Transcriptomic Dysregulation of Inflammation-Related Genes in Leukocytes of Patients with Gestational Diabetes Mellitus (GDM) during and after Pregnancy: Identifying Potential Biomarkers Relevant to Glycemic Abnormality.

Although the immune system has been implicated in the pathophysiology of gestational diabetes mellitus (GDM) and postpartum abnormal glucose tolerance (AGT), little is known about the transcriptional response of inflammation-related genes linked to metabolic phenotypes of GDM women during and after pregnancy, which may be potential diagnostic classifiers for GDM and biomarkers for predicting AGT. To address these questions, gene expression of IL6, IL8, IL10, IL13, IL18, TNFA, and the nuclear factor κB (NFκB)/RELA transcription factor were quantified in leukocytes of 28 diabetic women at GDM diagnosis (GDM group) and 1-year postpartum (pGDM group: 10 women with AGT and 18 normoglycemic women), using a nested RT-PCR method. Control pregnancies with normal glucose tolerance (NGT group; n = 31) were closely matched for maternal age, gestational age, pre-pregnancy BMI, pregnancy weight, and gestational weight gain. Compared with the NGT group, IL8 was downregulated in the GDM group, and IL13 and RELA were upregulated in the pGDM group, whereas IL6, IL10, and IL18 were upregulated in the GDM and pGDM groups. The TNFA level did not change from pregnancy to postpartum. Associations of some cytokines with glycemic measures were detected in pregnancy (IL6 and RELA) and postpartum (IL10) (p < 0.05). Receiver operating characteristic (ROC) curves showed that IL6, IL8, and IL18, if employed alone, can discriminate GDM patients from NGT individuals at GDM diagnosis, with the area under the ROC curves (AUCs) of 0.844, (95% CI 0.736−0.953), 0.771 (95% CI 0.651−0.890), and 0.714 (95% CI 0.582−0.846), respectively. By the logistic regression method, we also identified a three-gene panel (IL8, IL13, and TNFA) for postpartum AGT prediction. This study demonstrates a different transcriptional response of the studied genes in clinically well-characterized women with GDM at GDM diagnosis and 1-year postpartum, and provides novel transcriptomic biomarkers for future efforts aimed at diagnosing GDM and identifying the high risk of postpartum AGT groups.

Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM).

BACKGROUND: Although the WW-domain-containing oxidoreductase (WWOX)/Hypoxia-inducible factor 1 (HIF1) pathway is a well-known regulator of cellular glucose and energy metabolism in pathophysiological processes, its role in gestational diabetes mellitus (GDM), remains elusive. We undertook this study to determine the effect of WWOX/HIF1A signaling on the expression of glucose metabolism genes in GDM patients. METHODS: Leukocytes were obtained from 135 pregnant women with (n = 98) or without (n = 37) GDM and, in turn, 3 months (n = 8) and 1 year (n = 12) postpartum. Quantitative RT-PCR was performed to determine gene expression profiles of the WWOX/HIF1A-related genes, including those involved in glucose transport (SLC2A1, SLC2A4), glycolytic pathway (HK2, PKM2, PFK, LDHA), Wnt pathway (DVL2, CTNNB1), and inflammatory response (NFKB1). RESULTS: GDM patients displayed a significant downregulation of WWOX with simultaneous upregulation of HIF1A which resulted in approximately six times reduction in WWOX/HIF1A ratio. As a consequence, HIF1A induced genes (SLC2A1, HK2, PFK, PKM) were found to be overexpressed in GDM compared to normal pregnancy and negative correlate with WWOX/HIF1A ratio. The postpartum WWOX expression was higher than during GDM, but its level was comparable to that observed in normal pregnancy. CONCLUSIONS: The obtained results suggest a significant contribution of the WWOX gene to glucose metabolism in patients with gestational diabetes. Decreased WWOX expression in GDM compared to normal pregnancy, and in particular reduction of WWOX/HIF1A ratio, indicate that WWOX modulates HIF1α activity in normal tissues as described in the tumor. The effect of HIF1α excessive activation is to increase the expression of genes encoding proteins directly involved in the glycolysis which may lead to pathological changes in glucose metabolism observed in gestational diabetes.

Continuous subcutaneous insulin infusion does not correspond with pregnancy outcomes despite better glycemic control as compared to multiple daily injections in type 1 diabetes - Significance of pregnancy planning and prepregnancy HbA1c.

OBJECTIVE: The aim of the study was to compare pregnancy outcomes with glycemic control, total increase in insulin requirement, and body weight gain in the women with Type 1 Diabetes Mellitus (T1DM) using continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). MATERIAL AND METHODS: This was a single center retrospective observational study involving 209 pregnant Caucasian women. Among the study participants, 95 subjects were treated with MDI and 114 patients were using CSII therapy. The primary outcomes were pregnancy results, while secondary ones were HbA1c, increase in daily dose of insulin (DDI), and body weight gain. RESULTS: At baseline, the CSII users were older (P = 0.0373), they were diagnosed with T1DM at a younger age (P = 0.047), and more often planned pregnancy (P = 0.032). A majority of the women were classified as class D, according to the White classification. Among the CSII users, a significantly higher proportion of the subjects in class B was noted than in the MDI users, with no differences in the proportion of the remaining White classes. Prepregnancy HbA1c was insignificantly lower in the CSII group, however, a significantly higher proportion of the CSII users reached the target value of HbA1c (P = 0.008). A prepregnancy daily dose of insulin (both total and per kg of body weight), body weight, and body mass index (BMI) did not differ between the groups. The 1st and 2nd trimester HbA1c was lower among the CSII users (6.83 ± 1.38 vs 7.52 ± 2.11%, P = 0.01 and 6.17 ± 0.9 vs 6.57 ± 1.12%, P = 0.009, respectively), while the 3rd trimester HbA1c as well as the total change in HbA1c were comparable. Neither DDI and body weight in concecutive trimesters, nor their total gestational increase, differed between the groups. The rate of pregnancy loss, such as abortions, fetal and neonatal death did not differ between the groups. As regards composite pregnancy loss, prepregnancy HbA1c was 8.41%±2.81% among the MDI cohort vs 7.22%±1.31% in the CSII users (P = 0.517). No differences were found in the gestational age at delivery, the mode of delivery, neonatal birth weight, the rate of macrosomy, LGA or SGA. A higher Apgar score was noted among the CSII users (8.63 ± 1.63 vs 8.03 ± 2.49%, P = 0.047), however, the proportion of neonates with an Apgar score lower than 7 points was similar. In the women planning pregnancy, as compared to the subjects who did not, HbA1c was significantly lower in the 1st trimester, together with a significantly higher rate of the women achieving the target HbA1c value during planning as well as in the 1st trimester. In the group of women planning pregnancy, significantly lower 1st trimester HbA1c and composite outcome of pregnancy loss were observed in the CSII users vs the MDI treated women. Lack of pregnancy planning and a high HbA1c level in the 1st trimester were independent predictors of both LGA (OR = 4.99 [95%CI 1.12-21.0], P = 0.033 and OR = 3.02 [95%CI 1.19-7.65], P = 0.019, respectively) and macrosomia (OR = 8.43 [95%CI 1.36-51.93], P = 0.021 and OR = 5.47 [95%CI 1.77-16.87], P = 0.003, respectively). CONCLUSIONS: The course of pregnancy and obstetric outcomes were not dependent on the mode of insulin delivery, but only on pregnancy planning and HbA1c in early pregnancy. Further studies are needed to explore more precise parameters describing both glycemic control in pregnant women as well as perinatal infant well-being.

Impact of Foehn Wind and Related Environmental Variables on the Incidence of Cardiac Events.

In Poland there is no data related to the impact of halny wind and the related environmental variables on the incidence of cardiac events. We decided to investigate the relationship between this weather phenomenon, as well as the related environmental variables, and the incidence of cardiac events in the population of southern Poland, a region affected by this type of wind. We also decided to determine whether the environmental changes coincide with or predate the event examined. We analysed data related to 465 patients admitted to the cardiology ward in a large regional hospital during twelve months of 2011 due to acute myocardial infarction. All the patients in the study group lived in areas affected by halny wind and at the time of the event were staying in those areas. The frequency of admissions on halny days did not differ significantly from the admissions on the remaining days of the year (p = 0.496). No statistically significant differences were found between the number of admissions on halny days and on the remaining days during halny months (p = 0.084). We have identified a difference in the number of admissions between days with no halny and days immediately preceding onset of halny (p = 0.001). However, no effects of the related environmental variables have been observed in the incidence of cardiac events (p = 0.866, F = 0.37). On the days with halny wind, incidence of cardiac events is similar to that on the remaining days of the year.

The Influence of Dietary Fatty Acids on Immune Responses.

Diet-derived fatty acids (FAs) are essential sources of energy and fundamental structural components of cells. They also play important roles in the modulation of immune responses in health and disease. Saturated and unsaturated FAs influence the effector and regulatory functions of innate and adaptive immune cells by changing membrane composition and fluidity and by acting through specific receptors. Impaired balance of saturated/unsaturated FAs, as well as n-6/n-3 polyunsaturated FAs has significant consequences on immune system homeostasis, contributing to the development of many allergic, autoimmune, and metabolic diseases. In this paper, we discuss up-to-date knowledge and the clinical relevance of the influence of dietary FAs on the biology, homeostasis, and functions of epithelial cells, macrophages, dendritic cells, neutrophils, innate lymphoid cells, T cells and B cells. Additionally, we review the effects of dietary FAs on the pathogenesis of many diseases, including asthma, allergic rhinitis, food allergy, atopic dermatitis, rheumatoid arthritis, multiple sclerosis as well as type 1 and 2 diabetes.

Expression Profile of Diabetes-Related Genes Associated with Leukocyte Sirtuin 1 Overexpression in Gestational Diabetes.

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.

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer.

The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric Curcuma longa, has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.

Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer.

BACKGROUND: The incidence of both type 2 diabetes (T2DM) and cancer is increasing worldwide, making these diseases a global health problem along with increasing healthcare expenditures. The current therapeutic approaches for treating these multifactorial diseases are far from satisfactory. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT and, moreover, discusses several future directions of research regarding MLT application as potential therapeutic agent. METHODS: Critical literature analysis in PubMed central combined with personal expertise. RESULTS: Numerous in vitro and in vivo studies have revealed that MLT possesses a number of antidiabetic health benefits by diminishing hyperglycemia, insulin resistance, oxidative stress, and inflammation through modulating various intracellular signaling pathways or other targets involved in the pathophysiology of this disease. Mounting evidence also indicates that MLT exhibits multi-targeted anticancer effects in numerous human malignancies, mainly resulting from its ability to modulate several signal transduction pathways associated with cell survival, proliferation, and apoptosis. Furthermore, beneficial synergistic action of MLT with chemotherapy and radiotherapy has also been observed. Importantly, no adverse outcomes have been found from the clinical use of MLT, which highlights its therapeutic usefulness, either alone or in combination with other conventional therapies, in cancer treatment. CONCLUSION: The findings described in this review suggest that MLT may confer potential benefits to human health, particularly in respect to T2DM and cancer.

Comparison of leukocyte IL6 expression in patients with gestational diabetes mellitus (GDM) diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria.

INTRODUCTION: Controversial data exist in the literature regarding relationship of IL-6 with gestational diabetes mellitus (GDM), partially resulting from different criteria for GDM classification. In the present study, we revised this linkage by investigating leukocyte IL6 expression and its associations with clinical characteristics of patients diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria. MATERIAL AND METHODS: A total of 145 pregnant women underwent 75 g two-hour OGTT, and GDM was diagnosed according to PDA 2011 criteria (GDM/PDA 2011 group; n = 113) and PDA 2014 criteria (GDM/PDA 2014 group; n = 104). IL6 gene expression was investigated in leukocytes of all participants by using real-time PCR method. RESULTS: Compared to respective NGT control groups, the GDM/PDA 2011 group exhibited higher FPG, two-hour OGTT, HbA1C and IL6 expression and lower HDL-C, whereas the GDM/PDA 2014 group had higher FPG, one-hour and two-hour OGTT, HbA1C and HOMA-IR, lower QUICKI-IS, and unchanged IL6 expression. No differences in metabolic parameters and IL6 expression were found between the two GDM groups. Compared to the NGT/PDA 2011 group, the NGT/PDA 2014 group had lower one-hour and higher two-hour OGTT and increased IL6 expression. With PDA 2014 criteria, IL6 expression correlated positively with two-hour OGTT in both NGT and GDM groups as well as with LDL-C in NGT group, and negatively with HDL-C in NGT group. With PDA 2011 criteria, no associations were evident in NGT and GDM groups. Nevertheless, significant positive correlation of IL6 mRNA with two-hour OGTT was observed in the entire study group. CONCLUSIONS: Differences in metabolic phenotypes as well as gene expression and correlation data between GDM and NGT groups, categorised based on PDA 2011 and 2014 criteria, are related to changes in gestational glucose tolerance status resulting from using PDA 2014 criteria. Moreover, our findings support the hypothesis that IL-6 is associated with glucose metabolism during pregnancy.

Increased expression of immune-related genes in leukocytes of patients with diagnosed gestational diabetes mellitus (GDM).

Compelling evidence indicates that the immune system is linked to metabolism in gestational diabetes mellitus (GDM), but factors participating in these processes still are awaiting identification. Inducible nitric oxide synthase, encoded by the NOS2 gene, and surfactant protein D, encoded by the SFTPD gene, have been implicated in diabetes. We investigated NOS2 and SFTPD mRNA levels in leukocytes obtained from 125 pregnant women with (n = 87) or without (control group; n = 38) GDM, and, in turn, correlated their expression with clinical parameters of subjects. Leukocytes were isolated from the blood of pregnant women and NOS2 and SFTPD expression in these cells was determined by quantitative real time PCR (qRT-PCR). Univariate correlation analyses were performed to assess an association between leukocyte NOS2 and SFTPD expression and clinical characteristics of patients. qRT-PCR experiments disclosed significantly increased leukocyte NOS2 and SFTPD mRNA levels in hyperglycemic GDM patients (P < 0.05). In the entire study group, there were significant positive associations of leukocyte NOS2 and SFTPD mRNAs with C-reactive protein. Additionally, transcript level of SFTPD also correlated positively with fasting glycemia and insulin resistance. This study demonstrates that an impaired glucose metabolism in GDM may be predominant predictor of leukocyte NOS2 and SFTPD overexpression in diabetic patients. Furthermore, alterations in the expression of these genes are associated with glucose metabolism dysfunction and/or inflammation during pregnancy. In addition, these findings support the utilization of leukocytes as good experimental model to study a relationship between immune-related genes and metabolic changes in women with GDM, as well as to assess the potential mechanisms underlying these alterations.

Gestational diabetes mellitus is associated with increased leukocyte peroxisome proliferator-activated receptor γ expression.

INTRODUCTION: Peroxisome 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 METHODS: Leukocytes 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. RESULTS: Leukocyte 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). CONCLUSIONS: The 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.

Family, anthropometric and biochemical factors affecting birth weight of infants born to GDM women.

OBJECTIVES: Gestational diabetes mellitus (GDM) affects up to 25% of all pregnancies worldwide. If untreated, GDM leads to increased complication rates both, in the mother and the fetus. Early diagnosis and adequate management of GDM are essential to avoid macrosomia. Nonetheless, neonates born to GDM mothers often have high birth weight. The aim of the study was to evaluate selected factors which can affect neonatal birth weight. MATERIAL AND METHODS: The study included 152 women with GDM and 58 healthy pregnant controls. Anthropometric data of both parents, maternal biochemical parameters, and neonatal birth weight were collected. RESULTS: The independent factors influencing neonatal birth weight were pregnancy duration, maternal smoking, as well as birth weight and current weight of the father. The risk of delivering a large for gestational age (LGA) infant increases with the diagnosis of GDM, higher maternal pre-pregnancy weight, and higher fasting glycaemia. No correlation between maternal fasting glycaemia, HbA1c, 1,5-AG, lipids and neonatal birth weight was found. CONCLUSIONS: Risk factors for LGA include gestational diabetes, high maternal pre-pregnancy weight, and current body weight of the father. Neither HbA1c nor 1,5-AG were reliable predictors of neonatal birth weight and occurrence of LGA in the studied population.

Dual stimulus-dependent effect of Oenothera paradoxa extract on the respiratory burst in human leukocytes: suppressing for Escherichia coli and phorbol myristate acetate and stimulating for formyl-methionyl-leucyl-phenylalanine.

Although a growing body of evidence suggests that plant polyphenols can modulate human immune responses, their simultaneous action on monocyte and neutrophil oxidative burst is currently poorly understood. Based on the hypothesis that various polyphenols contained in plant extracts might affect the oxidative burst of phagocytes, we evaluated the effects of ethanolic O. paradoxa extract polyphenols on monocyte and neutrophil oxidative burst in vitro activated by different stimuli, including opsonized bacteria E. coli, phorbol 12-myristate 13-acetate (PMA), and formyl-methionyl-leucyl-phenylalanine (fMLP). Samples were analyzed by the dihydrorhodamine flow cytometry assay. Our results showed that the extract repressed significantly and dose-dependently reactive oxygen species production in both cell types stimulated with E. coli and PMA (P < 0.05) and its inhibitory efficiency was stimulus- and cell-type-dependent. Interestingly, there was significant stimulatory effect of the extract on bursting phagocytes induced by fMLP (P < 0.05). Additionally, several flavonoids and phenolic compounds as well as penta-galloyl-ß-(D)-glucose (PGG), the representative of hydrolyzable tannins, were identified in the 60% extract by high-performance liquid chromatography (HPLC) coupled to electrospray ionization in negative ion mode. In summary, the ethanolic O. paradoxa extract, rich in flavonoids and phenolic compounds, exhibits dual stimulus-dependent effect on the respiratory burst in human leukocytes; hence, it might affect immune responses in humans.

The relationship between adipose tissue-derived hormones and gestational diabetes mellitus (GDM).

Gestational diabetes mellitus (GDM) is defined as a glucose intolerance of varying severity with onset or first recognition during pregnancy. The prevalence of GDM is growing rapidly worldwide, resulting in numerous and serious complications for both mother and foetus. Two major metabolic disorders, insulin resistance and ß cells dysfunction, are currently linked to the pathogenesis of GDM, although the cellular mechanisms involved in the development of GDM are not yet completely understood. Increasing evidence from clinical and experimental studies indicates that adipose tissue dysfunction, characterised by abnormal production of adipokines, is an essential factor linked to insulin resistance and GDM. To date, several adipose tissue-derived hormones have been identified, including leptin, adiponectin, resistin, visfatin, apelin, retinol-binding protein 4 (RBP-4), vaspin, and omentin. The relationship of leptin and adiponectin to insulin resistance in GDM is relatively well documented, but the molecular mechanisms by which these hormones affect insulin resistance are not yet fully known. The other aforementioned adipokines appear to be also important players in the pathophysiology of GDM, although their precise function in this complex process remains to be established. The aim of this article is to review the literature concerning the relationship between the above-mentioned adipokines and GDM, and to clarify their role in the pathophysiology of GDM.

The association of leukocyte phosphatidylinositol 3-kinase delta overexpression with gestational diabetes mellitus (GDM).

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.

The elevated gene expression level of the A(2B) adenosine receptor is associated with hyperglycemia in women with gestational diabetes mellitus.

BACKGROUND: Adenosine receptors denoted by A1 , A2A , A2B , and A3 and encoded by ADORA1, ADORA2A, ADORA2B, and ADORA3 genes, respectively, are adenosine-activated G-protein-coupled receptors that play an important role in obesity and type 2 diabetes mellitus. However, little is known about their significance in gestational diabetes mellitus (GDM). The purpose of this study was to investigate whether there are changes in leukocyte AR expression in GDM patients and whether these alterations are linked to well-known diabetic genes. METHODS: Leukocytes were isolated from the blood of normal glucose tolerant (NGT; n = 35) and GDM (n = 82) pregnant women, and expression of ARs was determined by a semi-quantitative polymerase chain reaction (PCR). Univariate correlation analysis was performed to investigate associations between expression of ARs and anthropometric and metabolic parameters of patients. Furthermore, the identification of diabetic genes linked to significantly differentiated leukocyte adenosine receptors expression in GDM women was also carried out with the use of the human diabetes RT(2) profiler PCR arrays. RESULTS: ADORA2B mRNA expression was significantly higher in GDM versus NGT pregnant women (p < 0.05), and positively correlated with the glucose level at 1-h 75-g oral glucose tolerance test (OGTT; r = 0.21, p = 0.044). Nineteen diabetic genes linked to leukocyte ADORA2B overexpression associated with hyperglycemia in GDM women were also identified. CONCLUSIONS: 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 role of peroxisome proliferator-activated receptors γ (PPARγ) in obesity and insulin resistance]. / Rola receptorów aktywowanych przez proliferatory peroksysomów γ (PPARγ) w otylosci i insulinoopornosci.

Obesity, defined as abnormal or excessive fat accumulation, is currently believed to be a major public health problem worldwide. Over the past 20 years, the prevalence of obesity has increased rapidly in both industrialized and developing countries, resulting in a considerably increased risk of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Although the exact pathophysiological mechanisms underlying these diseases remain unclear, clinical and epidemiological studies support the existence of a relationship between obesity-induced inflammation and insulin resistance linked with the development and progression of metabolic diseases. Adipokines, produced and released by adipose tissue, are considered as factors linking obesity-induced inflammation with insulin resistance, and their regulation through peroxisome proliferator-activated receptors γ (PPARγ also known as NR1C3) is essential in these processes. PPARγ are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily which directly regulate the expression of a large number of genes involved in adipocyte differentiation, lipid and carbohydrate metabolism as well as adipokine synthesis; thereby they are implicated in various metabolic disorders, including obesity, insulin resistance, dyslipidemia, and hypertension. This review summarizes the current literature on a functional relationship of PPARγ with obesity and insulin resistance and, moreover, highlights the significance of synthetic ligands of these receptors in the mentioned metabolic disorders.

Adenosine receptors expression is elevated in leukocytes of gestational diabetes mellitus (GDM) subjects--a preliminary study.

INTRODUCTION: Adenosine receptors (ARs), belonging to the G-protein-coupled receptors (GPCRs), are present in the majority of human cells and tissues. Depending on their biochemical and pharmacologic properties, four subtypes of ARs (i.e. A1, A(2A), A(2B), and A3) have been distinguished. Currently, these receptors are attractive molecular targets for pharmacological interventions in various diseases, including diabetes. The literature published to date has shown an altered expression of ARs in several types of cells under diabetic conditions. However, there has been no publication devoted to the investigation of ARs expression in leukocytes of subjects with gestational diabetes mellitus (GDM). Therefore, this study was aimed to determine the expression level of AR subtypes in leukocytes of GDM patients and its relationship to anthropometric and biochemical parameters. MATERIAL AND METHODS: Gene expression of four AR subtypes in leukocytes of both healthy (n = 34) and GDM (n = 67) subjects in the third trimester of pregnancy (from 24 to 33 weeks) was investigated. Multiple regression analyses were used to assess the association between the expression level of ARs and both anthropometric and biochemical parameters. RESULTS: Statistically significant (p < 0.05) higher levels of A(2A) and A(2B) mRNAs were observed in leukocytes of the GDM subjects compared to the control group. There was a positive correlation of A(2B) mRNA level with glucose concentration at 120 min of oral glucose tolerance test (OGTT) (r = 0.24, p = 0.041). CONCLUSIONS: Overexpression of A2BAR in leukocytes of the GDM subjects and, additionally, the existence of a relationship between its elevated expression level in these cells and abnormal values of glucose concentration at 120 min of OGTT for GDM, suggest that this subtype might be involved in the pathogenesis of GDM.

The effect of divalent cations on the catalytic activity of the human plasma 3'-exonuclease.

The 3'-exonuclease from human plasma is a soluble form of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) (EC 3.1.4.1/EC 3.6.1.9). Here, the possibility of divalent cation influence for the 3'-exonuclease activity was investigated using the phosphorothioate congener of oligonucleotide containing all phosphorothioate internucleotide linkages of the [R(P)]-configuration ([R(P)-PS]-d[T(12)]) as the substrate for this enzyme. It was found that the 3'-exonuclease is a metalloenzyme, i.e. its phosphodiesterase activity was completely abolished at 0.8 mM concentration EDTA and, in turn, it was restored in the presence of Mg(2+) or Mn(2+) ions. In addition, Mg(2+) can be replaced effectively by Ca(2+), Mn(2+), or Co(2+), but not by Ni(2+) and Cd(2+) during the hydrolysis of the phosphorothioate substrate in human plasma. In addition, the mechanism is postulated, by which a single internucleotide phosphorothioate bond of the S(P)-configuration at the 3'-end of unmodified phosphodiesters (PO-oligos), or their phosporothioate analogs (PS-oligos) protects these compounds against degradation in blood.