Abstract
The long-term influence of gestational diabetes mellitus (GDM) on offspring and the effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on GDM offspring are poorly understood. We studied the long-term diabetic risk in GDM offspring and evaluated the effect of n-3 PUFA intervention. Healthy offspring rats were fed standard diet (soybean oil) after weaning. GDM offspring were divided into three groups: GDM offspring (soybean oil), n-3 PUFA adequate offspring (fish oil), and n-3 PUFA deficient offspring (safflower oil), fed up to 11 months old. The diabetic risk of GDM offspring gradually increased from no change at weaning to obvious impaired glucose and insulin tolerance at 11 months old. N-3 PUFA decreased oxidative stress and inflammation in the liver of older GDM offspring. There was a differential effect of n-3 PUFA and n-6 PUFA on hepatic telomere length in GDM offspring. Non-targeted metabolomics showed that n-3 PUFA played a modulating role in the liver, in which numerous metabolites and metabolic pathways were altered when GDM offspring grew to old age. Many metabolites were related to diabetes risk, such as α-linolenic acid, palmitic acid, ceramide, oxaloacetic acid, tocotrienol, tetrahydro-11-deoxycortisol, and niacinamide. In summary, GDM offspring exhibited obvious diabetes risk at old age, whereas n-3 PUFA decreased this risk.
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Key Points
Telomeres, which are termini of chromosomes, contain specific DNA sequences. Telomeres are essential for chromosomal integrity. The length of telomeres shortens with age. Accelerated telomere shortening is caused by some adverse factors such as oxidative stress and inflammation. Several studies based on metabolomics have focused on GDM mothers, investigating the correlation between abnormal metabolites and GDM or finding biomarkers that can predict GDM risk.
Theory of developmental origins of health and disease (DOHaD theory) and fetal programming hypothesis reveal that the risk of adult diseases later in life is associated with adverse intrauterine conditions. The aim of this study was to investigate the risk of developing diabetes during GDM offspring rats’ growth, particularly when they grow to 11 months old. The effect of n-3 PUFA on diabetes risk of GDM offspring was studied. For the first time, this study discovered the differential effect of n-3 PUFA and n-6 PUFA on the length of hepatic telomeres in GDM offspring. Moreover, metabolomics analysis revealed obvious metabolic alterations of the liver of GDM offspring at an old age. n-3 PUFA played an important role in modulating the metabolism of the liver of GDM offspring.
To study the long-term diabetic risk of GDM offspring, this study evaluated two hypotheses. The first is that GDM can lead to aging of the liver of offspring, which increases the risk of developing diabetes. To evaluate this hypothesis, the study measured oxidative stress, inflammation, and telomere length. The second is that GDM can cause long-term metabolic changes in the liver of offspring. If so, an evaluation of whether such changes are associated with diabetic risk was conducted. Hepatic TG was increased in “lean” offspring from “lean” GDM rats induced by STZ. This result indicates that regardless of the GDM model, intrauterine hyperglycemia can lead to hepatic lipid metabolism disorders in offspring, and these disorders can even continue to old age, which increases the risk of developing diabetes. n-3 PUFA decreased the levels of triglyceride and cholesterol in the liver of GDM offspring, suggesting a protective effect on diabetic risk in GDM offspring.
The study showed that the liver of GDM offspring exhibited oxidative stress and inflammation at 11 months of age, which were important factors in inducing diabetic risk. SOD is an important defense enzyme catalyzing dismutation of superoxide radicals. The decreased activity of SOD in the liver of GDM offspring lowers cellular capacity to scavenge free radicals, which reduces hepatic cell protection from oxidant exposure, resulting in diabetic risk.
The length of telomere in the liver of GDM offspring was nearly significantly shortened at 11 months of age, indicating potential aging of the liver. An opposite result on the length of the hepatic telomeres in the liver between n-3 Adq-GDM offspring and n-3 Def-GDM offspring was found, suggesting that n-3 PUFA and n-6 PUFA played a differential role in telomere length. GDM offspring with an-3 PUFA deficient diet exhibited the shortest telomere length, whereas n-3 PUFA postponed shortening of the telomere. ALA is also associated with the lowest risk of type 2 diabetes. ALA was decreased in the liver of GDM offspring, which might be related to the risk of developing diabetes.
n-3 PUFA played a role in improving the overall metabolism of the liver of GDM offspring. Changing trends of some metabolites were even aggravated in the high n-6 PUFA group. For the first time, the differential effects of n-3 PUFA and n-6 PUFA on hepatic metabolism of GDM offspring were compared in this study. In summary, GDM offspring exhibited an obvious increased risk for diabetes when they grew to an old age, whereas n-3 PUFA decreased this risk. This is the first study to investigate the long-term influence of GDM on metabolism of the liver of offspring and the modulating effect of n-3 PUFA on hepatic metabolism. Surprisingly, the differential effect of n-3 PUFA and n-6 PUFA on the length of hepatic telomeres in GDM offspring was discovered in this study. Finally, the results also provide evidence and a molecular basis for the DOHaD theory and fetal programming hypothesis.