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Open access

Jana Ernst, Katharina Gert, Frank Bernhard Kraus, Ulrike Elisabeth Rolle-Kampczyk, Martin Wabitsch, Faramarz Dehghani and Kristina Schaedlich

The rapid increase of obesity during the last decades and its future prospects are alarming. Besides the general discussed causes of obesity, the ‘Developmental Origins of Health and Disease’ (DOHaD) hypothesis received more attention in recent years. This hypothesis postulates an adverse influence during early development that programs the unborn child for metabolic dysfunctions later in life. Childhood obesity – an as much increasing problem – can be predisposed by maternal overweight and diabetes. Both, obesity and hyperinsulinemia are major causes of female hyperandrogenemia. As predicted by the DOHaD hypothesis and shown in animal models, developmental androgen excess can lead to metabolic abnormalities in offspring. In this study, we investigated, if androgen exposure adversely affects the adipogenic differentiation of preadipocytes and the endocrine function of adult adipocytes. The human SGBS preadipocyte model was used to affirm the de novo biosynthesis of steroid hormones under normal adipogenesis conditions. Normal adipogenesis was paralleled by an increase of corticosteroids and androgens, whereas estrogen remained at a steady level. Treatment with androstenedione had no effect on SGBS proliferation and differentiation, but adult adipocytes exhibited a significant higher accumulation of triglycerides. Progesterone (up to 2-fold), testosterone (up to 38-fold) and cortisone (up to 1.4-fold) – but not cortisol – were elevated by androstenedione administration in adult adipocytes. Estrogen was not altered. Data suggest that androgen does not negatively influence adipogenic differentiation, but steroidogenic function of SGBS adipocytes.

Open access

Cheng Han Ng, Yip Han Chin, Marcus Hon Qin Tan, Jun Xuan Ng, Samantha Peiling Yang, Jolene Jiayu Kiew and Chin Meng Khoo

Purpose: Primary hyperparathyroidism (PHPT) is common condition, affecting people of all ages and is mainly treated with parathyroidectomy. Cinacalcet has been widely used in secondary or tertiary hyperparathyroidism, but the use of cinacalcet in PHPT is less clear.

Methods: Searches were conducted in Medline and Embase for cinacalcet use in PHPT from induction to 10th April 2020. Articles and conferences abstracts describing the use of cinacalcet for PHPT in prospective or retrospective cohorts and randomized controlled trials restricted to English Language only. We initially identified 1301 abstracts. Each article went extraction by two blinded authors on a structured proforma. Continuous outcomes were pooled with weight mean difference (WMD). Quality of included articles was assessed with Newcastle Ottwa Scale and Cochrane risk of Bias 2.0.

Results: 28 articles were included. Normalization rate of serum calcium levels was reported at 90% (CI: 0.82 to 0.96). Serum levels of calcium and PTH levels were significantly reduced (calcium, WMD: 1.647 (CI: -1.922 to -1.371; PTH, WMD: -31.218, CI: -41.671 to -20.765) and phosphate levels significantly increased (WMD: 0.498, CI: 0.400 to 0.596) after cinacalcet therapy The higher the baseline calcium levels, the greater calcium reduction with cinacalcet treatment. Age and gender did not modify the effect of cinacalcet on serum calcium levels.

Conclusion: The results from the meta-analysis support the use of cinacalcet as an alternative or bridging therapy to treat hypercalcemia in people with PHPT.

Open access

David Koeckerling, Jeremy W Tomlinson and Jeremy Cobbold

Non-alcoholic fatty liver disease is a chronic liver disease which is closely associated with components of the metabolic syndrome. Its high clinical burden results from the growing prevalence, inherent cardiometabolic risk and potential of progressing to cirrhosis. Patients with non-alcoholic fatty liver disease show variable rates of disease progression through a histological spectrum ranging from steatosis to steatohepatitis with or without fibrosis. The presence and severity of fibrosis are the most important prognostic factors in non-alcoholic fatty liver disease. This necessitates risk stratification of patients by fibrosis stage using combinations of non-invasive methods such as composite scoring systems and/or transient elastography. A multidisciplinary approach to treatment is advised, centred on amelioration of cardiometabolic risk through lifestyle and pharmacological interventions. Despite the current lack of licensed, liver-targeted pharmacotherapy, several promising agents are undergoing late-phase clinical trials to complement standard management in patients with advanced disease. This review summarises the current concepts in diagnosis and disease progression of non-alcoholic liver disease, focusing on pragmatic approaches to risk assessment and management in both primary and secondary care settings.

Open access

Chunliang Yang, Junyi Li, Fei Sun, Haifeng Zhou, Jia Yang and Chao Yang

Hyperglycemia is the consequence of blood glucose dysregulation and a driving force of diabetic complications including retinopathy, nephropathy and cardiovascular diseases. The serum and glucocorticoid inducible kinase-1 (SGK1) has been suggested in the modulation of various pathophysiological activities. However, the role of SGK1 in blood glucose homeostasis remains less appreciated. In this review, we intend to summarize the function of SGK1 in glucose level regulation and to examine the evidence supporting the therapeutic potential of SGK1 inhibitors in hyperglycemia. Ample evidence points to the controversial roles of SGK1 in pancreatic insulin secretion and peripheral insulin sensitivity, which reflects the complex interplay between SGK1 activation and blood glucose fluctuation. Furthermore, SGK1 is engaged in glucose absorption and excretion in intestine and kidney, and participates in the progression of hyperglycemia induced secondary organ damage. As a net effect, blockage of SGK1 activation via either pharmacological inhibition or genetic manipulation seems to be helpful in glucose control at varying diabetic stages.

Open access

Yuka Goto, Yoshie Otsuka, Kenji Ashida, Ayako Nagayama, Nao Hasuzawa, Shimpei Iwata, Kento Hara, Munehisa Tsuruta, Nobuhiko Wada, Seiichi Motomura, Yuji Tajiri and Masatoshi Nomura

Background and Aims:

It is currently unclear whether sodium–glucose co-transporter 2 (SGLT2) inhibitor administration can improve the insulin sensitivity as well as rapidly reduce plasma glucose concentrations in humans during the early phase of treatment initiation. This study aimed to investigate the effect of SGLT2 inhibitor on insulin sensitivity in the early phase of treatment initiation.

Methods and Results

This single-center, open label, and single-arm prospective study recruited 20 patients (14 men) with type 2 diabetes mellitus (T2DM). We examined the patients’ metabolic parameters before and 1 week after SGLT2 inhibitor (10 mg/day of empagliflozin) administration. The glucose infusion rate (GIR) was evaluated using the euglycemic hyperinsulinemic glucose clamp technique. Changes in laboratory and anthropometric parameters before and after SGLT2 inhibitor administration were analyzed according to the change in the GIR. The BMI, body fat amount, skeletal muscle amount, systolic blood pressure, and triglyceride level significantly decreased along with the treatment, while urinary glucose level and log GIR value significantly increased. Notably, changes in the GIR after SGLT2 inhibitor administration, which indicated improvement in peripheral insulin sensitivity, were negatively correlated with T2DM duration and positively with reduction in fluctuation of daily plasma glucose profiles before and after treatment.

Conclusion

SGLT2 inhibitor improved insulin sensitivity in the skeletal muscle independent of anthropometric changes. Patients with short duration of T2DM and insulin resistance can be good candidates for short-term SGLT2 inhibitor administration to improve insulin sensitivity in the skeletal muscle.

Open access

Anne Jouinot, Juliane Lippert, Martin Fassnacht, Bruno De La Villeon, Amandine Septier, Mario Neou, Karine Perlemoine, Silke Appenzeller, Mathilde Sibony, Sebastien Gaujoux, Bertrand Dousset, Rosella Libe, Lionel Groussin, Cristina L Ronchi, Guillaume Assie and Jerome Bertherat

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n=26), chromosome alteration profiles were determined using SNP arrays (n=14) and methylation profiles were determined using 4-gene bisulfite pyrosequencing (n=12).

Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were 'Noisy' (numerous and anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable, and might be more robust for the prognostic assessment.

Open access

Ya-Fen Hu, Lin Hua, Xiu Tuo, Ting-Ting Shi, Yi-Lin Yang, Yun-Fu Liu, Zhong-Yu Yan and Zhong Xin

Background

The pathogenesis underlying the alterations of orbital architecture in Graves’ orbitopathy (GO) is not yet fully understood. The present study aimed to investigate the association of DNA methylation in peripheral blood and orbital volumetry in Chinese patients with GO.

Methods

A total of 35 GO subjects (70 orbits) were subjected to CT scan. The total cross-sectional area of the extraocular muscles (orbital muscles, OM), total orbit area (TOA), and the exophthalmometry were measured and OM/TOA ratio was calculated. Targeted bisulfite sequencing was performed on seven candidate genes.

Results

No significant correlation was established between the DNA methylation levels of these genes and exophthalmometry. The MBP methylation level was found to be correlated with OM/TOA ratio (P < 0.05). Multiple linear regression analysis on parameters including age, sex, TRAb, duration of GO, and DNA methylation levels of seven genes with OM/TOA ratio confirmed that MBP and OM/TOA ratio had a significant correlation (P < 0.05). The partial least squares analysis showed that the top three genes with the highest loadings were MBP, BOLL, and BECN1 and that OM/TOA ratio affected the DNA methylation block than exophthalmometry.

Conclusions

This study provided preliminary evidence that MBP is a potential gene associated with OM enlargement in GO patients according to the combination of DNA methylation sequencing and orbital CT measurement.

Open access

T Grimmichova, M Haluzik, K Vondra, P Matucha and M Hill

Objective

Patients with type 2 diabetes (T2DM) generally experience a higher incidence of cancer. However, the association between T2DM and thyroid cancer is inconclusive.

Methods

Case-control prospective study, where 722 patients were screened for T2DM and prediabetes (PDM) and underwent thyroid ultrasound and biochemical tests. The patients were assigned to groups of PDM (n = 55), T2DM (n = 79) or a non-diabetes group (NDM) (n = 588). Fine-needle aspiration biopsy was carried out in 263 patients. Histological examinations were done for 109 patients after surgery, with findings of 52 benign (BS) and 57 malignant tumors (MS).

Results

Thirty-three percent of patients with T2DM and especially PDM were newly diagnosed by our screening: 6.5% with T2DM and 72% with PDM, respectively. The percentage of thyroid cancers did not significantly differ between the groups (χ2 test = 0.461; P = 0.794). Relevant positive thyroid predictors for T2DM (t-statistic = 25.87; P < 0.01) and PDM (21.69; P < 0.01) contrary to NDM (−26.9; P < 0.01) were thyroid volume (4.79; P < 0.01), thyroid nodule volume (3.25; P < 0.01) and multinodular thyroid gland (4.83; P < 0.01), while negative relevant predictors included the occurrence of autoimmune thyroid disease (AITD) (−2.01; P < 0.05).

Conclusion

In general, we did not observe an increased risk for thyroid cancer in the diabetic and prediabetic groups in comparison to controls, in spite of well-established increased risk for other malignancies. Structural and benign changes such as larger and multinodular thyroid glands, in comparison to autoimmune thyroid disease, are present more often in diabetics.

Open access

Milica Popovic, Fahim Ebrahimi, Sandrine Andrea Urwyler, Marc Yves Donath and Mirjam Christ-Crain

Arginine vasopressin (AVP) was suggested to contribute to cardiovascular risk and type 2 diabetes in patients with metabolic syndrome. The proinflammatory cytokine interleukin-(IL)-1 is able to induce AVP secretion and plays a causal role in cardiovascular mortality and type 2 diabetes. We investigated in two studies whether copeptin levels – the surrogate marker for AVP – are regulated by IL-1-mediated chronic inflammation in patients with metabolic syndrome. Study A was a prospective, interventional, single-arm study (2014-2016). Study B was a randomized, placebo-controlled, double-blind study (2016-2017). n=73 (Study A) and n=66 (Study B) adult patients with metabolic syndrome were treated with 100 mg anakinra or placebo (only in study B) twice daily for 1 day (study A), and 28 days (study B). Fasting blood samples were drawn at day 1, 7, and 28 of treatment for measurement of serum copeptin. Patients with chronic low-grade inflammation (C-reactive protein levels ≥2 mg/l) and BMI >35 kg/m2 had higher baseline copeptin levels (7.7 [IQR 4.9-11.9] vs. 5.8 [IQR 3.9-9.3] pmol/l, pinflamm=0.009; 7.8 [IQR 5.4-11.7] vs. 4.9 [IQR 3.7-9.8] pmol/l, pBMI=0.008). Copeptin levels did not change neither in the anakinra nor in the placebo group and remained stable throughout the treatment (p=0.44). Subgroup analyses did not reveal effect modifications. Therefore, we conclude that although IL-1-mediated inflammation is associated with increased circulating copeptin levels, antagonizing IL-1 does not significantly alter copeptin levels in patients with metabolic syndrome.

Open access

Marie Reeberg Sass, Nicolai Jacob Wewer Albrechtsen, Jens Pedersen, Kristine Juul Hare, Nis Borbye Pedersen, Katalin Kiss, Tina Vilsbøll, Filip Krag Knop, Steen S. Poulsen, Niklas Rye Jørgensen, Jens Juul Holst, Cathrine Ørskov and Bolette Hartmann

Objective: Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.

Methods: Intact PTH was measured in plasma from patients with T1D and matched healthy individuals employing 4-hour oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion on two separate experimental. In addition, expression of insulin receptors on archived, surgical specimens of parathyroid glands were assessed by immunochemistry (IHC) and quantitative polymerase chain reaction (qPCR).

Results: The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0-240min: -5256 ± 3954 min×ng/L and -2408 ± 1435 min×ng/L, P=0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P=0.002). Expression of insulin receptors in human parathyroid gland were detected by IHC and qPCR.

Conclusion: Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.