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Open access

Chun-feng Lu, Xiao-qin Ge, Yan Wang, Jian-bin Su, Xue-qin Wang, Dong-mei Zhang, Feng Xu, Wang-shu Liu, and Min Su

Background

Prolonged heart rate-corrected QT (QTc) interval may reflect poor prognosis of patients with type 2 diabetes (T2D). Serum adenosine deaminase (ADA) levels are related to hyperglycemia, insulin resistance (IR) and inflammation, which may participate in diabetic complications. We investigated the association of serum ADA levels with prolonged QTc interval in a large-scale sample of patients with T2D.

Methods

In this cross-sectional study, a total of 492 patients with T2D were recruited. Serum ADA levels were determined by venous blood during fasting. QTc interval was estimated from resting 12-lead ECGs, and prolonged QTc interval was defined as QTc > 440 ms.

Results

In this study, the prevalence of prolonged QTc interval was 22.8%. Serum ADA levels were positively associated with QTc interval (r = 0.324, P < 0.0001). The proportion of participants with prolonged QTc interval increased significantly from 9.2% in the first tertile (T1) to 24.7% in the second tertile (T2) and 39.0% in the third tertile (T3) of ADA (P for trend < 0.001). After adjusting for other possible risk factors by multiple linear regression analysis, serum ADA level was still significantly associated with QTc interval (β = 0.217, t = 3.400, P < 0.01). Multivariate logistic regression analysis showed that female (OR 5.084, CI 2.379–10.864, P < 0.001), insulin-sensitizers treatment (OR 4.229, CI 1.290–13.860, P = 0.017) and ADA (OR 1.212, CI 1.094–1.343, P < 0.001) were independent contributors to prolonged QTc interval.

Conclusions

Serum ADA levels were independently associated with prolonged QTc interval in patients with T2D.

Open access

Nikolaj Rittig, Mads Svart, Niels Jessen, Niels Møller, Holger J Møller, and Henning Grønbæk

Background

Macrophage activation determined by levels of soluble sCD163 is associated with obesity, insulin resistance, diabetes mellitus type 2 (DM2) and non-alcoholic fatty liver disease (NAFLD). This suggests that macrophage activation is involved in the pathogenesis of conditions is characterised by adaptions in the lipid metabolism. Since sCD163 is shed to serum by inflammatory signals including lipopolysaccharides (LPS, endotoxin), we investigated sCD163 and correlations with lipid metabolism following LPS exposure.

Methods

Eight healthy male subjects were investigated on two separate occasions: (i) following an LPS exposure and (ii) following saline exposure. Each study day consisted of a four-hour non-insulin-stimulated period followed by a two-hour hyperinsulinemic euglycemic clamp period. A 3H-palmitate tracer was used to calculate the rate of appearance (Rapalmitate). Blood samples were consecutively obtained throughout each study day. Abdominal subcutaneous adipose tissue was obtained for western blotting.

Results

We observed a significant two-fold increase in plasma sCD163 levels following LPS exposure (P < 0.001), and sCD163 concentrations correlated positively with the plasma concentration of free fatty acids, Rapalmitate, lipid oxidation rates and phosphorylation of the hormone-sensitive lipase at serine 660 in adipose tissue (P < 0.05, all). Furthermore, sCD163 concentrations correlated positively with plasma concentrations of cortisol, glucagon, tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 (P < 0.05, all).

Conclusion

We observed a strong correlation between sCD163 and stimulation of lipolysis and fat oxidation following LPS exposure. These findings support preexisting theory that inflammation and macrophage activation play a significant role in lipid metabolic adaptions under conditions such as obesity, DM2 and NAFLD.

Open access

Natalio García-Honduvilla, Alberto Cifuentes, Miguel A Ortega, Marta Pastor, Garazi Gainza, Eusebio Gainza, Julia Buján, and Melchor Álvarez-Mon

Wound healing is a complex process that can be severely impaired due to pathological situations such as diabetes mellitus. Diabetic foot ulcers are a common complication of this pathology and are characterized by an excessive inflammatory response. In this work, the effects of local treatment with recombinant human epidermal growth factor (rhEGF) were studied using a full-thickness wound healing model in streptozotocin-induced diabetic rats. Wound healing process was assessed with different concentrations of rhEGF (0.1, 0.5, 2.0 and 8.0 µg/mL), placebo and both diabetic and non-diabetic controls (n = 53). The macroscopic healing observed in treated diabetic rats was affected by rhEGF concentration. Histologically, we also observed an improvement in the epithelialization, granulation tissue formation and maturation in treated groups, finding again the best response at doses of 0.5 and 2.0 µg/mL. Afterwards, the tissue immune response over time was assessed in diabetic rats using the most effective concentrations of rhEGF (0.5 and 2.0 µg/mL), compared to controls. The presence of macrophages, CD4+ T lymphocytes and CD8+ T lymphocytes, in the reparative tissue was quantified, and cytokine expression was measured by quantitative real-time PCR. rhEGF treatment caused a reduction in the number of infiltrating macrophages in the healing tissue of diabetic, as well as diminished activation of these leukocytes. These findings show that local administration of rhEGF improves the healing process of excisional wounds and the quality of the neoformed tissue in a dose-dependent manner. Besides, this treatment reduces the local inflammation associated with diabetic healing, indicating immuno-modulatory properties.

Open access

Helle Keinicke, Gao Sun, Caroline M Junker Mentzel, Merete Fredholm, Linu Mary John, Birgitte Andersen, Kirsten Raun, and Marina Kjaergaard

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased dramatically worldwide and, subsequently, also the risk of developing non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis and cancer. Today, weight loss is the only available treatment, but administration of fibroblast growth factor 21 (FGF21) analogues have, in addition to weight loss, shown improvements on liver metabolic health but the mechanisms behind are not entirely clear. The aim of this study was to investigate the hepatic metabolic profile in response to FGF21 treatment. Diet-induced obese (DIO) mice were treated with s.c. administration of FGF21 or subjected to caloric restriction by switching from high fat diet (HFD) to chow to induce 20% weight loss and changes were compared to vehicle dosed DIO mice. Cumulative caloric intake was reduced by chow, while no differences were observed between FGF21 and vehicle dosed mice. The body weight loss in both treatment groups was associated with reduced body fat mass and hepatic triglycerides (TG), while hepatic cholesterol was slightly decreased by chow. Liver glycogen was decreased by FGF21 and increased by chow. The hepatic gene expression profiles suggest that FGF21 increased uptake of fatty acids and lipoproteins, channeled TGs toward the production of cholesterol and bile acid, reduced lipogenesis and increased hepatic glucose output. Furthermore, FGF21 appeared to reduce inflammation and regulate hepatic leptin receptor-a expression. In conclusion, FGF21 affected several metabolic pathways to reduce hepatic steatosis and improve hepatic health and markedly more genes than diet restriction (61 vs 16 out of 89 investigated genes).

Open access

Marianna Martino, Paolo Falcioni, Giulia Giancola, Alessandro Ciarloni, Gianmaria Salvio, Francesca Silvetti, Augusto Taccaliti, and Giorgio Arnaldi

Objective

Dysnatremia is common in hospitalized patients, often worsening the prognosis in pneumopathies and critical illnesses. Information on coronavirus disease-19 (COVID-19)-related hyponatremia is partially conflicting, whereas data on hypernatremia in this context are scarce. We assessed, in a cohort of COVID-19 inpatients: the prevalence of sodium alterations at admission and throughout their hospitalization; their association with inflammation/organ damage indexes; their short-term prognostic impact.

Study design and methods

117 patients (81 males, 64 ± 13 years) hospitalized for COVID-19 between 1 March and 30 April 2020 were retrospectively followed-up for their first 21 days of stay by collecting all serum sodium measurements, basal CRP and serum lactate levels, maximum IL-6 and information on care setting, required ventilation, length of hospitalization, in-hospital death.

Results

At admission, 26.5% patients had hyponatremia, and 6.8% had hypernatremia. During their hospitalization, 13.7% patients experienced both disorders ('mixed dysnatremia'). Lower sodium levels at admission were correlated with higher C reactive protein (CRP) (P = 0.039) and serum lactate levels (P = 0.019), but not interleukin-6 (IL-6). Hypernatremia and a wider sodium variability were associated with maximum required ventilation, need for ICU assistance and duration of the hospitalization. Mean estimated time to Intensive Care Unit (ICU) admission was 20 days shorter in patients exposed to sodium alterations at any time of their hospital course (log-rank test P = 0.032).

Conclusions

Sodium alterations frequently affect hospitalized COVID-19 patients. Hyponatremia could indicate pulmonary involvement, whereas hypernatremia is associated to prolonged hospitalization and the need for intensive care/mechanical ventilation, particularly when resulting from prior hyponatremia. Optimizing in-hospital sodium balance is crucial to improve patients’ prognosis.

Open access

T P McVeigh, R J Mulligan, U M McVeigh, P W Owens, N Miller, M Bell, F Sebag, C Guerin, D S Quill, J B Weidhaas, M J Kerin, and A J Lowery

Introduction

MicroRNAs (miRNAs) are small noncoding RNA molecules that exert post-transcriptional effects on gene expression by binding with cis-regulatory regions in target messenger RNA (mRNA). Polymorphisms in genes encoding miRNAs or in miRNA–mRNA binding sites confer deleterious epigenetic effects on cancer risk. miR-146a has a role in inflammation and may have a role as a tumour suppressor. The polymorphism rs2910164 in the MIR146A gene encoding pre-miR-146a has been implicated in several inflammatory pathologies, including cancers of the breast and thyroid, although evidence for the associations has been conflicting in different populations. We aimed to further investigate the association of this variant with these two cancers in an Irish cohort.

Methods

The study group comprised patients with breast cancer (BC), patients with differentiated thyroid cancer (DTC) and unaffected controls. Germline DNA was extracted from blood or from saliva collected using the DNA Genotek Oragene 575 collection kit, using crystallisation precipitation, and genotyped using TaqMan-based PCR. Data were analysed using SPSS, v22.

Results

The total study group included 1516 participants. This comprised 1386 Irish participants; 724 unaffected individuals (controls), 523 patients with breast cancer (BC), 136 patients with differentiated thyroid cancer (DTC) and three patients with dual primary breast and thyroid cancer. An additional cohort of 130 patients with DTC from the South of France was also genotyped for the variant. The variant was detected with a minor allele frequency (MAF) of 0.19 in controls, 0.22 in BC and 0.27 and 0.26 in DTC cases from Ireland and France, respectively. The variant was not significantly associated with BC (per allele odds ratio = 1.20 (0.98–1.46), P = 0.07), but was associated with DTC in Irish patients (per allele OR = 1.59 (1.18–2.14), P = 0.002).

Conclusion

The rs2910164 variant in MIR146A is significantly associated with DTC, but is not significantly associated with BC in this cohort.

Open access

Eva Novoa, Marcel Gärtner, and Christoph Henzen

Objective

The study aimed to assess the possible systemic effects of intratympanic dexamethasone (IT-Dex) on the hypothalamic–pituitary–adrenal (HPA) axis, inflammation, and bone metabolism.

Design

A prospective cohort study including 30 adult patients of a tertiary referral ENT clinic treated with 9.6 mg IT-Dex over a period of 10 days was carried out.

Methods

Effects on plasma and salivary cortisol concentrations (basal and after low-dose (1 μg) ACTH stimulation), peripheral white blood cell count, and biomarkers for bone turnover were measured before (day 0) and after IT-Dex (day 16). Additional measurements for bone turnover were performed 5 months after therapy. Clinical information and medication with possible dexamethasone interaction were recorded.

Results

IT-Dex was well tolerated, and no effect was detected on the HPA axis (stimulated plasma and salivary cortisol concentration on day 0: 758±184 and 44.5±22.0 nmol/l; day 16: 718±154 and 39.8±12.4 nmol/l; P=0.58 and 0.24 respectively). Concentrations of osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP) did not differ after dexamethasone (OC on days 0 and 16 respectively: 24.1±10.5 and 23.6±8.8 μg/l; BSAP on day 0, 16, and after 5 months respectively: 11.5±4.2, 10.3±3.4, and 12.6±5.06 μg/l); similarly, there was no difference in the peripheral white blood cell count (5.7×1012/l and 6.1×1012/l on days 0 and 16 respectively).

Conclusions

IT-Dex therapy did not interfere with endogenous cortisol secretion or bone metabolism.

Open access

Janko Sattler, Jinwen Tu, Shihani Stoner, Jingbao Li, Frank Buttgereit, Markus J Seibel, Hong Zhou, and Mark S Cooper

Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo-pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. 11β-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11β-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis. The expression of 11β-HSD1, and other components of glucocorticoid signaling, were examined in various brain regions and the pituitary gland of mice with experimentally induced arthritis. Two arthritis protocols were employed: The K/BxN spontaneous arthritis model for chronic arthritis and the K/BxN serum transfer arthritis model for acute arthritis. 11β-HSD1 mRNA (Hsd11b1) was expressed in the hippocampus, hypothalamus, cortex, cerebellum and pituitary gland. Hypothalamic Hsd11b1 expression did not change in response to arthritis in either model. Pituitary Hsd11b1 expression was however significantly increased in both chronic and acute arthritis models. Hippocampal Hsd11b1 was decreased in acute but not chronic arthritis. Chronic, but not acute, arthritis was associated with a reduction in hypothalamic corticotropin-releasing hormone and arginine vasopressin expression. In both models, serum adrenocorticotropic hormone and corticosterone levels were no different from non-inflammatory controls. These findings demonstrate inflammation-dependent regulation of Hsd11b1 expression in the pituitary gland and hippocampus. The upregulation of 11β-HSD1 expression in the pituitary during both chronic and acute arthritis, and thus, an increase in glucocorticoid negative feedback, could contribute to the abnormalities in HPA axis activity seen in immune-mediated arthritis.

Open access

Sandra N Slagter, Robert P van Waateringe, André P van Beek, Melanie M van der Klauw, Bruce H R Wolffenbuttel, and Jana V van Vliet-Ostaptchouk

Introduction

To evaluate the prevalence of metabolic syndrome (MetS) and its individual components within sex-, body mass index (BMI)- and age combined clusters. In addition, we used the age-adjusted blood pressure thresholds to demonstrate the effect on the prevalence of MetS and elevated blood pressure.

Subjects and methods

Cross-sectional data from 74,531 Western European participants, aged 18–79 years, were used from the Dutch Lifelines Cohort Study. MetS was defined according to the revised NCEP-ATPIII. Age-adjusted blood pressure thresholds were defined as recommended by the eight reports of the Joint National Committee (≥140/90 mmHg for those aged <60 years, and ≥150/90 mmHg for those aged ≥60 years).

Results

19.2% men and 12.1% women had MetS. MetS prevalence increased with BMI and age. Independent of BMI, abdominal obesity dominated MetS prevalence especially in women, while elevated blood pressure was already highly prevalent among young men. Applying age-adjusted blood pressure thresholds resulted in a 0.2–11.9% prevalence drop in MetS and 6.0–36.3% prevalence drop in elevated blood pressure, within the combined sex, BMI and age clusters.

Conclusions

We observed a gender disparity with age and BMI for the prevalence of MetS and, especially, abdominal obesity and elevated blood pressure. The strict threshold level for elevated blood pressure in the revised NCEP-ATPIII, results in an overestimation of MetS prevalence.

Open access

Sebastião Freitas de Medeiros, Márcia Marly Winck Yamamoto, Matheus Antônio Souto de Medeiros, Bruna Barcelo Barbosa, José Maria Soares Junior, and Edmund Chada Baracat

Objective

To verify whether aging can modify the clinical and biochemical characteristics of women with polycystic ovary syndrome (PCOS).

Material and methods

This observational cross-sectional study was conducted at the reproductive endocrinology clinics of Julio Muller University Hospital and Tropical Institute of Reproductive Medicine in Cuiabá, MT, Brazil, between 2003 and 2017. Both, 796 PCOS and 444 non-PCOS normal cycling women underwent the same examination. PCOS was diagnosed using the Rotterdam criteria as recommended for adolescent and adult subjects. Anthropometric, metabolic, and endocrinological modifications with aging were initially examined in the two groups: control and PCOS. Further analyses were performed after a 5-year age stratification of data throughout the reproductive period. All participants signed a consent form approved by the local ethical committee.

Results

Biomarkers of adiposity were more remarkable in African descendant PCOS women. Body weight, waist/hip ratio, fat mass, and BMI were higher in PCOS women and tended to increase at all 5 age-strata, between ≤19 and 35 years of age. Serum androgen levels decreased with aging, markedly in PCOS subjects (P < 0.01 for all age-strata comparisons), but remained elevated when compared with the levels found in controls. Carbohydrate markers, triglycerides, and total cholesterol tended to increase over time in PCOS (P < 0.01 for all age-strata comparisons). Total cholesterol also tended to increase with age in non-PCOS women (P = 0.041).

Conclusion

The present study has shown that the advancing age influences many features of PCOS women. Biochemical hyperandrogenism, the core criterion recommended in the current systems to define the syndrome, showed statistically significant tendencies to decrease with aging progression but did not normalize. The use of age-adjusted features for the diagnosis of PCOS are recommended.