Bosch i Tubert, Fàtima

Crosa, Mireia

Universitat Autònoma de Barcelona. Facultat de Biociències

Crosa-Bonell, Mireia

Diposit Digital de Documents de la UAB

DEVELOPMENT OF TYPE 2 DIABETES MELLITUS FOLLOWING INTRAUTERINE GROWTH RETARDATIONMireia CrosaIUGR pancreasCONCLUSIONSIUGR leads to a reprogramming process that persists throughout life and to a progressive development of a T2DM phenotype. Mitochondrial dysfunction plays an important role in β-cells because of their vulnerability to ROS. On the other hand, the epigenetic silencing of Pdx1 suggests therapeutic agents for the prevention of common diseases with late-onsetphenotypes.β-cells: Are especially vulnerable to ROS  Have a high oxidative energy requirement Impair insulin secretion Decrease gene expression β-cell deathT2DM adulthoodIUGR↓ ↓ activity of complexes of the electron chain ↑ [reactive oxygen species (ROS)]Oxidative reactionsDamage mitochondrial DNA (mtDNA)↓[ATP]INTRODUCTIONIntrauterine growth retardation (IUGR) is a common complication of pregnancycharacterized by decreased body weight and body mass of foetus, related to other foetus atsame gestational weeks. Many studies correlate IUGR with the later development of adultdiseases (e.g. pregnant women exposed to the Dutch Hunger Winter of 1944-1945 deliveredinfants with lower birth weight. By age 50, these offspring has impaired glucose tolerance).These studies led to the formulation of the ‘developmental plasticity theory’ which consistsin the ability of the organism to change structure and function in response to environmentalsignals. IUGR displays a significant risk for:Developmental plasticity theory: in utero epigenetic programming.T2DMassociated lociGLUT4HNF4APDX1H19/IGF2KNCJ11PANCREATIC DUODENAL HOMEOBOX 1(PDX1)A transcription factor that plays an essential rolein: Early pancreas development β-cell differentiation Maintenance of mature β-cell functionPdx1 is a gene susceptible to increasedepigenetic modifications (especially DNAmethylation).Pdx1 role in early pancreas development and β-cell differentiationEpigenetic silencing process in Pdx1 gene Obesity Hypertension Dyslipidaemia Insulin resistance Type 2 diabetes mellitusEPIGENETIC MODIFICATIONS IN KEY GENES OF T2DM DEVELOPMENTT2DM adulthood(a), (b)(c)(d) β-cell dysfunction Impair insulin secretionHistone deacetylation (loss USF-1 binding + repressor complex recruitment) DNA methyltransferase 1 (Dnmt1) recruitment ↓H3K4 trimethylation / ↑H3K9 dimethylationDNA methyltransferase 3a (Dnmt3a) recruitmentDNA methylation CpG islandsPermanent repression of Pdx1EPIGENETIC SILENCING OF PDX1MITOCHONDRIAL DYSFUNCTIONMolecular process in mitochondriaTYPE 2 DIABETES MELLITUSA chronic metabolic disease caused by an impaired sensitivity to insulin of insulin-responsive tissues coupledwith insufficient β-cell compensation, characterized by hyperglycaemia and altered lipid metabolism. Therefore,the pancreas is a key player for the development of T2DM.

Development of type 2 diabetes mellitus following intrauterine growth retardation

http://ddd.uab.cat/pub/tfg/2013/114211/TFG_mireiacrosabonell.pdf.pdf

Development of type 2 diabetes mellitus following intrauterine growth retardation

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