Abstracts

#32 Early-life exposure to gestational diabetes alters mitochondrial bioenergetics and cardiac function in the rat offspring


Stephanie M Kereliuk, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Prasoon Agarwal, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Laura K Cole, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Bo Xiang, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Mario A Fonseca, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Grant M Hatch, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Jonathan McGavock, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba; Vernon W Dolinsky, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba


Introduction

Gestational diabetes mellitus (GDM) is the most common complication of pregnancy. Children of mothers with GDM are at increased risk for cardiometabolic diseases later in life. We hypothesize that GDM induces fetal cardiomyocyte mitochondrial dysfunction, conditioning offspring for heart disease later in life.


Methods

To induce GDM, female rats were fed 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 (FRVCs) were isolated from e20.5 offspring for analysis of mitochondrial respiration. To assess cardiac function over the entire life course of the offspring, serial echocardiography was performed at e18.5 and at 3, 6, 9 and 12-months of age using a Vevo 2100 ultrasound. Metabolites from the serum of 3-month old offspring were measured using a UPLC-MS/MS interfaced with a HESI-II source and mass analyzer.


Results

Fetal and 3-month old offspring exposed to GDM exhibit increased left ventricle posterior wall thickness (p<0.05), a marker of cardiac hypertrophy. At 6- and 12-months of age offspring exposed to GDM exhibit increased isovolumetric relaxation time (p<0.05), indicating impaired diastolic heart function. Basal and maximal mitochondrial oxygen consumption was reduced for glucose (35% & 68%) and fatty acid (49% & 52%) substrates in FRVCs isolated from GDM offspring (p<0.05). Long chain fatty acids and acyl carnitines were elevated, while pyruvate and other citric acid cycle intermediates were reduced in serum from 3-month old offspring, indicative of altered mitochondrial metabolism.


Conclusion

Impaired early-life cardiomyocyte mitochondrial substrate oxidation and ATP production that elicit a compensatory cardiomyocyte hypertrophy in the offspring of GDM dams likely contributed to the development of diastolic dysfunction in the heart. These findings outline potential mechanisms that link early-life GDM exposure to later in life heart disease development in the offspring.