[Show abstract][Hide abstract] ABSTRACT: Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs' minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk.
[Show abstract][Hide abstract] ABSTRACT: Background Nephropathia epidemica (NE) is a mild form of hemorrhagic fever with renal syndrome (HFRS) that is caused by the Puumala virus. Periodic outbreaks have been described in endemic areas, with a substantial number of previously healthy individuals developing acute kidney injury (AKI). There is a considerable diversity in the clinical course of the disease, and few patients require renal replacement therapy. Methods We tested whether urinary neutrophil gelatinase associated lipocalin (uNGAL), urine albumin/creatinine ratio (uACR), urine protein/creatinine ratio (uPCR), urine dipstick protein, C-reactive protein, procalcitonin, leukocyte and platelet count, determined on admission to the hospital, can predict the severity of AKI. Sixty-one patients were analyzed during admission in the emergency department. Results The variables most strongly associated with peak plasma creatinine concentration were uNGAL (β = 0.70, p <0.0001), uPCR (β = 0.64, p = 0.001), uACR (β = 0.61, p = 0.002), and dipstick proteinuria (β = 0.34, p = 0.008). The highest AUC-ROC to predict stage 3 AKI according to the acute kidney injury network’s (AKIN) classification was seen for uNGAL (0.81, p = 0.001). Conclusion uNGAL accurately predicts the severity of AKI in NE. This could help emergency room physicians predict disease severity and allow for initial risk stratification.
Full-text · Article · Dec 2015 · BMC Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Context:
Previous studies revealed that the common sequence variant I148M in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with liver fat content and liver diseases but not with insulin resistance. Recent data suggests that the PNPLA3 I148M variant has reduced retinyl-palmitate lipase activity in hepatic stellate cells.
We hypothesized that the PNPLA3 I148M variant is associated with elevated retinyl-palmitate storage in human liver as potential link to the clinical pathology. Design/Setting and Participants: Using high pressure liquid chromatography (HPLC) we quantified the retinoid metabolites in liver tissue extracts obtained from 42 human subjects including 13 heterozygous and 6 homozygous carriers of the minor PNPLA3 I148M variant.
Main outcome measure(s):
Retinyl-palmitate is elevated in human livers of homozygous PNPLA3 I148M allele carriers Results: The PNPLA3 I148M variant was associated with a significant increase (1.4-fold) in liver fat. The content of retinyl-palmitate was elevated and the ratio of retinol/retinyl-palmitate was reduced in liver extracts obtained from homozygous PNPLA3 I148M minor allele carriers. In a multivariate model including liver fat content, these differences remained significant independent of liver fat content. The content of the minor retinyl-fatty acid esters was similarly increased in homozygous PNPLA3 I148M carriers.
The increased content of hepatic retinyl-palmitate and the reduced ratio of retinol/retinyl-palmitate in PNPLA3 I148M minor allele carriers support in vitro findings of an altered retinyl-palmitate lipase activity. Our results indicate that the PNPLA3 I148M variant is relevant for the retinyl-palmitate content in human liver providing a possible link to chronic liver disease.
No preview · Article · Oct 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Background: Biomarker fatty acids (FAs) reflecting de novo lipogenesis (DNL) are strongly linked to the risk of cardiometabolic diseases. Liver fat accumulation could mediate this relation. There is very limited data from human population-based studies that have examined this relation. Objective: The aim of this study was to investigate the relation between specific FAs in the DNL pathway and liver fat accumulation in a large population-based study. Methods: We conducted a cross-sectional analysis of a subsample (n = 1,562) of the EPIC-Potsdam study, which involves 27,548 middle-aged men and women. Baseline blood samples have been analyzed for proportions of 32 FAs in erythrocyte membranes (determined by gas chromatography) and biomarker concentrations in plasma. As indicators for DNL, the DNL-index (16:0/18:2n-6) and proportions of individual blood FAs in the DNL pathway were used. Plasma parameters associated with liver fat content (fetuin-A, ALT, and GGT) and the algorithm-based fatty liver index (FLI) were used to reflect liver fat accumulation. Results: The DNL-index tended to be positively associated with the FLI and was positively associated with GGT activity in men (p for trend: 0.12 and 0.003). Proportions of 14:0 and 16:0 in erythrocytes were positively associated with fetuin-A, whereas 16:1n-7 were positively associated with the FLI and GGT activity (all p for trends in both sexes at least 0.004). Furthermore, the proportion of 16:1n-7 was positively related to fetuin-A in women and ALT activity in men (all p for trend at least 0.03). The proportion of 16:1n-9 showed positive associations with the FLI and GGT activity in men and fetuin-A in both sexes, whereas 18:1n-7 was positively associated with GGT activity in men (all p for trend at least 0.048). Conclusion: Findings from this large epidemiological study suggest that liver fat accumulation could link erythrocyte FAs in the DNL pathway to the risk of cardiometabolic diseases.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.
Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF) samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.
In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT) in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.
This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.
[Show abstract][Hide abstract] ABSTRACT: Background/aims:
Determination of peptide biomarkers such as troponins, natriuretic peptides or the recently reported FGF23 can be useful to identify hemodialysis patients with a high risk of mortality. However, it is desirable to focus on few robust parameters to warrant their routine application.
In a prospective cohort study with 239 prevalent hemodialysis patients we studied the prognostic significance of 10 simultaneously determined modern peptide biomarkers (high sensitive troponin I and T, NT-pro-BNP, BNP, MR-pro-ANP, MR-pro-ADM, CT-pro-ET1, copeptin, FGF23 and a-Klotho) and compared them with parameters traditionally associated with mortality (PTH, Ca, Pi, albumin, CRP, cholesterol, AP).
After a follow-up of 4 years, plasma concentration of troponins, natriuretic peptides, MR-pro-ADM, FGF23 as well as PTH, CRP, AP were significantly higher in deceased patients (n=95). Hazard ratios from cox regression on a continuous scale (doubling of plasma concentration) or relative in tertiles were highest for high sensitive troponins, followed by natriuretic peptides and MR-pro-ADM (1.6-2.0 and 2.3-5.5, resp.). C-indices were also highest for troponins (0.708-0.746), followed by natriuretic peptides (0.706-0.731). Traditional parameters had low c-indices (0.598-0.655). Stepwise cox regression revealed that among all parameters troponin I, NT-pro-BNP, PTH and CRP remained independent predictors of mortality and a composite score had the highest c-index (0.799 [0.740-0.849]).
Among peptide biomarkers high sensitive troponins and to a lesser extent natriuretic peptides are strong predictors of mortality in asymptomatic hemodialysis patients, followed by markers of mineral-bone disease and inflammation.
Full-text · Article · Dec 2014 · Kidney and Blood Pressure Research
[Show abstract][Hide abstract] ABSTRACT: Background:
Besides its advantages, bariatric surgery implicates a risk of nutritional deficiencies, which might result in impaired bone metabolism. We assessed the effect of laparoscopic sleeve gastrectomy (LSG) on blood markers of bone metabolism in obese patients during a 3-year observation period.
In 39 obese patients (29 women, 10 men, mean BMI 51.8 ± 6.8 kg/m(2)) undergoing LSG, we measured blood concentrations of 25-hydroxyvitamin D (25(OH)D), calcium, parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and N-telopeptides crosslinks (NTx) before LSG and up to 3 years postoperatively. Vitamin D and calcium supplementations were recorded.
LSG caused an excess weight loss (EWL) of 54 ± 20 % after 3 years. Before surgery, we found decreased levels of 25(OH)D and calcium in 80 and 5 % of the subjects, respectively, while increased levels of PTH, BAP, and NTx were found in 39, 28, and 21 %, respectively. Mean levels of NTx and the prevalence of elevated levels of NTx increased within 2 years (p < 0.001 and p < 0.01). Neither mean blood concentrations of 25(OH)D, calcium, PTH, and BAP nor relative prevalence of deficiencies regarding these markers changed during the study period. The supplementation rates of calcium and vitamin D increased postoperatively.
Morbid obesity is associated with pronounced changes of markers of bone metabolism; LSG did neither aggravate nor ameliorate vitamin D metabolism within a 3-year time period, but led to increased bone resorption 2 years postoperatively. Routine supplementation of calcium and vitamin D is not likely sufficient to compensate the obesity-associated deficiencies in bone metabolism.
[Show abstract][Hide abstract] ABSTRACT: To evaluate reticulocyte haemoglobin content (CHr), compared with ferritin, transferrin saturation (TS) and mean corpuscular volume (MCV), as a marker of iron deficiency (ID).
Retrospective analysis of clinically indicated blood samples taken between February 2010 and October 2012.
Single-centre neonatal care unit.
210 very preterm (gestational age <32 weeks) or very low birthweight infants (birth weight <1500 g) at 3-4 months corrected age.
Complete blood count, CHr, ferritin and TS determined as part of a standard follow-up examination. To detect the optimal CHr cut-off, ID was defined by the presence of more than two of the following three criteria: MCV <75 fL, TS <10%, ferritin <30 µg/L.
210 preterm infants were included at a corrected age of (median (IQR)) 3.5 (3.0-4.0) months and with a CHr of 29.7 (28.6-30.7) pg. There were correlations between CHr and MCV (r=0.54, p <0.0001) and between CHr and TS (r=0.44, p <0.0001). There were 27 (13.4%) iron-deficient infants, and two infants (1%) fulfilled criteria of ID-anaemia. CHr was lower in infants with ID (26.4 (23.8-28.7) pg) than in those without (29.9 (29.0-30.8) pg, p <0.0001). The optimal CHr cut-off for detecting ID was 29 pg (sensitivity 85%, specificity 73%). Areas under the receiver operating characteristic curve for detection of ID tended to be higher for CHr compared with ferritin (0.92 vs 0.75), TS (0.90 vs 0.82) and MCV (0.81 vs 0.72).
CHr seems to be a suitable marker for latent ID in preterm infants at 3-4 months corrected age and may be superior to ferritin, TS and MCV.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
No preview · Article · Dec 2014 · Archives of Disease in Childhood - Fetal and Neonatal Edition
[Show abstract][Hide abstract] ABSTRACT: Background and aims Hepcidin, which acts as a negative feedback regulator of iron homeostasis, may in future serve as a non-invasive iron status parameter to monitor iron supplementation in preterm infants. For this, coexisting influencing factors should be taken into account. Our objective was to evaluate in preterm infants whether red blood cell (RBC) transfusions have a short-term effect on hepcidin concentrations in serum (Hep(S)) and urine (Hep(U)).
Methods Prospective observational study including very preterm infants receiving RBC transfusions. The concentration of the mature, 25 amino-acid form of hepcidin was determined in serum und urine by enzyme-linked immunosorbent assay together with cellular indices before and after RBC transfusion.
Results The study was conducted between May 2009 and September 2010 at Tübingen University Hospital. 20 preterm infants born at a mean gestational age of 26.0 (interquartile range: 24.9–27.4) weeks and with a mean postnatal age of 30.8 (interquartile range 29.9–32.1) daysreceived 27 RBC transfusions. When measured shortly after transfusion (mean 10 h), hematocrit values increased from a median of 26.6% (SD 2.8) to 40.9% (SD 3.2; p < 0.0001); Hep(S) also increased (geometric mean: 44.3 ng/mL (95% confidence interval: 30.8–63.8) vs. 58.0 ng/mL (95% confidence interval: 35.7–94.3; p < 0.05) but Hep(U) remained unaffected.
Conclusion These data indicate a short-term effect of RBC transfusions on serum hepcidin concentrations in preterm infants. Further longer-term observational studies are needed to understand the dynamics of hepcidin regulation in preterm infants.
Preview · Article · Oct 2014 · Archives of Disease in Childhood
[Show abstract][Hide abstract] ABSTRACT: Animal studies suggest that insulin action in the brain is involved in the regulation of peripheral insulin sensitivity. Whether this holds true in humans is unknown. Using intranasal application of insulin to the human brain, we studied impacts of brain insulin action on whole-body insulin sensitivity and mechanisms involved in this process.Insulin sensitivity was assessed by hyperinsulinemic euglycemic glucose clamp, before and after intranasal application of insulin and placebo in randomized order in lean and obese men. After insulin spray application in lean, higher glucose infusion rate was necessary to maintain euglycemia compared to placebo. Accordingly, clamp-derived insulin sensitivity index improved after insulin spray. In obese subjects, this insulin sensitizing effect could not be detected.Change in the high frequency band of heart rate variability, an estimate of parasympathetic output, correlated positively with change in whole-body insulin sensitivity after intranasal insulin. Improvement in whole-body insulin sensitivity correlated with the change in hypothalamic activity as assessed by functional magnetic resonance imaging.In summary, intranasal insulin improves peripheral insulin sensitivity in lean but not in obese men. Furthermore, brain-derived peripheral insulin sensitization is associated with hypothalamic activity and parasympathetic outputs. Thus, our findings provide novel insights into the regulation of insulin sensitivity and the pathogenesis of insulin resistance in humans.
[Show abstract][Hide abstract] ABSTRACT: History and admission findings:
A 90-year-old female patient treated with dabigatran for atrial fibrillation presented emergently with a spontaneous vaginal bleeding due to endometrium carcinoma.
Laboratory analysis revealed azotemia consistent with acute-on-chronic renal failure. Coagulation was deranged (prolongation of activated partial thromboplastin time (aPTT) by 3.5-fold, international normalized ratio (INR) 7.8) due to a massive accumulation of dabigatran (measured plasma concentration 2230 ng/ml).
Diagnosis, treatment and course:
Vaginal bleedings were treated with external tamponade. Hemodialysis treatment was commenced due to uremia and dabigatran accumulation. Over night, the patient was dialysed with a SLED (sustained low efficiency dialysis) regimen. After volume resuscitation renal function promptly ensued indicating prerenal azotemia as a cause of renal failure. After two more hemodialysis sessions dabigatran concentrations were no longer detecable and this was paralleled by normalization of coagulation tests.
Dabigatran can accumulate massively during acute renal failure and evoke a life-threatening bleeding diathesis. Dabigatran can be removed with low efficient dialysis (such as SLED).
No preview · Article · Jul 2014 · DMW - Deutsche Medizinische Wochenschrift