Pre- and Postnatal Methyl Deficiency in the Rat Differentially Alters Glucose Homeostasis

Abstract

Background/Aims: Early-life methyl-donor deficiency is implicated in growth restriction and later-life development of type 2 diabetes mellitus. We ascertained whether dietary methyl-donor deficiency in the mother during pregnancy or during postweaning growth in the rat would impair glucose homeostasis, insulin secretion and pancreatic endocrine development in young adults. Methods: Effects of maternal methyl deficiency (90% deficiency in methionine, folate and choline) were compared with those of postweaning methyl deficiency and with control diets for effects on growth, impaired glucose tolerance, insulin secretion and pancreas development in offspring. Studies focussed on male offspring, which have been shown more susceptible to early-life influences on later disease development. Results: Prenatal methyl deficiency delayed delivery, restricted birthweight by 22%, reduced litter size by 33% and increased offspring mortality to 23% shortly after birth. It reduced relative endocrine pancreatic mass in adult male offspring to 46% of endocrine mass in controls, but only mildly impaired their glucose tolerance and insulin secretion. In contrast, postweaning methyl deficiency restricted growth of male rats and reduced relative pancreatic endocrine mass (–40%), but improved their glucose tolerance, despite decreased insulin secretion. Conclusion: It is clear that the global undernutrition (UN) during pregnancy in rodents alters glucose metabolism in adult offspring. It has been hypothesised that alterations in epigenetic mechanisms may underlie this phenotype. However, removing all methyl donors during pregnancy, which are essential for epigenetic processes in development, did not cause any alteration in glucose metabolism in offspring as seen in the global UN model.

Maternal Betaine Supplementation during Gestation Enhances Expression of mtDNA-Encoded Genes through D-Loop DNA Hypomethylation in the Skeletal Muscle of Newborn Piglets

“…It was reported that the plasma concentrations of folic acid, choline, and betaine in pregnant women are positively associated with the birth weight of their offsprings. 29 In agreement with the findings in humans, maternal methyl donor restriction significantly reduces birth weight in rats 30,31 and in pigs. 32 However, an excess of methyl donor in the perinatal period also significantly decreases the birth weight of female but not male offspring rats.…”

Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets

“…These include 9 KEGG pathways relevant to pancreatic islet function, e.g. type 1 diabetes [88], [97], cell adhesion molecules [98], extracellular-receptor matrix (ECM) interaction [99] and folate biosynthesis [100]. It should be noted, however, that many individual genes are included in multiple KEGG pathways and the significant pathways that do not seem to be relevant for pancreatic islet function, such as viral myocarditis, contain numerous individual genes with important roles in pancreatic islets e.g.…”

High novelty-seeking rats are resilient to negative physiological effects of the early life stress

“…Numerous studies show that MS stress produces lifelong changes in the HPA axis, including exaggerated neuroendocrine response to acute stress (Rosenfeld et al, 1992, Plotsky and Meaney, 1993, Huot et al, 2004, Waterland, 2006, Daniels et al, 2009, Smith et al, 2011, Bird, 2002), altered CRF and glucocorticoid receptor expression (Bravo et al, 2011, Meaney et al, 1996), and increased noradrenergic input to the PVN (Wang et al, 2010). Neuroendocrine responsivity in bHR rats was only subtly affected by MS, with MS-exposed bHRs showing diminished ACTH secretion following the LDB test compared to control bHRs and no differences in CORT secretion.…”