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.

Targeted and untargeted metabolomic approach for GDM diagnosis.

Gestational diabetes mellitus (GDM) is a disorder which manifests itself for the first time during pregnancy and is mainly connected with glucose metabolism. It is also known that fatty acid profile changes in erythrocyte membranes and plasma could be associated with obesity and insulin resistance. These factors can lead to the development of diabetes. In the reported study, we applied the untargeted analysis of plasma in GDM against standard glucose-tolerant (NGT) women to identify the differences in metabolomic profiles between those groups. We found higher levels of 2-hydroxybutyric and 3-hydroxybutyric acids. Both secondary metabolites are associated with impaired glucose metabolism. However, they are products of different metabolic pathways. Additionally, we applied lipidomic profiling using gas chromatography to examine the fatty acid composition of cholesteryl esters in the plasma of GDM patients. Among the 14 measured fatty acids characterizing the representative plasma lipidomic cluster, myristic, oleic, arachidonic, and α-linoleic acids revealed statistically significant changes. Concentrations of both myristic acid, one of the saturated fatty acids (SFAs), and oleic acid, which belong to monounsaturated fatty acids (MUFAs), tend to decrease in GDM patients. In the case of polyunsaturated fatty acids (PUFAs), some of them tend to increase (e.g., arachidonic), and some of them tend to decrease (e.g., α-linolenic). Based on our results, we postulate the importance of hydroxybutyric acid derivatives, cholesteryl ester composition, and the oleic acid diminution in the pathophysiology of GDM. There are some evidence suggests that the oleic acid can have the protective role in diabetes onset. However, metabolic alterations that lead to the onset of GDM are complex; therefore, further studies are needed to confirm our observations.

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.

Metformin administration during pregnancy - current insight.

The main mechanism of gestational diabetes mellitus (GDM) is insulin resistance, therefore using metformin as a medicine reducing insulin resistance appears to be promising. Currently, the majority of medical associations do not recommend using metformin during pregnancy as the first-line of therapy when the diet regimen is insufficient for glycaemic control. However, they do allow its administration if there is no possibility of insulin treatment. There is some evidence which suggests that using metformin during pregnancy is not related to an increased risk of obstetric complications during delivery and that its influence on the foetus can be beneficial. Since metformin crosses the placenta, the major argument for cautious use of this drug are the potential long-term effects of the treatment for the child and its development in later life. In this article, the authors attempt to discuss the use of metformin during pregnancy and the safety of the treatment in the light of current studies and recommendations.

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.

Associations of Arginine with Gestational Diabetes Mellitus in a Follow-Up Study.

In the reported study we applied the targeted metabolomic profiling employing high pressure liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-MS/MS) to understand the pathophysiology of gestational diabetes mellitus (GDM), early identification of women who are at risk of developing GDM, and the differences in recovery postpartum between these women and normoglycemic women. We profiled the peripheral blood from patients during the second trimester of pregnancy and three months, and one year postpartum. In the GDM group Arg, Gln, His, Met, Phe and Ser were downregulated with statistical significance in comparison to normoglycemic (NGT) women. From the analysis of the association of all amino acid profiles of GDM and NGT women, several statistical models predicting diabetic status were formulated and compared with the literature, with the arginine-based model as the most promising of the screened ones (area under the curve (AUC) = 0.749). Our research results have shed light on the critical role of arginine in the development of GDM and may help in precisely distinguishing between GDM and NGT and earlier detection of GDM but also in predicting women with the increased type 2 diabetes mellitus (T2DM) risk.

The Impact of Pregnancy and Parity on Type 1 Diabetes Complications.

BACKGROUND: The potential influence of pregnancy and parity on the risk of chronic diabetic complications is a matter of great concern and constant discussion. This aspect seems relevant and should be the subject of thorough discussion with the woman planning childbirth. INTRODUCTION: Current data concerning the impact of pregnancy and parity covers primarily retinopathy and nephropathy, while the aspects of neuropathy and macrovascular complications are unsatisfactorily documented. Majority of studies focus on single complication only, while the number of papers assessing this problem in a complex setting is limited. The available body of evidence concerns mainly the short-term impact of pregnancy on diabetic chronic complications while the data concerning the longer perspective are scarce. Moreover, the results found in the available literature are conflicting. The aim of the study was to summarize all available data concerning the longer impact of parity on the chronic complications in the women with type 1 diabetes. METHODS: PubMed database has been searched between October 2013 and September 2018 and all relevant papers were selected. This review summarizes data on the impact of pregnancy and parity on chronic complications in type 1 diabetic women. RESULTS: Current data assessing this matter in a complex way are limited, and the available results are controversial. It seems however that pregnancy itself may rather influence pre-existing diabetic complication than affect risk of its development. Additionally, evidence suggests that any deleterious changes appearing during pregnancy are transient and tend to remit after delivery. CONCLUSION: It seems that neither pregnancy nor parity affects the risk of diabetic chronic complications in the longer perspective.

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.

Lipid profile changes in erythrocyte membranes of women with diagnosed GDM.

Gestational diabetes mellitus (GDM) is a glucose intolerance that begins or is first recognized during pregnancy. It is currently a growing health problem worldwide affecting from 1% to 14% of all pregnant women depending on racial and ethnic group as well as the diagnostic and screening criteria. Our preliminary study aimed at investigating the erythrocyte membrane fatty acid profiles of pregnant women, in particular with diagnosed with gestational diabetes mellitus (GDM), and with normal glucose tolerant (NGT) pregnant women as a control group. The study group comprised 43 pregnant women, 32 of whom were diagnosed with GDM according to the WHO criteria, and 11 with normal glucose tolerance. The erythrocyte membrane phospholipids were obtained according to the Folch extraction procedure. Fatty acids (FA) were analyzed by gas chromatography (GC) as the corresponding fatty acid methyl esters (FAME). A cluster of 14 fatty acids identified contained >98% of the recognized peaks in the GC analysis. The analysis of fatty acids from erythrocytes revealed important differences between GDM and NGT women in the third trimester, and the results were correlated with biochemical data. Among the 14 measured FA representing the membrane lipidomic profile, the levels of three saturated FA (myristic, palmitic, stearic acids) tended to decrease in GDM patients, with the percentage content of stearic acid significantly changed. The relative content of monounsaturated fatty acids (MUFA) tended to increase, in particular the oleic acid and vaccenic acid contents were significantly increased in erythrocyte membranes of the GDM group in comparison with the NGT group. The GDM group demonstrated higher sapienic acid levels (+29%) but this change was not statistically significant. This study revealed association between an impaired cis-vaccenic acid concentration in erythrocytes membrane and GDM development. No significant changes of polyunsaturated fatty acids (PUFA) were observed in GDM and NGT erythrocytes. We postulate, basing on the differences between the GDM and NGT lipidomic profiles, that stearic and cis-vaccenic acids can be considered as dual biomarkers of specific SFA-MUFA conversion pathway, involving the coupling of delta-9 desaturase and elongase enzymes. Our results indicate that the SFA-MUFA families may be involved in the pathophysiology of metabolic diseases such as GDM, but the further studies are needed to confirm our hypothesis. In conclusion, the erythrocyte membranes of GDM women undergo remodeling resulting in abnormal fatty acid profiles, which are reflection of the long-term status of organism and can have great impact on both the mother and her offspring.

Parity does not affect diabetes complications in women with type 1 diabetes.

INTRODUCTION: The problem concerning the impact of pregnancy on diabetic complications is a matter for discussion as there is some evidence suggesting that pregnancy may trigger development or progression of diabetic chronic complications. However, currently available data concerning this issue is still controversial. OBJECTIVE: The aim of the study was to evaluate the impact of obstetric history on the development of chronic microangiopatic and macroangiopatic complications in type 1 diabetic women. MATERIAL AND METHODS: The retrospective study comprised 226 white Caucasian type 1 diabetic women, including 190 parous and 36 nulliparous women. Anthropometric data, information concerning the course of the disease, including metabolic control and chronic complications, together with obstetric history, were registered. RESULTS: Parous women were older (p<0.001), but did not differ significantly regarding metabolic control in the course of the disease (p>0.05) and diabetes duration (p>0.05) from nulliparous subjects. There were no significant differences in the incidence (p>0.05) nor onset (p>0.05) of chronic diabetes complications between the groups. The number of deliveries did not correlate with either the incidence nor the onset of chronic complications. Longer DM duration at the moment of first delivery was related to the higher incidence of retinopathy (p<0.01), nephropathy (p<0.05) and neuropathy (p<0.001). CONCLUSIONS: The incidence of chronic diabetic complications does not differ between parous women and the subjects that were never pregnant, and is not related to the number of pregnancies.

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.

Obstetric results of the multicenter, nationwide, scientific-educational program for pregnant women with gestational diabetes mellitus (GDM).

OBJECTIVES: The aim of the present study was to compare the obstetric results in women with GDM in a Polish population based on the criterion for the diagnosis of GDM. MATERIAL AND METHODS: The study was a questionnaire study covering the data of 2853 patients with GDM treated in centers nationwide in the years 2011-2013. The principles of self-control, glycemic targets and treatment were based on the then-current PDA guidelines. Analysis of the collected data included an assessment of obstetric results based on the diagnostic criteria for GDM. Depending on the result of the glucose tolerance test, the patients were divided into subgroups. RESULTS: 6.28% of births were preterm, and 47% were caesarean. A significant difference was observed in the number of preterm births between a subgroups: PDA(+) meeting only criterion 0' and a PDA(+)meeting only criterion 120' (16.67% vs. 5.83%); and between WHO(+) subgroup meeting only criterion 0' with respect to the subgroup PDA(+) meeting only criterion 0' (4.69% vs. 16.67%). Significant difference was found in the frequency of LGA between the WHO(-)PDA(+) and WHO(+)PDA(-) subgroups (6,57% vs. 14.93%), and between the WHO(-)PDA(+) group and a group of isolated hyperglycemia in 60'(6.57% vs. 12.5%). Also a significant positive correlation was observed between birth weight, the occurrence of LGA and macrosomia, and maternal weight and BMI before pregnancy. CONCLUSIONS: The results of the analysis indicate the new criteria have greater sensitivity in the prediction of prematurity and birth weight. However, it cannot be ruled out that the final results were affected by the therapeutic intervention employed.

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.

The impact of having siblings - analysis of "hygiene theory" of chronic diseases in patients with type 1 diabetes in population of the Lódz region Hygiene theory and type 1 diabetes.

INTRODUCTION: In the recent years there has been a significant increase in the incidence of the type 1 diabetes mellitus. Therefore, numerous studies are underway to evaluate the possible factors underlying this trend. Some studies suggest that better sanitary conditions and lack of contact with microorganisms might be important, thus increasing the risk of disease in firstborns. Moreover, siblings could play an important role in the transmission of pathogens, which, by stimulating the immune system, may prevent the development of atopic and autoimmune diseases including such as type 1 diabetes. Current data, however, are still inconclusive. PURPOSE: The aim of the study was to evaluate the effect of having siblings on the incidence of type 1 diabetes among children and adults. MATERIALS AND METHODS: A group of 469 patients with type 1 diabetes was selected. The study population was composed of 245 adults and 224 youth patients. Information from Outpatient Diabetologic Departments database was gathered. Data such as age at the diagnosis of diabetes, sex of siblings, number and birth order were analyzed. RESULTS: In the studied population, 4.5% were only children, and 30.3% patients came from large families. In the group of type 1 diabetic patients 39.7% were firstborns and this proportion was comparable to the group of healthy subject. The highest proportion of firstborns was noted in the group that was diagnosed after 18 years of age (45,1%) compared to the group that was diagnosed between 10 and 14 (29,1%) (p<0.05). Type 1 diabetic patients that were not firstborns much more often had older siblings of the opposite sex than the same sex. CONCLUSIONS: he firstborns in the population of type 1 diabetes from the Lódz region did not outnumber the healthy subjects. Significantly higher proportion of firstborns in the group that was diagnosed after 18 years of age compared to the group that was diagnosed between 10 an 14 years was noted.

Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Shows that Fetal Heart Rate Correlates with Maternal Glycemia.

BACKGROUND: Much evidence has shown that pregnancies in women with preexisting diabetes are affected by an increased risk of maternal and fetal adverse outcomes, probably linked to poor glycemic control. Despite great progress in medical care, the rate of stillbirths remains much higher in diabetes patients than in the general population. Recent technological advances in the field of glucose monitoring and noninvasive fetal heart rate monitoring made it possible to observe the fetal-maternal dependencies in a continuous manner. SUBJECTS AND METHODS: Fourteen type 1 diabetes patients were involved into the study and fitted with a blinded continuous glucose monitoring (CGM) recorder. Fetal electrocardiogram data were recorded using the Monica AN24™ device (Monica Healthcare Ltd., Nottingham, United Kingdom), the recordings of which were matched with CGM data. Statistical analysis was performed using a generalized mixed-effect logistic regression to account for individual factors. RESULTS: The mean number of paired data points per patient was 254±106, representing an observation period of 21.2±8.8 h. Mean glycemia equaled 5.64±0.68 mmol/L, and mean fetal heart rate was 135±6 beats/min. Higher glycemia correlated with fetal heart rate (R=0.32; P<0.0001) and was associated with higher odds of the fetus developing small accelerations (odds ratio=1.05; 95% confidence interval, 1.00-1.10; P=0.04). CONCLUSIONS: Elevated maternal glycemia of mothers with diabetes is associated with accelerations of fetal heart rate.

Gene polymorphisms and antigen levels of matrix metalloproteinase-1 in type 2 diabetes mellitus coexisting with coronary heart disease.

BACKGROUND AND AIM: Diabetes mellitus is a major risk factor for coronary heart disease (CHD). Matrix metalloproteinases (MMPs) can play a pivotal role in the remodelling of extracellular matrix associated with the development of atherosclerosis. Therefore, the aim of the study was to compare the distribution of genotypes and frequency of alleles of two polymorphisms of the MMP-1 gene promoter, an A/G substitution and a 1G/2G insertion, in correlation with antigen levels of matrix metalloproteinase-1 (MMP-1) in type 2 diabetic patients with or without CHD as well as individuals with normal glucose level without CHD. METHODS: Genotypes of 115 patients with type 2 diabetes mellitus (T2DM) and a subpopulation of 66 patients with coexisting CHD as well as 120 non-diabetic control subjects were determined by PCR-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: We demonstrated that antigen levels of MMP-1 in the serum of diabetic patients were significantly higher than those of individuals with normal glucose metabolism (p <0.05). Elevated levels of MMP-1 positively correlated with CHD occurrence in T2DM patients (p <0.01). The distribution of genotypes revealed higher frequency of the 2G/2G polymorphism variant in diabetic patients with CHD [OR 5.76, 95% CI (1.24; 26.87)], thus suggesting its strong association with high level of MMP-1. In T2DM patients with coexisting CHD, a higher frequency of the 2G allele of 1G/2G [OR 1.74, CI 95% (1.01; 2.99)] and the G allele of A/G polymorphism [OR 2.15, 95% CI (1.22; 3.80)] was also found. CONCLUSION: Our results suggest that type 2 diabetes mellitus is linked with elevated blood level of MMP-1, and polymorphisms of the promoter region of its gene might be associated with CHD.

Effect of gliclazide modified release on adiponectin, interleukin-6, and tumor necrosis factor-alpha plasma levels in individuals with type 2 diabetes mellitus.

OBJECTIVE: The aim of the study was to evaluate the effect of gliclazide modified release (MR) treatment on adiponectin, interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) plasma concentrations in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: 24 randomly selected type 2 diabetic patients, aged 61.2 +/- 15.4 years, with poorly controlled glucose level (mean glycated hemoglobin [HbA1c] 7.6 +/- 1.1%) despite treatment with diet and/or oral hypoglycemic agents, were included in the study. All of the patients, after a 2-week run-in period, were given gliclazide MR for 12 weeks. At baseline, and after gliclazide MR treatment, HbA(1c) and plasma concentrations of IL-6, TNF-alpha, and adiponectin were measured. RESULTS: Gliclazide MR treatment produced significant reductions in fasting plasma glucose (from 7.6 +/- 1.4 to 6.6 +/- 1.2 mmol/L, p < 0.01), HbA(1c) (from 7.6 +/- 1.1 to 6.9 +/- 0.8%, p < 0.01), and plasma IL-6 concentrations (from 2.5 +/- 1.8 to 1.8 +/- 1.2 pg/mL, p < 0.05). A significant increase in plasma adiponectin level was noted (from 6.4 +/- 3.3 to 7.6 +/- 4.4 mug/mL, p < 0.05). Plasma TNF-alpha concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) decreased after treatment, but these changes did not reach statistical significance. CONCLUSIONS: Gliclazide MR improves glycemic control and, in addition, has a positive influence on the plasma level of some inflammatory markers and adiponectin. Increased plasma adiponectin and decreased plasma IL-6, and TNF-alpha levels may explain, at least in part, the anti-atherogenic action of this drug reported elsewhere.

[Inflammatory markers and adiponectin plasma level in patients with type 2 diabetes]. / Stezenie markerów zapalenia i adyponektyny w surowicy u chorych na cukrzyce typu 2.

INTRODUCTION: In patients with carbohydrate or lipid disturbances higher inflammatory markers levels and lower adiponectin levels were observed. These observations suggest the potential role of those markers in the pathogenesis of diabetes, obesity and atherosclerosis. INVESTIGATED GROUP AND METHODS: 25 type 2 diabetic patients (group A) and 15 patients without diabetes (group B) were included into the study. Glycated haemoglobin (HbAlc), total cholesterol and triglycerides, interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha) and adiponectin levels were measured in blood samples. Fasting plasma glucose and fasting plasma insulin were measured to calculate index of insulin resistance (homeostasis model assessment--IR/HOMA-IR/). RESULTS: Mean adiponectin level was significantly lower in patients with type 2 diabetes than in control patients (7,4 microg/ml vs 12,3 microg/ml; p<0,05). Blood levels of fasting insulin, IL-6, TNFalpha and HOMA-IR index were higher in people with diabetes than in control subjects but the differences were not statistically significant. No significant correlations were observed between adiponectin and inflammatory markers level and total cholesterol, triglyceride, HOMA-IR level and blood pressure. CONCLUSIONS: The findings indicate that adiponectin level is lower in patients with type 2 diabetes. We did not manage to confirm significantly elevated inflammatory markers levels in this group of patients.