Abstract 547: Metabolomic and Transcriptomic Profiling of Rat Offspring Exposed to Gestational Diabetes Reveals Altered Cardiac Gene Expression and Metabolism

Abstract

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. Children exposed to GDM are at an increased risk of developing cardiometabolic diseases later in life, though the mechanisms responsible are unknown. We hypothesize that fetal exposure to GDM induces alterations in cardiomyocyte metabolism and concomitant left ventricular (LV) dysfunction with age. GDM was induced in female rats with a high fat (45% kcal) and sucrose diet prior to mating, throughout pregnancy and lactation. Lean control females received a low fat (10% kcal) diet. Fetal rat ventricular cardiomyocytes (FRVC) were isolated from e20.5 offspring for U-13C glucose metabolic flux analysis and mitochondrial respiration. Serum metabolites and cardiac transcriptome profiles were measured in 3-month old offspring. LV morphology and function was assessed through the life course of the offspring (e18 to 12-months of age) by transthoracic ultrasound. Offspring exposed to GDM exhibited increased LV posterior wall thickness across their life course (fetal to 12-months of age; p<0.05) and impaired LV filling beginning at 6-months of age (p<0.05). U-13C glucose metabolic flux through glycolysis and the citric acid cycle was reduced in FRVC from GDM offspring when treated with isoproterenol, and compared to Lean FRVC. Basal and maximal mitochondrial oxygen consumption was reduced for glucose (35% and 68%) and fatty acid (49% and 52%) substrates in FRVC isolated from GDM offspring (p<0.05). In 3-month old GDM offspring, serum metabolomics revealed elevated levels of beta-hydroxybutyrate (2.4-fold, p<0.05) and reduced levels of several citric acid cycle intermediates, which also corresponded to alterations in gene expression patterns identified by RNASeq transcript analysis. Large-scale profiling revealed GDM induced alterations in the cardiac gene expression profile leading to modified serum metabolite levels in the offspring. These alterations corresponded with mitochondrial dysfunction, impaired cardiomyocyte metabolic flux and contractility, in concert with LV hypertrophy and diastolic dysfunction in the rat offspring. Our findings identify several mechanisms that link early-life GDM exposure to the development of cardiovascular disease later in life.