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.

Genetic risk score is associated with T2DM and diabetes complications risks.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences. METHODS: This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs). RESULTS: The strongest T2DM markers (P < 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P < 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (>0.6) further improved (P < 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P < 0.0001), nephropathy (P < 0.005) and leg ischemia (P < 0.0005). CONCLUSIONS: If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.

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.

The APOE4 allele is associated with a decreased risk of retinopathy in type 2 diabetics.

BACKGROUND: Common polymorphisms within the apolipoprotein E (APOE) gene are suggested to be associated with the development of type 2 diabetes mellitus (T2DM), but the potential association with T2DM complications (nephropathy, neuropathy and retinopathy) remains unclear. We perform the case-control study to analyse the association between the APOE polymorphism and risk of T2DM and to analysed the potential relationship between the APOE and T2DM complications. METHODS AND RESULTS: APOE variants (rs429358 and rs7412) were genotyped by TaqMan assay in T2DM patients (N = 1274; N = 829 with complications including retinopathy, neuropathy and nephropathy status) and with PCR-RFLP in healthy nondiabetic controls (N = 2055). The comparison of subjects with genotypes associated with low plasma cholesterol (APOE2/E2 and APOE2/E3 carriers vs. others) did not show an association with T2DM (OR [95% CI] = 0.88 [0.71-1.08). The differences remained insignificant after adjusting for diabetes duration, sex and BMI. Carriers of at least one APOE4 allele (rs429358) are protected against T2DM related retinopathy (OR [95% CI] = 0.65 [0.42-0.99]. Protection against retinopathy is driven mostly by females (OR [95% CI] = 0.50 [0.25-0.99]); and remains significant (P = 0.044) after adjustment for diabetes duration and BMI. CONCLUSION: Common APOE polymorphism was not associated with T2DM in the Czech population. Yet, APOE4 allele revealed an association with retinopathy. In particular, female T2DM patients with at least one APOE4 allele exhibit lower prevalence of retinopathy in our study subjects.

Development of a New Risk Score for Stratification of Women with Gestational Diabetes Mellitus at High Risk of Persisting Postpartum Glucose Intolerance Using Routinely Assessed Parameters.

The aims of the study were (i) to find predictive factors for early postpartum conversion of gestational diabetes mellitus (GDM) into persisting glucose intolerance (PGI), (ii) to evaluate potential differences in adverse perinatal outcomes in GDM women with and without early postpartum PGI and, finally, (iii) to establish a risk score to predict postpartum PGI. A cross-sectional study comprised 244 GDM patients with known age, parity, positive family history of diabetes, pre-gestational BMI, comorbidities, smoking history, results of mid-trimester oral glucose tolerance test, HbA1c, obstetric complications, neonatal outcomes and mode of delivery. A risk score was calculated using parameters with highest odds ratios in a statistic scoring model. Significant differences between women with and without PGI postpartum were ascertained for mid-trimester fasting plasma glucose (p < 0.001), HbA1c above 42 mmol/mol (p = 0.035), prevalence of obesity (p = 0.007), hypothyroidism, family history of diabetes and smoking. We also observed higher incidence of prolonged and complicated delivery in PGI group (p = 0.04 and 0.007, respectively). In conclusion, this study identified several parameters with predictive potential for early PGI and also adverse peripartal outcomes. We established a simple risk-stratification score for PGI prediction applicable for GDM affected women prior their leaving maternity ward. Yet, given a relatively small sample size as a main limitation of this study, the proposed score should be validated in the larger cohort.

Pathophysiological Implication of Vitamin D in Diabetic Kidney Disease.

BACKGROUND: Vitamin D is a hormone regulating not only calcium and phosphate homeostasis but also, at the same time, exerting many other extraskeletal functions via genomic effects (gene transcription) and probably by non-genomic effects as well. Availability is ensured by dietary intake of its precursors and by de novo production via sunlight. Yet, vitamin D deficiency and insufficiency are very common across the globe and are connected to many pathophysiological states, for example, diabetes mellitus, allergies, autoimmune diseases, pregnancy complications, and recently have also been associated with worse COVID-19 clinical outcomes. SUMMARY: In this review, we summarize current knowledge about vitamin D metabolism in general, its role in diabetes mellitus (mainly type 2) and diabetic complications (mainly diabetic kidney disease), and potential therapeutic perspectives including vitamin D signalling as a druggable target. Key Messages: Vitamin D is not only a vitamin but also a hormone involved in many physiological processes. Its insufficiency or deficiency can lead to many pathological states.

Metformin in Oncology - How Far Is Its Repurposing as an Anticancer Drug?

BACKGROUND: Metformin is the most commonly used antidiabetic drug with a plethora of proven metabolic and cardiovascular beneficial effects and exceptional safety profile. On top of the established metabolic effects, retrospective epidemiologic evidence shows that metformin use is associated with decreased cancer risk and/or improved disease prognosis in diabetic cancer patients on metformin compared to those treated with different antidiabetic drugs. This is a sound argument for eventual repurposing metformin as an adjuvant drug in oncology; however, evidence-based data are currently needed to establish this. Metformin is a biguanide that in the context of type 2 diabetes primarily targets the liver. Metformin inhibits oxidative phosphorylation which leads to the suppression of gluconeogenesis and causes decrease of blood glucose concentration. Mechanisms responsible for metformin anti-neoplastic effect have been investigated extensively, and key events seem to centralize around its ability to induce intracellular energetic stress with subsequent changes of metabolism resulting in cytostatic or cytotoxic action. Large clinical experience with metformin in the treatment of diabetes together with its plausible effects on different cancer cell types initiated a number of clinical trials that tested the hypothesis that metformin might have a beneficial effect in the treatment of cancer. PURPOSE: The aim of this review is to compile recent advances in our understanding of metformin antineoplastic effects and to give a summary of the results of recent clinical trials of metformin for treatment of different cancer types.

AGR2 silencing contributes to metformin-dependent sensitization of colorectal cancer cells to chemotherapy.

There is growing epidemiological evidence indicating an association between diabetes mellitus and the increased incidence of colorectal cancer (CRC). The preferred initial and most widely used pharmacological agent for the treatment of type 2 diabetes is metformin, which in parallel reduces the risk of CRC and improves patient prognosis. AMP-activated protein kinase (AMPK) appears to be tightly associated with the beneficial metabolic effects of metformin, serving as a cellular energy sensor activated in response to a variety of conditions that deplete cellular energy levels. Such conditions include nutrient starvation (particularly glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. The aim of the present study was to determine the effect of metformin on CRC cell lines, with different levels of anterior gradient 2 (AGR2) expression, exposed to 5-fluorouracil (5-FU) and oxaliplatin, alone or in combination with metformin. AGR2 has recently emerged as a factor involved in colon carcinogenesis. In AGR2-knockout cells, markedly higher levels of phosphorylated-AMPK were observed in comparison with control cells transfected with GFP-scrambled guide RNA, which indicated that the presence of AGR2 may interfere with the metformin-dependent activation of AMPK. In addition, metformin in combination with 5-FU and oxaliplatin induced ROS production and attenuated autophagy. This effect was enhanced in AGR2-knockout cells.

Interleukin-1 Gene Variability and Plasma Levels in Czech Patients with Chronic Periodontitis and Diabetes Mellitus.

Recent studies have suggested a bidirectional relationship between chronic periodontitis (CP) and diabetes mellitus (DM). Immunoregulatory factors such as cytokines play an important role in etiopathogenesis of both diseases. The aim of this study was to analyze variability in interleukin-1 (IL-1) gene cluster and IL-1ß plasma levels in patients with CP, DM, and a combination of both diseases. A total of 1016 individuals participating in this case-control study-225 healthy controls, 264 patients with CP, 132 with type 1 diabetes (T1DM), and 395 patients with type 2 diabetes (T2DM)-were genotyped using methods based on polymerase chain reaction for IL-1 gene polymorphisms (IL-1A (-889C/T, rs1800587), IL-1B (+3953C/T, rs1143634), and IL-1RN (gene for IL-1 receptor antagonist, IL-1RA, 86 bp tandem repeats in intron 2)). Levels of IL-1ß were measured by Luminex methods in subgroups of controls, CP, T1DM + CP, and T2DM + CP subjects. Although no significant associations were found in the genotype and allele frequencies of IL-1A (-889C/T), significant differences in the allele frequencies of IL-1B (+3953C/T) were observed between controls and CP patients (P < 0.05). In T1DM patients, IL-1RN ∗ S "short" allele and IL-1RN 12 genotype were significantly less frequent than those in controls (P < 0.01). In haplotype analysis, TTL haplotype decreased the risk of CP development (P < 0.01), whereas CCS and CTL haplotypes (P < 0.01 and P < 0.05) were associated with T1DM. Although IL-1ß levels were measured significantly higher in mononuclear cells after stimulation by mitogens, HSP70, or selected periodontal bacteria than in unstimulated cells, IL-1 genotypes did not correlate with circulating IL-1ß levels. In the Czech population, significant associations between the IL-1B polymorphism with CP and the IL-1RN variant with T1DM were found. Haplotype analysis suggests that variability in IL-1 gene cluster may be one of the factors in the CP and T1DM pathogenesis, although single variants of these polymorphisms are not substantial for protein production.

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.

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.

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.

Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus.

AIMS: The aims of the study were (i) to ascertain prognostic value of serum uric acid (SUA) for diabetic kidney disease (DKD) progression and major adverse cardiovascular event (MACE) in a cohort of T2DM patients, (ii) to ascertain eventual protective effect of allopurinol treatment, (iii) to determine the effect of genetic variability in UA transporters on DKD progression, and (iv) to define optimal cut-off values for SUA in patients with DKD. METHODS: Study comprised 422 subjects with diabetes duration at least 15years followed-up for a median of 43 [IQR 22-77] months. Participants were categorized into stable or progressors according to their change in albuminuria or chronic kidney disease (CKD) stage. At baseline, 68% patients had hyperuricemia (SUA≥420µmol/l for men and ≥360µmol/l for women and/or allopurinol treatment). Five SNPs in the SLC2A9 and ABCG2 genes were determined by PCR. RESULTS: Time-to-event analysis with subgroups defined by the presence/absence of initial hyperuricemia revealed significant differences in all three end-points (P<0.0001 for DKD progression, P=0.0022 for MACE and P=0.0002 for death, log-rank test). Subjects with normal SUA not requiring allopurinol had median time to DKD progression 49months compared with remaining subjects (32months, P=0.0002, log-rank test). Multivariate Cox regression model revealed hyperuricemia (i.e. high SUA and/or allopurinol treatment) significant predictor of DKD progression independent of baseline CKD stage. Optimal cut-off values identified by ROC analysis for T2DM subjects were ≤377.5µmol/l for men and ≤309.0µmol/l for women. We found no differences in allele or genotype frequencies in selected SNPs between patients with and without hyperuricemia (all P>0.05). CONCLUSIONS: Our study demonstrated that initial hyperuricemia or need for allopurinol is an independent risk factor for DKD progression and that SUA levels in diabetic subjects conferring protection against DKD progression might be lower than current cut-offs for general population.

Dysfunctional protection against advanced glycation due to thiamine metabolism abnormalities in gestational diabetes.

While the pathogenic role of dicarbonyl stress and accelerated formation of advanced glycation end products (AGEs) to glucose intolerance and to the development of diabetic complications is well established, little is known about these processes in gestational diabetes mellitus (GDM), a condition pathogenically quite similar to type 2 diabetes. The aims of the present study were (i) to determine plasma thiamine and erythrocyte thiamine diphosphate (TDP) and transketolase (TKT) activity in pregnant women with and without GDM, (ii) to assess relationships between thiamine metabolism parameters and selected clinical, biochemical and anthropometric characteristics and, finally, (iii) to analyse relationship between variability in the genes involved in the regulation of transmembrane thiamine transport (i.e. SLC19A2 and SLC19A3) and relevant parameters of thiamine metabolism. We found significantly lower plasma BMI adjusted thiamine in women with GDM (P = 0.002, Mann-Whitney) while levels of erythrocyte TDP (an active TKT cofactor) in mid-trimester were significantly higher in GDM compared to controls (P = 0.04, Mann-Whitney). However, mid-gestational TKT activity - reflecting pentose phosphate pathway activity - did not differ between the two groups (P > 0.05, Mann-Whitney). Furthermore, we ascertained significant associations of postpartum TKT activity with SNPs SLC19A2 rs6656822 and SLC19A3 rs7567984 (P = 0.03 and P = 0.007, resp., Kruskal-Wallis). Our findings of increased thiamine delivery to the cells without concomitant increase of TKT activity in women with GDM therefore indicate possible pathogenic role of thiamine mishandling in GDM. Further studies are needed to determine its contribution to maternal and/or neonatal morbidity.

Effect of glucose variability on pathways associated with glucotoxicity in diabetes: Evaluation of a novel in vitro experimental approach.

AIMS: Glycaemic variability (GV) has been hypothesized to increase the risk of diabetes complications; however, results of clinical studies are contradictory. The effect of GV on cell phenotypes has been investigated in vitro showing that GV may have more deleterious effect on cells that high glucose itself. However, methodology used to study GV in vitro differs significantly between studies and does not reflect in vivo situation. Therefore we aimed to establish clinically relevant an in vitro experimental approach for the study of GV that reflects intra-day glucose fluctuations of subjects with type 1 diabetes mellitus (T1DM) and of healthy subjects and to test how low and high GV affect expression of genes that protects cells from hyperglycaemia-induced damage. METHODS: Human umbilical vein endothelial cells (HUVEC) were cultured 24h in medium with different glucose profiles: high GV, low GV and GV of healthy subjects-profiles created according to CGM of T1DM patients and healthy subjects. These profiles were compared to commonly used 5.5 and 25mmol/l glucose concentrations. Gene expression was determined using quantitative PCR. RESULTS: Our results showed general down-regulation of enzymes that are involved in the protection against hyperglycaemia-induced intracellular changes in both low and high GV compared to normal glycaemia similarly to the decrease induced by continuous hyperglycaemia. Gene expressions did not differ between high and low GV. CONCLUSION: Our data indicate that GV may have similar or even greater effect than continuous hyperglycaemia on the expression of several genes relevant to pathogenesis of diabetes microvascular complications.

1,25-Dihydroxyvitamin D increases the gene expression of enzymes protecting from glucolipotoxicity in peripheral blood mononuclear cells and human primary endothelial cells.

Besides its classical function as an orchestrator of calcium and phosphorus homeostasis, vitamin D also affects insulin secretion and tissue efficiency. A number of studies have consistently reported the inverse relationship between vitamin D deficiency and type 2 diabetes. Activation of certain metabolic pathways and down-stream transcription factors may protect from glucolipotoxicity and their targeted activation -e.g. by vitamin D - might explain the detrimental role of vitamin D deficiency in diabetes. The aim of the study was to quantify gene and protein expression of selected enzymes involved in the protection from glucolipotoxicity, specifically glyoxalase 1 (GLO1), and other enzymes with antioxidant activity - hemoxygenase (HMOX), thiamin pyrophosphokinase (TPK1) and transketolase (TKT), under normo- and hyperglycemic conditions and upon addition of vitamin D in peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVEC). The results of our study indicate that the active form of vitamin D regulates gene expression of enzymes opposing the harmful effect of glucolipotoxicity whose activities appear to be suppressed by hyperglycemia. However, we were unable to confirm this effect on protein expression. While we cannot speculate on the effect of vitamin D on diabetes itself our results support its role in the protection against existing glucolipotoxicity therefore possibly translating into the prevention of development of diabetic complications.

Interleukin-17A Gene Variability in Patients with Type 1 Diabetes Mellitus and Chronic Periodontitis: Its Correlation with IL-17 Levels and the Occurrence of Periodontopathic Bacteria.

Interleukin-17 contributes to the pathogenesis of type 1 diabetes mellitus (T1DM) and chronic periodontitis (CP). We analyzed IL-17A -197A/G and IL-17F +7488C/T polymorphisms in T1DM and CP and determined their associations with IL-17 production and occurrence of periopathogens. Totally 154 controls, 125 T1DM, and 244 CP patients were genotyped using 5' nuclease TaqMan(®) assays. Bacterial colonization was investigated by a DNA-microarray kit. Production of IL-17 after in vitro stimulation of mononuclear cells by mitogens and bacteria was examined by the Luminex system. Although no differences in the allele/genotype frequencies between patients with CP and T1DM + CP were found, the IL-17A -197 A allele increased the risk of T1DM (P < 0.05). Levels of HbA1c were significantly elevated in carriers of the A allele in T1DM patients (P < 0.05). Production of IL-17 by mononuclear cells of CP patients (unstimulated/stimulated by Porphyromonas gingivalis) was associated with IL-17A A allele (P < 0.05). IL-17A polymorphism increased the number of Tannerella forsythia and Treponema denticola in patients with CP and T1DM + CP, respectively (P < 0.05). IL-17A gene variability may influence control of T1DM and the "red complex" bacteria occurrence in patients with CP and T1DM + CP. Our findings demonstrated the functional relevance of the IL-17A polymorphism with higher IL-17 secretion in individuals with A allele.

Resting Heart Rate Does Not Predict Cardiovascular and Renal Outcomes in Type 2 Diabetic Patients.

Elevated resting heart rate (RHR) has been associated with increased risk of mortality and cardiovascular events. Limited data are available so far in type 2 diabetic (T2DM) subjects with no study focusing on progressive renal decline specifically. Aims of our study were to verify RHR as a simple and reliable predictor of adverse disease outcomes in T2DM patients. A total of 421 T2DM patients with variable baseline stage of diabetic kidney disease (DKD) were prospectively followed. A history of the cardiovascular disease was present in 81 (19.2%) patients at baseline, and DKD (glomerular filtration rate < 60 mL/min or proteinuria) was present in 328 (77.9%) at baseline. Progressive renal decline was defined as a continuous rate of glomerular filtration rate loss ≥ 3.3% per year. Resting heart rate was not significantly higher in subjects with cardiovascular disease or DKD at baseline compared to those without. Using time-to-event analyses, significant differences in the cumulative incidence of the studied outcomes, that is, progression of DKD (and specifically progressive renal decline), major advanced cardiovascular event, and all-cause mortality, between RHR

Serum carboxymethyl-lysine, a dominant advanced glycation end product, is increased in women with gestational diabetes mellitus.

AIMS: The objective of the study was to measure one of the circulating Advanced Glycation End Products (AGEs) - Nε-(carboxymethyl)lysine (CML) - in a case-control study (n = 307) of pregnant women with gestational diabetes mellitus (GDM) and physiological pregnancies and to ascertain the factors contributing to CML levels and the potential relevance of CML for selected perinatal and postpartum outcomes. METHODS: All subjects underwent oGTT between 24th and 30th week of gestation and GDM was diagnosed according to WHO criteria. CML was determined by ELISA using commercial kit. RESULTS: Unadjusted and plasma protein adjusted CML levels were significantly higher in women with GDM compared to healthy controls (P = 0.00043 and P = 1x10(-5), respectively, Mann-Whitney). CML was significantly inversely correlated with both pre- and mid-gestational BMI, however, differences between GDM and control group remained significant even after adjustment for BMI. CML levels correlated with 1-h and 2-h post-load glycaemia during oGTT. CONCLUSION: In conclusion, we found statistically significantly higher protein- and BMI-normalised CML levels measured during 24-30th week of gestation in women with GDM compared to healthy pregnant controls. Further studies are warranted to comprehensively asses the spectrum of AGEs in GDM and their relevance to future metabolic health of mother and offspring.