Morbidity and psychomotor development of offspring of women with gestational diabetes: a 5-year follow-up.

BACKGROUND: Gestational diabetes mellitus (GDM) represents a risk factor for both mother and her offspring in a short-term (perinatal morbidity) and long-term horizon (postpartum diabetes or foetal programming). Several studies focused at peri/postnatal outcomes of GDM mother´s offspring, however relatively few (and none in Czech population) were designed as prospective. The aim of the study was to ascertain eventual anthropometric and developmental abnormalities and/or morbidity in offspring of GDM mothers compare to controls in a 5-year follow-up using a parent-reported parameters related to psychomotor development and common paediatric morbidities including a sub-study of offspring of GDM mothers experiencing adverse perinatal outcomes. METHODS: A 5 year follow up study of offspring of GDM mothers (n = 26) vs those with a normal pregnancy (n = 63). An electronic questionnaire was used to obtain the parameters (such as growth, psychomotor development, vaccination, morbidity history etc.) available to parents from the parent-held infant health record. Data on pregnancy and delivery were available from the previous study. RESULTS: Offspring of GDM mothers had delayed psychomotor development in early childhood, but in 5 years of age they seemed to gradually achieve results of a control group. Children with macrosomia had a higher percentile of weight-for-height and were significantly more frequently ill than those with a normal birth weight. Offspring of obese mothers had worse verbal language skills in early childhood and a higher percentile of weight-for-height. CONCLUSION: Maternal gestational diabetes and obesity can be considered an important determinant of postnatal offspring development and health status, which further advocates for broader implementation of preventive strategies.

Uric Acid and Xanthine Levels in Pregnancy Complicated by Gestational Diabetes Mellitus-The Effect on Adverse Pregnancy Outcomes.

Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological pregnancy and pregnancy complicated by gestational diabetes mellitus (GDM), and to evaluate their impact on adverse perinatal outcomes. A total of 143 participants were included. Analyte levels were determined by HPLC with ultraviolet detection (HPLC-UV). Several single-nucleotide polymorphisms (SNPs) in UA transporters were genotyped using commercial assays. UA levels were higher within GDM women with pre-gestational obesity, those in high-risk groups, and those who required insulin during pregnancy. X levels were higher in the GDM group during pregnancy and also postpartum. Positive correlations between UA and X levels with body mass index (BMI) and glycemia levels were found. Gestational age at delivery was negatively correlated with UA and X levels postpartum. Postpartum X levels were significantly higher in women who underwent caesarean sections. Our data support a possible link between increased UA levels and a high-risk GDM subtype. UA levels were higher among women whose glucose tolerance was severely disturbed. Mid-gestational UA and X levels were not linked to adverse perinatal outcomes.

Deleterious Effect of Advanced CKD on Glyoxalase System Activity not Limited to Diabetes Aetiology.

Methylglyoxal production is increased in diabetes. Methylglyoxal is efficiently detoxified by enzyme glyoxalase 1 (GLO1). The aim was to study the effect of diabetic and CKD milieu on (a) GLO1 gene expression in peripheral blood mononuclear cells; (b) GLO1 protein levels in whole blood; and (c) GLO1 activity in RBCs in vivo in diabetic vs. non-diabetic subjects with normal or slightly reduced vs. considerably reduced renal function (CKD1-2 vs. CKD3-4). A total of 83 subjects were included in the study. Gene expression was measured using real-time PCR, and protein levels were quantified using Western blotting. Erythrocyte GLO1 activity was measured spectrophotometrically. GLO1 gene expression was significantly higher in subjects with CKD1-2 compared to CKD3-4. GLO1 protein level was lower in diabetics than in non-diabetics. GLO1 activity in RBCs differed between the four groups being significantly higher in diabetics with CKD1-2 vs. healthy subjects and vs. nondiabeticsfig with CKD3-4. GLO1 activity was significantly higher in diabetics compared to nondiabetics. In conclusion, both diabetes and CKD affects the glyoxalase system. It appears that CKD in advanced stages has prevailing and suppressive effects compared to hyperglycaemia. CKD decreases GLO1 gene expression and protein levels (together with diabetes) without concomitant changes of GLO1 activity.

Levels of heavy metals and their binding protein metallothionein in type 2 diabetics with kidney disease.

Hyperglycemia, a major metabolic disturbance present in diabetes, promotes oxidative stress. Activation of antioxidant defense is an important mechanism to prevent cell damage. Levels of heavy metals and their binding proteins can contribute to oxidative stress. Antiradical capacity and levels of metallothionein (MT), metals (zinc and copper), and selected antioxidants (bilirubin, cysteine, and glutathione) were determined in 70 type 2 diabetes mellitus (T2DM) subjects and 80 healthy subjects of Caucasian origin. Single nucleotide polymorphism (rs28366003) in MT gene was detected. Antiradical capacity, conjugated bilirubin, and copper were significantly increased in diabetics, whereas MT and glutathione were decreased. Genotype AA of rs28366003 was associated with higher zinc levels in the diabetic group. The studied parameters were not influenced by renal function. This is the first study comprehensively investigating differences in MT and metals relevant to oxidative stress in T2DM. Ascertained differences indicate increased oxidative stress in T2DM accompanied by abnormalities in non-enzymatic antioxidant defense systems.

Metabolic Syndrome Prevalence in Women with Gestational Diabetes Mellitus in the Second Trimester of Gravidity.

Background: Women with gestational diabetes (GDM) have an increased risk of metabolic syndrome (MS) after delivery. MS could precede gravidity. The aims of this study were (i) to detect the prevalence of MS in women at the time of GDM diagnosis, (ii) to detect the prevalence of MS in the subgroup of GDM patients with any form of impaired glucose tolerance after delivery (PGI), and (iii) to determine whether GDM women with MS have a higher risk of peripartal adverse outcomes. Methods: A cross-sectional observational study comprised n = 455 women with GDM. International Diabetes Federation (IDF) criteria for MS definition were modified to the pregnancy situation. Results: MS was detected in 22.6% of GDM patients in those with PGI 40%. The presence of MS in GDM patients was associated with two peripartal outcomes: higher incidence of pathologic Apgar score and macrosomia (p = 0.01 resp. p = 0.0004, chi-square). Conclusions: The presence of MS in GDM patients is a statistically significant risk factor (p = 0.04 chi-square) for PGI. A strong clinical implication of our findings might be to include MS diagnostics within GDM screening using modified MS criteria in the second trimester of pregnancy.

T2DM/CKD genetic risk scores and the progression of diabetic kidney disease in T2DM subjects.

This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.

Transketolase Activity but not Thiamine Membrane Transport Change in Response to Hyperglycaemia and Kidney Dysfunction.

AIM: Pentose phosphate pathway (PPP) with key enzyme transketolase (TKT), represents a potentially 'protective' mechanism in hyperglycaemia. Diabetic kidney disease (DKD), a common complication of both type 1 and type 2 diabetes associated with significant morbidity and mortality, represents the most common cause of chronic kidney disease (CKD). We hypothesized that protective PPP action in diabetes and eventually even more severely in concomitant DKD might be compromised by limited intracellular availability of an active TKT cofactor thiamine diphosphate (TDP). METHODS: Effect of hyperglycaemia on gene expression and protein levels of key PPP loci was studied in vitro using human cell lines relevant to diabetes (HUVEC and HRGEC) and (together with measurement of TKT activity, plasma thiamine and erythrocyte TDP concentration) in vivo in diabetic vs. non-diabetic subjects with comparable renal function (n=83 in total). RESULTS: Hyperglycaemia significantly decreased protein levels of RFC-1, THTR1, THTR2 and TKT (P<0.05) in vitro. Analysis of blood samples from CKD patients with and without diabetes and from controls did not reveal any difference in gene expression and protein levels of thiamine transporters while TKT activity and TDP in erythrocytes gradually increased with decreasing kidney function being highest in patients with CKD3-4 of both diabetic and non-diabetic aetiology. Hyperglycaemia and uremic serum mimicking CKD in diabetes did not affect TKT activity in vitro (P<0.05). CONCLUSION: Both in vitro and human experiments showed decrease or unchanged expression, respectively, of thiamine transporters induced by hyperglycaemia while TKT activity in parallel with intracellular TDP was increased in CKD patients with or without diabetes. Therefore, lack of adaptive increase of thiamine transmembrane transport allowing further increase of TKT activity might contribute to compromised PPP function in diabetes and CKD and to the development of glycotoxic injury.