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.

Procoagulant Disorders in Patients with Newly Diagnosed Pancreatic Adenocarcinoma.

Background and objectives: Cancer coagulopathy is thought to be partially due to the up-regulation of tissue factor (TF), thrombin-antithrombin complex (TAT) and soluble P-selectin (sP-selectin). The purpose of this study was to evaluate the clinical significance of TF, TAT and sP-selectin in patients with pancreatic cancer. Materials and methods: The study included 93 subjects: 73 newly diagnosed patients with pancreatic adenocarcinoma (42 with stage I-III and 31 with metastatic cancer (stage IV)) and a control group of 20 healthy subjects. Analyzed patients were hospitalized in the Department of Digestive Tract Diseases, Medical University of Lodz or in the Department of Digestive Tract Surgery, Silesian University, Katowice, Poland. All laboratory parameters were measured using ELISA procedures. Results: TF plasma levels were detectable in all patients and were significantly higher in metastatic cancer compared to stage I-III patients and the control group (p < 0.05). In patients with pancreatic adenocarcinoma, the median levels of TAT were also elevated compared to the control group. Moreover, patients with metastases had significantly higher TAT concentration compared to the I-III cancer group. On the other hand, only the metastatic patients group showed significantly higher plasma sP-selectin levels compared to the controls (p = 0.009), whereas there was no difference between localized and metastatic cancer patients. Conclusions: The coagulation disorders are present in the majority of patients with pancreatic adenocarcinoma already at the diagnosis stage and reflect cancer progression and spread.

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.

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.

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.

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 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.

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.

Recurrent hypoglycaemia in a type 2 diabetes patient - diagnostic difficulties.

Hypoglycaemia is the most frequent acute complication of diabetes, regardless of the type of diabetes and the treatment method. Hormonally active tumours of the pancreas, insulinomas, which belong to digestive tract neuroendocrine tumours, constitute one of the less frequent causes of hypoglycaemia. This paper presents a case of a 60-year-old type 2 diabetes patient with recurrent hypoglycaemic events, in whom an insulin-secreting hepatic neuroendocrine tumour was diagnosed. We suggest performing a diagnostic workup taking into consideration insulinoma in patients with diabetes who experience frequent otherwise inexplicable hypoglycaemic events, particularly when they recur despite decreased dose or discontinuation of hypoglycaemic agents.

Profile of peripheral blood neutrophil cytokines in diabetes type 1 pregnant women and its correlation with selected parameters in the newborns.

PROBLEM: Interleukin (IL)-12, IL-10, tumor necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 alter as pregnancy progresses, implying continuous immune regulation associated with the maintenance of pregnancy. We aimed to evaluate the peripheral blood neutrophil-derived production of these cytokines in the course of pregnancy complicated by type 1 diabetes. METHOD: of study These parameters were measured in samples from healthy non-pregnant (C), diabetic non-pregnant (D), healthy pregnant (P) and pregnant diabetic (PD) women. RESULTS: Neutrophil-derived secretion of TNF-alpha and IL-12 increased along with progression of pregnancy in PD and P groups. The concentration of IL-10 from lipopolysaccharide (LPS)-stimulated neutrophils increased during the course of uncomplicated pregnancy but decreased in diabetic pregnancy. Concentration of IL-8 decreased with the advancing gestational age in P and PD groups. LPS-stimulated neutrophil-derived IL-6 concentration increased only in PD patients. CONCLUSION: Our results show that diabetes creates pro-inflammatory environment thus potentially influencing the outcome of pregnancy. We conclude that neutrophil-derived cytokine production could contribute to the complications seen in pregnant women with type 1 diabetes.

Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus.

BACKGROUND AND AIM: Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy. SUBJECTS AND METHODS: The study group (GDM) consisted of 13 gestational women with diabetes mellitus in whom GDM was diagnosed according to the World Health Organization criteria (75-g oral glucose tolerance test (OGTT)). The control group consisted of 13 pregnant women with normal glucose tolerance (NGT), matched according to age and duration of pregnancy. For all patients, plasma glucose, insulin, GLP-1 and GIP concentrations were evaluated after an OGTT, i.e. at 0, 30, 60, 90 and 120 min after glucose load. RESULTS: Fasting plasma glucose concentrations were similar in both groups, but the 0-120 min area under the curve (AUC) for glucose was significantly greater in the GDM group than in the NGT group (p < 0.0005). Fasting insulin concentration was higher (p < 0.05) and the 2-h insulin response (AUCtotal) was significantly greater (p = 0.01) in the GDM group than in the NGT group. Insulin resistance was significantly higher in GDM compared with control women (homeostasis model assessment, p = 0.003). Fasting GLP-1 concentrations were higher in the GDM group (p = 0.05), but no differences were observed in GLP-1 response (AUC) between the studied groups. Fasting and stimulated GIP response did not differ between groups at any time of the study (p > 0.05). Positive correlations were observed between fasting GLP-1 and insulin concentration (r = 0.56, p < 0.004) and between fasting GLP-1 and insulin resistance (r = 0.43, p < 0.029). CONCLUSION: An impaired secretion of GLP-1 and GIP does not seem to play a major role in the pathogenesis of GDM.