Differences in lipid metabolism in acquired versus preexisting glucose intolerance during gestation: role of free fatty acids and sphingosine-1-phosphate

Abstract

Background The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. There is increasing evidence that GDM is a heterogeneous disease with different subtypes. An important question in this context is whether impaired glucose tolerance (IGT), which is a typical feature of the disease, may already be present before pregnancy and manifestation of the disease. The latter type resembles in its clinical manifestation prediabetes that has not yet manifested as type 2 diabetes (T2DM). Altered lipid metabolism plays a crucial role in the disorder's pathophysiology. The aim was to investigate the role of lipids which are relevant in diabetes-like phenotypes in these both models with different time of initial onset of IGT. Methods Two rodent models reflecting different characteristics of human GDM were used to characterize changes in lipid metabolism occurring during gestation. Since the New Zealand obese (NZO)-mice already exhibit IGT before and during gestation, they served as a subtype model for GDM with preexisting IGT (preIGT) and were compared with C57BL/6 N mice with transient IGT acquired during gestation (aqIGT). While the latter model does not develop manifest diabetes even under metabolic stress conditions, the NZO mouse is prone to severe disease progression later in life. Metabolically healthy Naval Medical Research Institute (NMRI) mice served as controls. Results In contrast to the aqIGT model, preIGT mice showed hyperlipidemia during gestation with elevated free fatty acids (FFA), triglycerides (TG), and increased atherogenic index. Interestingly, sphingomyelin (SM) concentrations in the liver decreased during gestation concomitantly with an increase in the sphingosine-1-phosphate (S1P) concentration in plasma. Further, preIGT mice showed impaired hepatic weight adjustment and alterations in hepatic FFA metabolism during gestation. This was accompanied by decreased expression of peroxisome proliferator-activated receptor alpha (PPARα) and lack of translocation of fatty acid translocase (FAT/CD36) to the hepatocellular plasma membrane. Conclusion The preIGT model showed impaired lipid metabolism both in plasma and liver, as well as features of insulin resistance consistent with increased S1P concentrations, and in these characteristics, the preIGT model differs from the common GDM subtype with aqIGT. Thus, concomitantly elevated plasma FFA and S1P concentrations, in addition to general shifts in sphingolipid fractions, could be an interesting signal that the metabolic disorder existed before gestation and that future pregnancies require more intensive monitoring to avoid complications. Graphical Abstract This graphical abstract was created with BioRender.com.

Mouse Models of Gestational Diabetes Mellitus and Its Subtypes: Recent Insights and Pitfalls

“…The decrease in the hepatic sphingomyelin reservoir associated with increased plasma S1P concentrations, which is a known marker of impaired lipid metabolism in diabetic rodent models, may have an inhibitory effect on insulin signaling and potentially mediate an increase in IR. Furthermore, female NZO mice show impaired hepatic weight adjustment and alterations in hepatic FFA metabolism during gestation [ 98 ]. To characterize the altered hepatic lipid metabolism of the NZO strain, hepatic fatty acid translocase (FAT/CD36) and its transcriptional regulator peroxisome proliferator-activated receptor alpha (PPARα) have been described.…”

“…Female NZO mice exhibit decreased PPARα expression within the liver and an absence of translocation of CD36 to the hepatocellular plasma membrane. This lack of CD36 translocation to the plasma membrane leads to reduced hepatic FFA uptake and increased plasma FFA concentrations [ 98 ]. Increased CD36 expression in the liver of male NZO mice is associated with higher production and accumulation of triglycerides and diacylglycerols.…”

“…The C57BL/6N strain exhibits both elevated blood glucose levels after 6 h of food deprivation and an IGT during gestation. Moreover, a deteriorating trend in glucose-stimulated insulin secretion was observed during gestation, which was accompanied by increased basal insulin concentrations [ 98 ]. It is already described that the C57BL/6 mouse strain may serve as a potential GDM model after feeding a high-fat diet.…”

“…To study glucose tolerance, the following parameters are recommended: 2 mg glucose per g body weight administered orally after a 6 h fasting period. These parameters were evaluated by Andrikopoulos et al and enabled robust results to study plasma glucose and insulin levels [ 79 , 98 , 109 ].…”

“…Increased CD36 expression is observed in patients with non-alcoholic fatty liver disease and contributes significantly to dyslipidemia in mice [ 110 , 111 ]. Therefore, expression of CD36 might be a marker for metabolic deterioration during gestation [ 98 ]. Due to the IGT first occurring during gestation, the C57BL/6N mouse strain represents an adequate model of human GDM.…”