Prenatal Hyperglycemia Exposure and Cellular Stress, a Sugar-Coated View of Early Programming of Metabolic Diseases

Abstract

Worldwide, the number of people with diabetes has quadrupled since 1980 reaching 422 million in 2014 (World Health Organization). This distressing rise in diabetes also affects pregnant women and thus, in regard to early programming of adult diseases, creates a vicious cycle of metabolic dysfunction passed from one generation to another. Metabolic diseases are complex and caused by the interplay between genetic and environmental factors. High-glucose exposure during in utero development, as observed with gestational diabetes mellitus (GDM), is an established risk factor for metabolic diseases. Despite intense efforts to better understand this phenomenon of early memory little is known about the molecular mechanisms associating early exposure to long-term diseases risk. However, evidence promotes glucose associated oxidative stress as one of the molecular mechanisms able to influence susceptibility to metabolic diseases. Thus, we decided here to further explore the relationship between early glucose exposure and cellular stress in the context of early development, and focus on the concept of glycemic memory, its consequences, and sexual dimorphic and epigenetic aspects.

High‐fat, sucrose and salt‐rich diet during rat spermatogenesis lead to the development of chronic kidney disease in the female offspring of the F2 generation

“…In good agreement with this hypothesis, we saw that multiple renal genes (ENPP6, TMEM144, ACTR3B, and CD300LF) and also the non‐coding RNA lncRNA XR‐146683 are associated with the development of the renal phenotype of female F2 offspring (decreased GFR, increased urinary albumin excretion, glomerulosclerosis and renal interstitial fibrosis). Alteration of just a single pathway or even single genes as a result of fetal programming events during spermatogenesis and fetal development are rather uncommon, the environmental stimuli ‐ high‐fat, high‐sucrose and high‐salt diet during spermatogenesis in two subsequent paternal generations in our case—rather induce complex epigenetic marks 4,8,36–39 inducing the observed renal phenotype. How the interaction of these different epigenetic induced alterations in various gene expression patterns in the kidney finally causes the observed renal phenotype in female F2 offspring is yet unknown.…”

Hyperglycemia in Pregnancy-Associated Oxidative Stress Augments Altered Placental Glucose Transporter 1 Trafficking via AMPKα/p38MAPK Signaling Cascade

“…The ambiguous results may be explained by the heterogeneity of participants, different diagnostic criteria, and glucose control levels. In PGDM, it was widely recognized that GLUT1 expression was elevated, mainly due to the enlarged surface area of nutrient exchange and efficient energy metabolism [ 13 , 14 , 15 , 16 , 45 ]. The placental volume was obviously larger in PGDM pregnancies and thus contributed to greater flows of glucose taken up.…”

“…In contrast, its expression is shown to be decreased in IUGR [ 14 ]. Given that ROS production or elimination is strongly associated with glycolysis and the subsequent metabolic pathways, the high glucose exposure is often accompanied by ROS accumulation and thus recapitulates the plausible relationships between hyperglycemia and increased metabolic activity through cellular stress-related mechanisms [ 15 ]. However, the GLUT1 regulation patterns with exaggerated OS in HIP were unclear.…”

Regulation of Pancreatic β-Cell Mass by Gene-Environment Interaction

“…As it is considered that environmental changes can affect gene expression, we should not forget this mechanism when we consider gene-environment interactions. In particular, changes in the intrauterine environment can have an impact on epigenetic modifications, and fetal nutritional conditions memorized in embryonic tissue have been found to lead to the development of various diseases in the future (metabolic memory) [49][50][51]. Park et al [52] generated an IUGR rat model by ligation of the uterine artery, and these rats developed pancreatic β-cell failure.…”