Genetic glucocorticoid receptor variants differ between ethnic groups but do not explain variation in age of diabetes onset, metabolic and inflammation parameters in patients with type 2 diabetes.

Aims: The effect of excess glucocorticoid receptor (GR) stimulation through glucocorticoid medication or cortisol on glucose metabolism is well established. There are genetic GR variants that result in increased or decreased GR stimulation. We aimed to determine the prevalence of genetic GR variants in different ethnic groups in a cohort of patients with type 2 diabetes, and we aimed to determine their association with age of diabetes onset and metabolic and inflammation parameters. Methods: A cross-sectional analysis was performed in a multiethnic cohort (n = 602) of patients with established type 2 diabetes. Polymorphisms in the GR gene that have previously been associated with altered glucocorticoid sensitivity (TthIIII, ER22/23EK N363S, BclI and 9ß) were determined and combined into 6 haplotypes. Associations with age of diabetes onset, HbA1c, hs-CRP and lipid values were evaluated in multivariate regression models. Results: The prevalence of the SNPs of N363S and BclI was higher in Dutch than in non-Dutch patients. We observed a lower prevalence of the SNP 9ß in Dutch, South(East) Asian and Black African patients versus Turkish and Moroccan patients. We did not detect an association between SNPs and diabetes age of onset or metabolic parameters. We only found a trend for lower age of onset and higher HbA1c in patients with 1 or 2 copies of haplotype 3 (TthIIII + 9ß). Conclusions: The prevalence of genetic GR variants differs between patients of different ethnic origins. We did not find a clear association between genetic GR variants and age of diabetes onset or metabolic and inflammation parameters. This indicates that the clinical relevance of GR variants in patients with established type 2 diabetes is limited.

Cellular origin and microRNA profiles of circulating extracellular vesicles in different stages of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a major complication of diabetes and the main cause of end-stage renal disease. Extracellular vesicles (EVs) are small cell-derived vesicles that can alter disease progression by microRNA (miRNA) transfer. METHODS: In this study, we aimed to characterize the cellular origin and miRNA content of EVs in plasma samples of type 2 diabetes patients at various stages of DN. Type 2 diabetes patients were classified in three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. The concentration and cellular origin of plasma EVs were measured by flow cytometry. A total of 752 EV miRNAs were profiled in 18 subjects and differentially expressed miRNAs were validated. RESULTS: Diabetic patients with microalbuminuria and/or macroalbuminuria showed elevated concentrations of total EVs and EVs from endothelial cells, platelets, leucocytes and erythrocytes compared with diabetic controls. miR-99a-5p was upregulated in macroalbuminuric patients compared with normoalbuminuric and microalbuminuric patients. Transfection of miR-99a-5p in cultured human podocytes downregulated mammalian target of rapamycin (mTOR) protein expression and downregulated the podocyte injury marker vimentin. CONCLUSIONS: Type 2 diabetes patients with microalbuminuria and macroalbuminuria display differential EV profiles. miR-99a-5p expression is elevated in EVs from macroalbuminuria and mTOR is its validated mRNA target.

Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy.

TAM receptors (Tyro3, Axl, and Mer) have been implicated in innate immunity. Circulating TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in urine, identifying the kidney as a source of sTAM.

Oral health information from the dentist to the diabetologist.

BACKGROUND: Diabetes care includes annual evaluation of micro- and macrovascular complications, however, oral pathologies are not included. We studied retrieving oral health information, in particular periodontal disease, from the dentist and studied the association between the reported periodontal condition and variables of both diabetes and dental care. METHODS: During their annual comprehensive diabetes evaluation, patients were asked to deliver an oral health questionnaire (OHQ) to their dentist. Based on the returned OHQs, the process of retrieving oral health information from the dentist was analyzed. In addition, reported oral health measures with special emphasis to periodontitis, using a Periodontal Screening Index (PSI), were related to diabetes-related variables. RESULTS: We included 889 patients of whom 102 patients (11%) did not visit a dentist at all and 252 (28%) were edentulous. The response rate was <50% for oral information on patients with diabetes. For the second aim, OHQs of 207 patients could be further analyzed. A moderate to high PSI-score was found in 106 patients, of whom 65% were untreated for periodontitis. Furthermore high PSI-scores were associated with poor oral hygiene, soft tissue pathologies and periodontal treatment, but not significantly with glycemic control and presence of diabetes complications. CONCLUSION: The transfer of information from the dentist to the diabetologist is far from optimal. An OHQ can be a valuable tool for the identification of patients with diabetes with poor oral health especially untreated periodontal disease, which is helpful for proper diabetes management.

Skin autofluorescence and complications of diabetes: does ethnic background or skin color matter?

AIMS: Skin autofluorescence (AF) has been associated with complications of diabetes. We evaluated the influence of skin color and ethnicity on the association between skin AF and the presence of diabetes-related complications. MATERIALS AND METHODS: In a multiethnic type 2 diabetes cohort we investigated all patients with available skin AF measurements. The associations between skin AF and hemoglobin A1c (HbA1c) and the presence of complications of diabetes were estimated, stratified for ethnicity and quartiles of ultraviolet reflectance percentage (R%). RESULTS: In total, 810 patients (438 native Dutch, 372 non-Dutch) were included. Because of too low an R%, 32% of black Africans and 19% of Hindustanis were excluded. Non-Dutch patients had lower AF values compared with Dutch patients (median AF=2.69 [interquartile range (IQR), 2.26-3.09] vs. 3.06 [IQR, 2.65-3.50] arbitrary units; P<0.001), but the R% was also lower (non-Dutch, median R%=12% [IQR, 9-15%]; Dutch, median R%=18% [IQR, 14-23%]; P=0.027). In the multivariate analysis, skin AF was only a determinant for complications in patients with R% 25(th) percentile (macrovascular, odds ratio [OR]=1.71 [95% confidence interval (CI), 1.05-2.77] vs. 1.15 [95% CI, 0.55-2.40] in the lowest quartile of R%; microvascular, OR=1.81 [95% CI, 1.20-2.75] vs. OR=0.87 [95% CI, 0.50-1.51]). A similar pattern was observed for nephropathy, neuropathy, and retinopathy separately. In non-Dutch patients AF was not a significant determinant for diabetes complication risk, whereas HbA1c was for nephropathy, retinopathy, and neuropathy. CONCLUSIONS: Skin AF measurement is a valuable tool for the assessment of micro- and macrovascular complication risk in patients with light skin color types. Even after exclusion of patients with too low a reflectance, the current performance of the AGE Reader™ (DiagnOptics Technologies BV, Groningen, The Netherlands) was insufficient in darker-skinned patients.

The longer-term effects of Roux-en-Y gastric bypass surgery on sodium excretion.

BACKGROUND: Obesity is an independent risk factor for hypertension and chronic kidney disease. During the first months after bariatric surgery, an improvement of sodium excretion has been described. The aim of this work was to study the influence of bariatric surgery on sodium excretion at more than a year after the intervention. METHODS: Patients who have undergone Roux-en-Y gastric bypass (RYGB) and who had collected a 24-h urine sample before surgery more than 12 months ago were asked to participate. A second 24-h urine sample was collected. Blood pressure and weight were measured. The difference in sodium excretion before and after surgery was calculated, and the relationship with blood pressure and weight loss was investigated. RESULTS: We included 33 patients; the median follow-up time was 21 months (range 14-41). Sodium excretion was high before surgery (median 195 mmol/day, IQR range 167-247) and decreased by 18 % after surgery (median 160 mmol/day, IQR range 118-205, p = 0.015), while there were significant improvements in body weight (% EWL 80.9 ± 21.8), systolic blood pressure (126 to 120 mmHg, p = 0.02), and diastolic blood pressure (84 to 77 mmHg, p = 0.002), even with a reduced number of antihypertensive drugs. CONCLUSIONS: After RYGB and considerable weight loss, sodium excretion remains high in the longer term. The profound improvement in blood pressure cannot be explained by reductions in sodium excretion after RYGB.

Low attack rate of novel influenza A (H1N1) virus infection among healthcare workers: a prospective study in a setting with an elaborated containment plan.

PURPOSE: This study aimed to determine incidence rates of novel influenza A (H1N1) infection among healthcare personnel with different exposure risks during the 2009 H1N1 pandemic. METHODS: From August 2009 until April 2010, 66 healthcare workers from a 410 bed teaching hospital in Amsterdam were monitored. The following three different exposure groups were created: a high- (n = 26), intermediate- (n = 20), and low-risk group (n = 20). Throat swabs were collected each week and analyzed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in order to detect the H1N1 virus. Blood was drawn at study enrollment and once monthly thereafter, and serum specimens were tested with an H1N1-specific hemagglutination-inhibition serologic assay. Influenza-like signs and symptoms were assessed weekly. RESULTS: One of 26 high-risk group participants proved H1N1 positive once by RT-PCR. This corresponds to an incidence rate in the high-risk group of 5.7/1,000 person weeks (95% CI 0-17/1,000). None of the intermediate- and low-risk group participants proved H1N1 positive by RT-PCR. Significant antibody titer rises in convalescent sera were demonstrated in three participants: one was a confirmation of the case that had proved H1N1 positive by RT-PCR; the others occurred in two asymptomatic participants belonging to the low- and high-risk groups. An influenza-like illness was assumed in four participants from the high- (n = 1), intermediate- (n = 1) and low-risk (n = 2) groups; these findings were not confirmed by positive results from either diagnostic test. CONCLUSIONS: This study demonstrates a low incidence rate of influenza A (H1N1) infection among healthcare workers during the 2009 H1N1 pandemic in a setting with high hygiene standards.