B lymphocytes are the source of autoantibodies against the thyroid-stimulating hormone receptor (TSHR) in Graves’ disease (GD). Characterization of autoimmune B-cell expression profiles might enable a better understanding of GD pathogenesis. To reveal this, the expression levels of long noncoding RNAs (lncRNAs) and mRNAs (genes) in purified B cells from patients with newly diagnosed GD and healthy individuals were compared using microarrays, which elucidated 604 differentially expressed lncRNAs (DE-lncRNAs) and 410 differentially expressed genes (DEGs). GO and pathway analyses revealed that the DEGs are mainly involved in immune response. A protein–protein interaction network presented experimentally validated interactions among the DEGs. Two independent algorithms were used to identify the DE-lncRNAs that regulate the DEGs. Functional annotation of the deregulated lncRNA–mRNA pairs identified 14 pairs with mRNAs involved in cell proliferation. The lncRNAs TCONS_00022357-XLOC_010919 and n335641 were predicted to regulate TCL1 family AKT coactivator A (TCL1A), and the lncRNA n337845 was predicted to regulate SH2 domain containing 1A (SH2D1A). TCL1A and SH2D1A are highly involved in B-cell proliferation. The differential expression of both genes was validated by qRT-PCR. In conclusion, lncRNA and mRNA expression profiles of B cells from patients with GD indicated that the lncRNA–mRNA pairs n335641–TCL1A, TCONS_00022357-XLOC_010919–TCL1A, and n337845–SH2D1A may participate in GD pathogenesis by modulating B-cell proliferation and survival. Therefore, the identified lncRNA and mRNA may represent novel biomarkers and therapeutic targets for GD.
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Xuechao Jiang, Yonghui Wang, Xiaoying Li, Leqi He, Qian Yang, Wei Wang, Jun Liu and Bingbing Zha
Yuan Zhou, ShengNan Wang, Jing Wu, JianJun Dong and Lin Liao
Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Many patients with MODY2 in Asia have delayed timely treatment because they did not receive the correct diagnosis. This study aims to analyze the clinical characteristics and GCK mutations in Asian MODY2.
We have collected 110 Asian patients with MODY2 from the PubMed, Embase, Medline, Web of Science, CNKI, and Wanfang with the following search terms: ‘maturity-onset diabetes of the young’ OR ‘MODY’ OR ‘maturity-onset diabetes of the young type 2’ OR ‘MODY2’ OR ‘GCK-DM’ OR ‘GCK-MODY’. Both mutations of GCK and clinical characteristics of MODY2 were analyzed.
There were 96 different mutations that occurred in coding regions and non-coding regions. Exon 5 and 7 were the most common location in coding regions and missense was the primary mutation type. The proportion of probands younger than 25 was 81.8%, and 81.4% of the probands had family history of hyperglycaemia. Ninety percent and 93% of Asian MODY2 probands exhibited mild elevation in FPG (5.4–8.3 mmol/L) and HbA1c (5.6–7.6%), respectively.
In most Asian patients, MODY2 occurred due to GCK mutation in coding regions, and exon 5 and 7 were the most common locations. FPG, HbA1c, and familial diabetes were important reference indicators for diagnosing MODY2. Altogether, the study indicates that for the young onset of diabetes with mild elevated blood glucose and HbA1c and family history of hyperglycaemia, molecular genetic testing is suggested in order to differentiate MODY2 from other types of diabetes earlier.
Rajae Talbi and Victor M Navarro
Kiss1 neurons are essential regulators of the hypothalamic–pituitary–gonadal (HPG) axis by regulating gonadotropin-releasing hormone (GnRH) release. Compelling evidence suggests that Kiss1 neurons of the arcuate nucleus (Kiss1ARC), recently identified as the hypothalamic GnRH pulse generator driving fertility, also participate in the regulation of metabolism through kisspeptinergic and glutamatergic interactions with, at least, proopiomelanocortin (POMC) and agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons, located in close apposition with Kiss1ARC. This review offers a comprehensive overview of the recent developments, mainly derived from animal models, on the role of Kiss1 neurons in the regulation of energy balance, including food intake, energy expenditure and the influence of circadian rhythms on this role. Furthermore, the possible neuroendocrine pathways underlying this effect, and the existing controversies related to the anorexigenic action of kisspeptin in the different experimental models, are also discussed.
Lianghui You, Yan Wang, Yao Gao, Xingyun Wang, Xianwei Cui, Yanyan Zhang, Lingxia Pang, Chenbo Ji, Xirong Guo and Xia Chi
Enhanced brown adipose tissue (BAT) mass and activity have been demonstrated to promote the expenditure of excess stored energy and reduce prevalence of obesity. Cold is known as a potent stimulator of BAT and activates BAT primarily through the β3-adrenergic-cAMP signaling. Here, we performed RNA-sequencing to identify differential miRNAs in mouse BAT upon cold exposure and a total of 20 miRNAs were validated. With the treatment of CL-316,243 (CL) and forskolin (Fsk) in mouse and human differentiated brown adipocyte cells in vitro, miR-23b-5p, miR-133a-3p, miR-135-5p, miR-491-5p, and miR-150-3p expression decreased and miR-455-5p expression increased. Among these deferentially expressed miRNAs, miR-23b-5p expression was differentially regulated in activated and aging mouse BAT and negatively correlated with Ucp1 expression. Overexpression of miR-23b-5p in the precursor cells from BAT revealed no significant effects on lipid accumulation, but diminished mitochondrial function and decreased expression of BAT specific markers. Though luciferase reporter assays did not confirm the positive association of miR-23b-5p with the 3′UTRs of the predicted target Ern1, miR-23b-5p overexpression may affect brown adipocyte thermogenic capacity mainly through regulating genes expression involving in lipolysis and fatty acid β-oxidation pathways. Our results suggest that miRNAs are involved in cold-mediated BAT thermogenic activation and further acknowledged miR-23b-5p as a negative regulator in controlling thermogenic programs, further providing potential molecular therapeutic targets to increase surplus energy and treat obesity.
Ulrik Ø Andersen, Dijana Terzic, Nicolai Jacob Wewer Albrechtsen, Peter Dall Mark, Peter Plomgaard, Jens F Rehfeld, Finn Gustafsson and Jens P Goetze
Neprilysin degrades natriuretic peptides in circulation and is also suggested to degrade the gut hormones gastrin and cholecystokinin. Neprilysin inhibition has become a therapeutic strategy and thus a regimen in need of further testing in terms of other hormonal axes besides natriuretic peptides. The aim of this study was to examine whether acute inhibition of neprilysin affects meal-induced responses in gastrin and cholecystokinin concentrations in healthy individuals.
Methods and results
Nine healthy young men were included in an open-labelled, randomized cross-over clinical trial. The participants received a standardized meal (25 g fat, 26 g protein, 42 g carbohydrate) on two separate days with or without a one-time dosage of sacubitril ((194 mg)/valsartan (206 mg)). Blood pressure, heart rate and blood samples were measured and collected during the experiment. Statistical differences between groups were assessed using area under the curve together with an ANOVA with a Bonferroni post hoc test. Sacubitril/valsartan increased the postprandial plasma concentrations of both gastrin and cholecystokinin (80% (AUC0-270 min, P = 0.004) and 60% (AUC0-270 min, P = 0.003), respectively) compared with the control meal. No significant hemodynamic effects were noted (blood pressure, AUC0-270 min, P = 0.86, heart rate, AUC0-270 min, P = 0.96).
Our study demonstrates that sacubitril/valsartan increases the postprandial plasma concentrations of gastrin and cholecystokinin in healthy individuals. The results thus suggest that neprilysin-mediated degradation of gastrin and cholecystokinin is physiologically relevant and may have a role in heart failure patients treated with sacubitril/valsartan.
Monika Karczewska-Kupczewska, Agnieszka Nikołajuk, Magdalena Stefanowicz, Natalia Matulewicz, Irina Kowalska and Marek Strączkowski
The aim of the study was to assess serum chemerin concentration and s.c. adipose tissue (SAT) chemerin expression in relation to insulin sensitivity and obesity in young healthy subjects.
We performed a cross-sectional study including 128 subjects, 44 with normal weight, 44 with overweight and 40 with obesity.
Hyperinsulinemic-euglycemic clamp and SAT biopsy were performed. Next, 30 subjects with obesity underwent 12-week weight-reducing dietary intervention.
Serum chemerin was higher and SAT chemerin expression was lower in subjects with obesity in comparison with other groups. The relationship of serum chemerin with SAT expression and insulin sensitivity were positive in normal weight and overweight individuals, and negative in individuals with obesity. In the entire study population, serum chemerin was also positively related to hsCRP, serum fetuin A and alanine aminotransferase. SAT chemerin was positively related to insulin sensitivity, SAT insulin signaling and adipogenic genes. Weight loss decreased serum chemerin, whereas SAT chemerin increased in subjects with the highest increase in insulin sensitivity.
Serum and SAT chemerin is differentially associated with insulin sensitivity and the relationship between serum chemerin and insulin sensitivity depends on adiposity. SAT chemerin is positively associated with insulin sensitivity across a wide range of BMIs and may be proposed as a biomarker of metabolically healthy SAT. Our results suggest that SAT is not the main source of serum chemerin in obesity.
Rolf Jorde and Guri Grimnes
In addition to its skeletal effects, vitamin D may also be important for health in general. It is uncertain what level of serum 25-hydroxyvitamin D (25(OH)D), marker of vitamin D status, is sufficient for these effects. With decreasing serum 25(OH)D levels there is an increase in serum PTH. The point at which this occurs has been considered as a threshold for vitamin D sufficiency. The thresholds found have varied widely and have mainly been based on observational studies. However, to truly establish a threshold for vitamin D effects, this has to be based on randomized controlled trials (RCTs).
The study included 2803 subjects from a general health survey, the Tromsø study, and pooled individual person data from five vitamin D intervention studies (n = 1544). Serum parathyroid hormone (PTH) and change in PTH after vitamin D supplementation were related to serum 25(OH)D levels in steps of 25 nmol/L (<24, 25–49, 50–74, 75–99, and >99 nmol/L).
In the Tromsø study, in the females there was a gradual decrease in serum PTH with increasing serum 25(OH)D with no apparent plateau, whereas in the males the decrease in PTH in subjects with serum 25(OH)D >74 nmol/l was marginal. In pooled RCTs, there was a significant reduction in serum PTH by vitamin D supplementation regardless of baseline serum 25(OH)D level.
The use of the serum PTH–25(OH)D relation from observational studies to determine a threshold for vitamin D sufficiency is highly questionable.
Thabiso R P Mofokeng, Salem A Beshyah, Fazleh Mahomed, Kwazi C Z Ndlovu and Ian L Ross
The burden and management of primary adrenal insufficiency (PAI) in Africa have not been well documented. We aimed to identify specific disease characteristics, patient demographics, and patterns of clinical management in established PAI in Africa.
An online survey of physicians’ experience relating to PAI.
There were 1334 responses received, 589 were complete, and 332 respondents reported managing patients with hypoadrenalism. The described responses were related to a calculated pool of 5787 patients with hypoadrenalism (2746 females, 3041 males), of whom 2302 had PAI. The likely causes of PAI in Sub-Saharan Africa (SSA) vs the Middle East and North Africa (MENA) regions included autoimmune disease (20% vs 60.3%; P < 0.001), tuberculosis (34% vs 4.1%; P < 0.001), AIDS (29.8% vs 1%; P < 0.001), malignancy, and genetic conditions. Sixteen percent of AD patients (376/2302) presented in an adrenal crisis. Medical emergency identification was not used by 1233 (83.6%) SSA vs 330 (40.4%) MENA patients (P < 0.001), respectively. Relative non-availability of diagnostic tests across both regions included adrenal antibodies 63% vs 69.6% (P = 0.328), s-cortisol 49.4 % vs 26.7% (P = 0.004), s-ACTH 55.7% vs 53.3% (P = 0.217), and adrenal CT scans 52.4% vs 31.8% (P = 0.017) in the SSA and MENA region, respectively. Across the entire cohort, the overall hydrocortisone use and extrapolated proportion of synacthen use were 59.4% and 50.7%, respectively.
Through the perception and practice of healthcare professionals, we identified significant challenges in the diagnosis and management of PAI which may herald high mortality. Differences between regions may reflect the allocation of healthcare resources.
Aleksandra Gilis-Januszewska, Łukasz Kluczyński and Alicja Hubalewska-Dydejczyk
Traumatic brain injury affects many people each year, resulting in a serious burden of devastating health consequences. Motor-vehicle and work-related accidents, falls, assaults, as well as sport activities are the most common causes of traumatic brain injuries. Consequently, they may lead to permanent or transient pituitary insufficiency that causes adverse changes in body composition, worrisome metabolic function, reduced bone density, and a significant decrease in one’s quality of life. The prevalence of post-traumatic hypopituitarism is difficult to determine, and the exact mechanisms lying behind it remain unclear. Several probable hypotheses have been suggested. The diagnosis of pituitary dysfunction is very challenging both due to the common occurrence of brain injuries, the subtle character of clinical manifestations, the variable course of the disease, as well as the lack of proper diagnostic algorithms. Insufficiency of somatotropic axis is the most common abnormality, followed by presence of hypogonadism, hypothyroidism, hypocortisolism, and diabetes insipidus. The purpose of this review is to summarize the current state of knowledge about post-traumatic hypopituitarism. Moreover, based on available data and on our own clinical experience, we suggest an algorithm for the evaluation of post-traumatic hypopituitarism. In addition, well-designed studies are needed to further investigate the pathophysiology, epidemiology, and timing of pituitary dysfunction after a traumatic brain injury with the purpose of establishing appropriate standards of care.
Willem de Ronde and Diederik L Smit
This review summarizes 10 years experience with male abusers of anabolic androgenic steroids (AAS). The typical user of AAS is male, aged between 20 and 40 and lifting weights. Illegal AAS are cheap and easily obtained via internet or local suppliers. AAS are mostly used in cycles with a duration between 6 and 18 weeks. Most AAS cycles contain multiple agents, used simultaneously in a dose vastly exceeding a substitution dose. A variety of other performance and image-enhancing drugs are commonly used, including human growth hormone, thyroid hormone, tamoxifen, clomiphene citrate and human chorionic gonadotrophin. Short-term clinical and biochemical side effects are well established. Long-term side effects are uncertain, but may include heart failure, mood-and anxiety disorders, hypogonadism and subfertility. We share our views on the management of common health problems associated with AAS abuse.