Accumulation of advanced glycation end products in the rabbit blastocyst under maternal diabetes

Abstract

Diabetes mellitus (DM) during pregnancy is one of the leading causes of perinatal morbidity and birth defects. The mechanism by which maternal hyperglycemia, the major teratogenic factor, induces embryonic malformations remains unclear. Advanced glycation end products (AGEs) are known to accumulate during the course of DM and contribute to the development of diabetic complications. Employing a diabetic rabbit model, we investigated the influence of maternal hyperglycemia during the preimplantation period on AGE formation (pentosidine, argpyrimidine, and N 3 -carboxymethyllysine (CML)) in the reproductive tract and the embryo itself. As a consequence of type 1 DM, the AGE levels in blood plasma increased up to 50%, correlating closely with an AGE accumulation in the endometrium of diabetic females. Embryos from diabetic mothers had increased protein-bound CML levels and showed enhanced fluorescent signals for AGE-specific fluorescence in the blastocyst cavity fluid (BCF). The quantification of CML by HPLC-mass spectrometry (MS/MS) showed a higher amount of soluble CML in the BCF of blastocysts from diabetic rabbits (0.26G0.05 mmol/l) compared with controls (0.18G0.02 mmol/l). The high amount of AGEs in blastocysts from diabetic mothers correlates positively with an increased AGER (receptor for AGE (RAGE)) mRNA expression. Our study gives alarming insights into the consequences of poorly controlled maternal diabetes for AGE formation in the embryo. Maternal hyperglycemia during the preimplantation period is correlated with an increase in AGE formation in the uterine environment and the embryo itself. This may influence the development of the embryo through increased AGE-mediated cellular stress by RAGEs.

Metabolic Profiling in Blastocoel Fluid and Blood Plasma of Diabetic Rabbits

“…Furthermore, sorbitol and fructose may also glycate nitrogens on proteins, such as collagen, producing advanced glycation end products (AGEs), like carboxymethyllysine (CML) and pentosidine [32]. We have recently shown that the total amount of AGEs was increased and that the level of CML was especially elevated in blastocysts from diabetic rabbits [33]. The metabolome analysis confirmed that N6-CML increased in plasma from diabetic rabbits.…”

AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration

“…In addition, AGEs have been implicated in the pathogenesis of infertility. As a consequence of type 1 diabetes mellitus in rabbits, high amounts of AGEs accumulated in the endometrium, follicular fluid, oocytes, and blastocysts . In human‐assisted reproductive technology, Jinno et al reported that AGEs accumulation in follicular fluid and serum negatively correlated with follicular growth, fertilization, and embryonic development.…”

The embryonic stress response to in vitro culture: insight from genomic analysis

“…Excess glucose also induces an inflammatory reaction, possibly because of increased advanced glycation end products (Haucke et al 2014) and activation of hexosamine pathways, in particular O-linked glycosylation (Pantaleon et al 2010, Pantaleon 2015, Wong et al 2015. Other pathways that are activated include protein kinase C signalling and extracellular matrix remodelling into the fibrotic-like phenotype.…”