Early life exposure to gestational diabetes mellitus induces cardiometabolic disease development in the rat offspring
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Date
2022-01
Authors
Kereliuk, Stephanie
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Abstract
Gestational diabetes mellitus (GDM) is a common complication of pregnancy. Children of mothers that had GDM are at increased risk for the development of cardiometabolic disease later in life, though the mechanisms responsible for these observations are unknown. We propose that impaired cardiac energy metabolism and mitochondrial function, programmed in utero, may be a contributing mechanism to cardiometabolic disease development and hypothesize that fetal exposure to GDM induces alterations in cardiomyocyte metabolism resulting in the development of cardiovascular and metabolic disease in the offspring with age. Using an established rodent model, GDM was induced by feeding female rats a high fat (45% kcal) and sucrose (HFS) diet prior to mating, throughout pregnancy and lactation. Lean control females received a low fat (10% kcal; LF) diet. Cardiomyocytes were isolated from fetal rat offspring to investigate glucose metabolic flux, mitochondrial bioenergetics and calcium handling. Offspring from Lean and GDM dams were weaned onto LF and HFS diets and aged to 12-months. To investigate cardiometabolic disease progression in the offspring, cardiac morphology and function was assessed by transthoracic ultrasound throughout the life course (fetal to 12-months of age) and the cardiac transcriptome and metabolome were measured in 3-month-old offspring. Offspring exposed to GDM exhibited increased left ventricular (LV) cardiac hypertrophy and impaired LV filling throughout their lifespan. Consistent with the development of diastolic dysfunction in vivo, alterations in calcium flux and sarcoplasmic reticulum-dependent calcium re-uptake were observed in fetal cardiomyocytes isolated from GDM offspring. In 3-month-old offspring cardiac and serum metabolomics revealed an altered acylcarnitine profile. Alterations in the metabolome corresponded to changes in gene expression patterns identified by RNA-Seq associated with glucose and fatty acid metabolism pathways. Large-scale multi-omics profiling revealed GDM induced alterations in the cardiac transcriptome resulting in modified serum and cardiac 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 implicate altered cardiac energy metabolism and mitochondrial function as a mechanism linking early life exposure to GDM to the development of cardiometabolic disease later in life.
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Keywords
Mitochondria, Cardiovascular disease, Gestational diabetes, Developmental origins of health and disease, Cardiometabolic disease, Metabolomics, Cardiac energy metabolism