NGN3 (after the notch-delta lateral specification) Beta 2 Pax 4 Brn 4? MafA? MafB Nkx2.2 Pdx-1 Pax 6 Nkx6.1 Pdx-1 Hnf 6 Ptf1a Mist1 PP β δ α Endocrine cells Duct cell Acinar cell

12 Differentiation of the endocrine pancreas Cell differentiation (after the notch-delta lateral specification) Beta 2 NGN3 1th -15th days NGN3 Pax 4 Brn 4? MafA? MafB Nkx2.2 Pdx-1 Pax 6 Nkx6.1 Pdx-1 Hnf 6 Ptf1a Mist1 PP β δ α Endocrine cells Duct cell Acinar cell

13 Beta cell markers of differentiation (day 15) NGN3 NGN3 / duct area (µm 2 x1).2 *.1 Dumortier et al., 27 PDX1 C LC LP PDX-1 / duct area (µm 2 x1 4 ) ** C LC LP

Islet vascularization Volume density (%) * 5 4 3 2 1 C LCL LC LPL LP

14 Islet vascularization Volume density (%) * C LCL LC LPL LP Numerical density (# /1 4 µm 2 ) Dumortier et al., ** C LCL LC LPL LP

15 Reduced β cells Mass Low calorie Apoptosis or necrosis 1/2 Low protein Apoptosis or necrosis Neogenesis Proliferation Neogenesis Proliferation Islet vascularization Glucocorticoids Taurine Islet vascularization Glucocorticoids Taurine

16 Insulin secretion by fetal islets in vitro 15 Insulin release (%) 1 5 G5.6 G16.7 +Leu +Arg +Tau +Met Cherif et al, 1998

17 Insulin secretion by fetal islets in vitro 15 Islet from LP foetuses secrete less insulin in response to secretagogues Insulin release (%) 1 5 G5.6 G16.7 +Leu +Arg +Tau +Met Cherif et al, 1998

18 Foetal islet cell sensitivity to cytotoxic molecules 2 15 Apoptosis (%) 1 5 Merezak et al, IL1 + SNP (NO)

19 Foetal islet cell sensitivity to cytotoxic molecules Beta cells from LP foetuses are more susceptible to cytokines 2 ** 15 Apoptosis (%) 1 5 Merezak et al, 21 ** ** - + IL1 + SNP (NO)

20 Acquired cell sensitivity to cytotoxic molecules in vitro Apoptosis (%) IL1+ TNF+IFN Merezak et al, 24

21 Acquired cell sensitivity to cytotoxic molecules in vitro Beta cells from LP adult remain more susceptible to cytokines Apoptosis (%) 5 ** - + IL1+ TNF+IFN Merezak et al, 24

22 General Nutritional Molecular Programming? Epigenetic programming Mitochondrial programming

23 Nutritional Mitochondrial Programming? IUGR after uterine artery ligation (Islets) ATP production Mitochondrial copy number Simmons & al., 25

medium Neoformed islets 1,299 / 1,343 genes Genes Microarray,

24 Nutritional Mitochondrial Programming? 2 % 8 % C Fetal pancreata LP 7 days in vitro in standard culture medium Neoformed islets 1,299 / 1,343 genes Genes Microarray, Affymetrix GeneChip Rat Expression 23A probe array Significance Analysis of Microarray (SAM) Reusens et al, 28

25 Nutritional Mitochondrial Programming? 11% of the genes of which the expression was modified encode for mitochondrial proteins Reusens et al, 28

26 Low protein diet targeted the Krebs cycle of the beta cells Energy reserve metabolism (3) [4.9% of 61] Chi Sq:.8 Glycogen met.(3) [6.5% of 46] Chi Sq:2.1 Glycolysis (6) [1% of 6] Chi Sq: 1.3 Glycogen catabolism (1) [16.6 of 6] Chi Sq: 3.9 Regulation of glycolysis (1) [2% of 5] Chi Sq: 5.3 Energy derivation by oxidation of organic Compounds (19) [9.5% of 196] Chi Sq: 31.2 Main path of carbohydrate (15) [11.5% of 13] Chi Sq: Gluconeogenesis (1) [4% of 25] Chi Sq:.9 TCA cycle intermediate metabolism (3) [11.1% of 27] Chi Sq: 6.2 Fumarate metabolism (1) [1% of 1] Chi Sq: Citrate metabolism (1) [2% of 5] Chi Sq: 5.3 Cellular respiration (12) [29.2% of 41] Chi Sq: Pentose-phosphate shunt (1) [1.1% of 1] Chi Sq: 1.71 Malate metabolism (1) [11.1% of 9] Chi Sq: 2.1 Reusens et al, 28 Aerobic respiration (11) [3.5 of 36] Chi Sq:95.26 TCA Cycle (1) [31.2% of 32] Chi Sq: 88.96

27 Maternal malnutrition C LP 2% 8% LC 5% HF gestation birth lactation weaning 3 months

28 ATP production in islets of LP adult progeny 35 ** 25 % of control 3.3 mm % of control 3.3 mm C LP C LP Glucose 3.3 mm 16.7 mm Theys et al, 29

Developmental programming of adult obesity and cardiovascular disease in rodent by maternal nutrition imbalance

Note: for non-commercial purposes only Developmental programming of adult obesity and cardiovascular disease in rodent by maternal nutrition imbalance Claude Remacle Institute of Life Sciences Université