Maternal leukocyte ADORA2B overexpression is associated with hyperglycemia in GDM subjects, and it is accompanied by complex alterations in the expression of diabetes-related genes involved in insulin action, carbohydrate and lipid metabolism, oxidative stress, and inflammation.

The human SIRT1 is a nuclear enzyme from the class III histone deacetylases (HDACs) which is widely distributed in mammalian tissues. A variety of SIRT1 substrates hints that this protein is involved in the regulation of diverse biological processes, including cell survival, apoptosis, gluconeogenesis, adipogenesis, lipolysis, stress resistance, muscle differentiation, and insulin secretion. This review emphasizes catalytic properties of SIRT1 and its role in apoptosis, insulin pathway, and neuron survival.

IntroductionPeroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor of the nuclear receptor superfamily that is involved in lipid and carbohydrate metabolism as well as inflammation; thereby it participates in metabolic diseases including diabetes. Although PPARγ expression has been observed in different tissues of diabetic patients, its level in leukocytes from subjects affected by gestational diabetes mellitus (GDM) has not yet been reported. This study aimed to investigate leukocyte PPARG expression in GDM patients at 24–33 weeks of gestation and, in turn, to correlate these alterations with anthropometric and metabolic parameters of patients.Material and methodsLeukocytes were isolated from the blood of normal glucose tolerant (NGT; n = 34) and GDM (n = 77) pregnant women between 24 and 33 weeks of gestation. Leukocyte PPARG mRNA expression was determined by semi-quantitative polymerase chain reaction. Univariate correlation analysis was performed to investigate associations between PPARG expression and clinical characteristics of patients.ResultsLeukocyte PPARG mRNA level was significantly higher in GDM than NGT women (p < 0.05). In the whole study group, PPARG expression positively correlated with plasma glucose concentrations at 1 h (r = 0.222, p = 0.049) and 2 h (r = 0.315, p = 0.020) of 75 g oral glucose tolerance test (OGTT), and negatively correlated with plasma HDL cholesterol concentration (r = -0.351, p = 0.010).ConclusionsThe correlation between leukocyte PPARG overexpression and hyperglycaemia suggests that PPARG mRNA expression in these cells might be up-regulated in high-glucose conditions in GDM patients at 24–33 weeks of gestation.

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Although compelling evidence indicates that Sirtuin 1 (SIRT1) plays a prominent role in type 2 diabetes, its relationship with gestational diabetes (GDM) remains elusive. This study was aimed at identifying diabetes-related genes and cellular pathways linked to changes of leukocyte SIRT1 expression at the time of GDM diagnosis. For this purpose, 122 GDM patients were screened for leukocyte SIRT1 expression, and two subgroups were distinguished, namely GDM/SIRT1(↑) (n = 30, p < 0.05) and GDM/SIRT1(↔) (n = 92, p > 0.05), with significant and insignificant changes in leukocyte SIRT1 expression compared to a normal glucose tolerant (NGT) group (n = 41), respectively. PCR array analysis identified 11 diabetes-related genes with at least a ± 2-fold difference in expression in GDM/SIRT1(↑) patients (n = 9) vs. NGT controls (n = 7); in addition, significant differences in the expression of four of the six investigated genes were confirmed between the entire GDM/SIRT1(↑) group and the whole NGT group (p < 0.05). Interestingly, of these four genes, only ACLY expression was found to significantly differ between GDM/SIRT1(↑) and GDM/SIRT1(↔). This study demonstrates that under hyperglycemic conditions, leukocyte SIRT1 overexpression is accompanied by an over-abundance of three transcripts and an under-abundance of another; these four govern related metabolism, inflammation, and transport functions, suggesting that such alterations might represent systemic biological adaptations with a unique ACLY under-expression in GDM/SIRT1(↑) women.

Introduction: An increasing body of evidence has linked diabetes to inflammation. The phosphatidylinositol 3-kinase delta (PI3-K delta), a member of the PI3K class IA family, has been implicated in the regulation of inflammation since it is predominantly expressed in leukocytes. To date, no information has been available on the relationship of leukocyte PI3-K delta with gestational diabetes mellitus (GDM). Therefore, the aim of this study was to investigate changes in leukocyte PIK3CD mRNA expression in GDM women and, in turn, to correlate them with anthropometric and metabolic parameters of patients. Additionally, an association between leukocyte mRNA expression of PIK3CD and Sirtuin 1 (SIRT1) was determined. Material and methods: Blood samples from women with normal glucose tolerance (NGT; n = 43) and GDM (n = 132) at 24-33 weeks of gestation were collected. After isolating leukocytes from the blood, quantitative real time PCR (qRT-PCR) was performed to determine PIK3CD gene expression in these cells. Univariate regression analyses were used to assess an association of leukocyte PIK3CD mRNA level with clinical characteristics of patients as well as with leukocyte SIRT1 mRNA expression. Results: Leukocyte PIK3CD mRNA was increased by 1.98-fold in the GDM v. NGT subjects and inversely correlated with low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) in diabetic pregnancy. There were also significant positive correlations of leukocyte PIK3CD mRNA with plasma glucose concentration at 2h of 75 g oral glucose tolerance test (OGTT) and SIRT1 mRNA in the whole study population (both P < 0.05). Conclusions: GDM is accompanied by leukocyte PIK3CD overexpression associated with reduced plasma LDL-C and TC levels, as well as with hyperglycaemia and elevated leukocyte SIRT1 mRNA. (Endokrynol Pol 2014; 65 (1): 17-24)

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Introduction WWOX gene is a tumour suppressor which loss of expression is demonstrated in many cancers. WWOX is involved in the regulation of glucose metabolism by interaction with HIF1a. WWOX knockdown regulates the metabolic switch from oxidative phosphorylation to aerobic glycolysis in breast cancer MCF7 cell line. This metabolic reprograming called the Warburg effect enhances glycolysis to generate energy over oxidative phosphorylation in aerobic conditions. We considered that aerobic glycolysis can be upregulated via changes in WWOX expression in case of women with gestational diabetes mellitus (GDM). We hypothesised that WWOX has a function in regulating glucose metabolism in GDM. Literature indicates that GDM may be associated with increased risk of breast cancer. Material and methods We analysed expression level of WWOX, HIF1A, glucose transporters SLC2A1, SLC2A4 and glycolytic genes HK2, PFK1, PKM2, LDHA by RT-qPCR in GDM and NGT blood samples. The expression of same genes, we analysed in normal/tumour pair of breast tissue from GEO database (GSE109169). The results, we referred to expression level of these genes in MCF7 and MCF7 sh WWOX cell line obtained by Abu-Remaileh et. al. Results and discussions Relative expression level of WWOX was lower in case of GDM than NGT. Opposite result we observed for HIF1A. Moreover, WWOX/HIF1A ratio is significantly lower in GDM than NGT. The increased level of HIF1A in GDM group is further associated with higher expression of glucose transporters and glycolytic genes. In GDM we observed negative correlation between WWOX/ HIF1A ratio and HIF1A, SLC2A1 as well as HK2, PFK and PKM2. WWOX knockout in MCF7 leads to increasing of HIF1a target glycolytic genes. Similar to GDM, WWOX expression level is lower and HIF1A is higher in breast cancer in comparison to normal breast tissue, which gives statistically lower WWOX/HIF1A ratio. Expression level of SLC2A1, HK2, PKM2, LDHA in breast cancer are higher than in normal. Conclusion We found elevated WWOX and HIF1A expression level, enhanced glycolysis, reduced WWOX/HIF1A ratio in GDM. Our results suggest that WWOX is responsible for Warburg effect occurrence in GDM via regulation of HIF1A, as like in breast cancer. Therefore, a hypothesis can be formed that elevated risk of breast cancer in diabetes mellitus patients could be associated with systemic WWOX function insufficiency.