Severe types of fetopathy are associated with changes in the serological proteome of diabetic mothers.

ABSTRACT: Pregestational or gestational diabetes are the main risk factors for diabetic fetopathy. There are no generalized signs of fetopathy before the late gestational age due to insufficient sensitivity of currently employed instrumental methods. In this cross-sectional observational study, we investigated several types of severe diabetic fetopathy (cardiomyopathy, central nervous system defects, and hepatomegaly) established in type 2 diabetic mothers during 30 to 35 gestational weeks and confirmed upon delivery. We examined peripheral blood plasma and determined a small proportion of proteins strongly associated with a specific type of fetopathy or anatomical malfunction. Most of the examined markers participate in critical processes at different stages of embryogenesis and regulate various phases of morphogenesis. Alterations in CDCL5 had a significant impact on mRNA splicing and DNA repair. Patients with central nervous system defects were characterized by the greatest depletion (ca. 7% of the basal level) of DFP3, a neurotrophic factor needed for the proper specialization of oligodendrocytes. Dysregulation of noncanonical wingless-related integration site signaling pathway (Wnt) signaling guided by pigment epithelium-derived factor (PEDF) and disheveled-associated activator of morphogenesis 2 (DAAM2) was also profound. In addition, deficiency in retinoic acid and thyroxine transport was exhibited by the dramatic increase of transthyretin (TTHY). The molecular interplay between the identified serological markers leads to pathologies in fetal development on the background of a diabetic condition. These warning serological markers can be quantitatively examined, and their profile may reflect different severe types of diabetic fetopathy, producing a beneficial effect on the current standard care for pregnant women and infants.

Molecular pathophysiology of diabetes mellitus during pregnancy with antenatal complications.

Gestational diabetes mellitus is a daunting problem accompanied by severe fetal development complications and type 2 diabetes mellitus in postpartum. Diagnosis of diabetic conditions occurs only in the second trimester, while associated antenatal complications are typically revealed even later. We acquired an assay of peripheral and cord blood samples of patients with different types of diabetes mellitus who delivered either healthy newborns or associated with fetopathy complications. Obtained data were handled with qualitative and quantitative analysis. Pathways of molecular events involved in diabetes mellitus and fetopathy were reconstructed based on the discovered markers and their quantitative alteration. Plenty of pathways were integrated to differentiate the type of diabetes and to recognize the impact of the diabetic condition on fetal development. The impaired triglycerides transport, glucose uptake, and consequent insulin resistance are mostly affected by faulted lipid metabolism (APOM, APOD, APOH, APOC1) and encouraged by oxidative stress (CP, TF, ORM2) and inflammation (CFH, CFB, CLU) as a secondary response accompanied by changes in matrix architecture (AFM, FBLN1, AMBP). Alterations in proteomes of peripheral and cord blood were expectedly unequal. Both up- and downregulated markers were accommodated in the cast of molecular events interconnected with the lipid metabolism, RXR/PPAR-signaling pathway, and extracellular architecture modulation. The obtained results congregate numerous biological processes to molecular events that underline diabetes during gestation and uncover some critical aspects affecting fetal growth and development.

Association of Proteins Modulating Immune Response and Insulin Clearance During Gestation with Antenatal Complications in Patients with Gestational or Type 2 Diabetes Mellitus.

BACKGROUND: The purpose of the study is to establish and quantitatively assess protein markers and their combination in association with insulin uptake that may be have value for early prospective recognition of diabetic fetopathy (DF) as a complication in patients with diabetes mellitus during gestation. METHODS: Proteomic surveying and accurate quantitative measurement of selected proteins from plasma samples collected from the patients with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) who gave birth of either healthy or affected by maternal diabetes newborns was performed using mass spectrometry. RESULTS: We determined and quantitatively measured several proteins, including CRP, CEACAM1, CNDP1 and Ig-family that were significantly differed in patients that gave birth of newborns with signs of DF. We found that patients with newborns associated with DF are characterized by significantly decreased CEACAM1 (113.18 ± 16.23 ng/mL and 81.09 ± 10.54 ng/mL in GDM and T2DM, p < 0.005) in contrast to control group (515.6 ± 72.14 ng/mL, p < 0.005). On the contrary, the concentration of CNDP1 was increased in DF-associated groups and attained 49.3 ± 5.18 ng/mL and 37.7 ± 3.34 ng/mL (p < 0.005) in GDM and T2DM groups, respectively. Among other proteins, dramatically decreased concentration of IgG4 and IgA2 subclasses of immunoglobulins were noticed. CONCLUSION: The combination of the measured markers may assist (AUC = 0.893 (CI 95%, 0.785-0.980) in establishing the clinical finding of the developing DF especially in patients with GDM who are at the highest risk of chronic insulin resistance.