Vitamin D has many physiological functions including upregulation of intestinal calcium and phosphate absorption, mobilization of bone resorption, renal reabsorption of calcium as well as actions on a variety of pleiotropic functions. It is believed that many of the hormonal effects of vitamin D involve a 1,25-dihydroxyvitamin D3-vitamin D receptor-mediated transcriptional mechanism involving binding to the cellular chromatin and regulating hundreds of genes in many tissues. This comprehensive historical review provides a unique perspective of the many steps of the discovery of vitamin D and its deficiency disease, rickets, stretching from 1650 until the present. The overview is divided into four distinct historical phases which cover the major developments in the field and in the process highlighting the: (a) first recognition of rickets or vitamin D deficiency; (b) discovery of the nutritional factor, vitamin D and its chemical structure; (c) elucidation of vitamin D metabolites including the hormonal form, 1,25-dihydroxyvitamin D3; (d) delineation of the vitamin D cellular machinery, functions and vitamin D-related diseases which focused on understanding the mechanism of action of vitamin D in its many target cells.
Anela Blažević, Anand M Iyer, Marie-Louise F van Velthuysen, Johannes Hofland, Peter M van Koestveld, Gaston J H Franssen, Richard A Feelders, Marina Zajec, Theo M Luider, Wouter W de Herder, and Leo J Hofland
Increased levels of serotonin secretion are associated with mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs). However, the profibrotic potential of serotonin differs between patients, and in this study, we aimed to gain an understanding of the mechanisms underlying this variability. To this end, we analyzed the proteins involved in tryptophan metabolism in SI-NETs.
Proteomes of tumor and stroma from primary SI-NETs and paired mesenteric metastases of patients with MF (n = 6) and without MF (n = 6) were identified by liquid chromatography–mass spectrometry (LC-MS). The differential expression of proteins involved in tryptophan metabolism between patients with and without MF was analyzed. Concurrently, monoamine oxidase A (MAO-A) expression was analyzed in the tumor and stromal compartment by immunohistochemistry (IHC) and reported as intensity over area (I/A).
Of the 42 proteins involved in tryptophan metabolism, 20 were detected by LC-MS. Lower abundance of ten proteins was found in mesenteric metastases stroma in patients with MF. No differential expression was found in primary SI-NETs. In patients with MF, IHC showed lower MAO-A expression in the stroma of the primary SI-NETs (median 4.2 I/A vs 6.5 I/A in patients without MF, P = 0.003) and mesenteric metastases (median 2.1 I/A vs 2.8 I/A in patients without MF, P= 0.019).
We found a decreased expression of tryptophan and serotonin-metabolizing enzymes in the stroma in patients with MF, most notably in the mesenteric stroma. This might account for the increased profibrotic potential of serotonin and explain the variability in the development of SI-NET-associated fibrotic complications.
Daniel Alexander Hescheler, Milan Janis Michael Hartmann, Burkhard Riemann, Maximilian Michel, Christiane Josephine Bruns, Hakan Alakus, and Costanza Chiapponi
Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC.
FDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response.
In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response.
While ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options.
Kjersti S Bakken, Kristina Randjelovic Nermo, Bjørn Gunnar Nedrebø, Tim I M Korevaar, and Tor A Strand
Thyroid disease during pregnancy is associated with adverse pregnancy outcomes and suboptimal fetal development. During the last decades, guidelines for diagnosing thyroid disease during pregnancy have changed considerably and there has been increased awareness. This study aimed to describe the prevalence of thyroid disease treatment over time among pregnant women in Norway.
Nationwide register-based study.
We combined historical data from the Medical Birth Registry of Norway and the Norwegian Prescription Database, identifying pregnant women using thyroid therapy from 2004 to 2018.
A total of 855,067 pregnancies were included in the analyses. The proportion of women using thyroid hormone replacement therapy during pregnancy increased from 1.46% (n = 800) in 2004 to 3.57% (n = 1940) in 2018. The proportion of women using antithyroid medications also increased from 0.04% (n = 20) in 2004 to 0.10% (n = 56). During these 15 years, the mean maternal age increased by 0.9 years. When adjusting for age, the risk for being on thyroid hormone replacement therapy during pregnancy increased by an average of 5% per year (odds ratio: 1.05, 95% CI: 1.05–1.05).
During the recent 15 years, there has been a substantial increase in the use of thyroid hormone therapy in Norwegian pregnant women. We speculate that this could be due to an increased awareness in combination with overdiagnosis because of inappropriate diagnostic criteria. To truly understand the possible causes and consequences of this development, further research is warranted.
Małgorzata Kałużna, Pola Kompf, Katarzyna Wachowiak-Ochmańska, Jerzy Moczko, Aleksandra Królczyk, Adam Janicki, Karol Szapel, Marian Grzymisławski, Marek Ruchała, and Katarzyna Ziemnicka
Polycystic ovary syndrome (PCOS) encompasses endocrine, reproductive and metabolic disturbances. Abdominal pain and bowel movement disturbances are common complaints of PCOS patients. It remains uncertain whether the characteristic features of PCOS are associated with an increased incidence of irritable bowel syndrome (IBS).
In the study, 133 patients with PCOS diagnosed according to international evidence-based guidelines and 72 age- and BMI-matched eumenorrheic controls were enrolled. Anthropometric measurements and biochemical and hormonal characteristics were collected. The Rome IV criteria were used for IBS diagnosis. Quality of life (QoL) and depressive symptoms were also assessed.
IBS symptom prevalence in PCOS was not significantly different than in controls. Hyperandrogenism and simple and visceral obesity did not appear to affect IBS prevalence in PCOS. There were no anthropometric, hormonal or biochemical differences between IBS-PCOS and non-IBS-PCOS patients, apart from IBS-PCOS patients being slightly older and having lower thyroid-stimulating hormone. Metabolic syndrome (MS) prevalence was higher in IBS-PCOS than non-IBS-PCOS. QoL appears to be significantly lower in IBS-PCOS compared to PCOS-only patients. The occurrence of depression was higher in IBS-PCOS vs non-IBS-PCOS patients. At least one alarm symptom was reported by 87.5% of IBS-PCOS; overall, this group experienced more alarm symptoms than the IBS-only group.
Since a link between PCOS and IBS comorbidity and increased MS prevalence was noted, patients presenting with both conditions may benefit from early MS diagnostics and management. The high incidence of alarm symptoms in PCOS women in this study highlights the need for differential diagnosis of organic diseases that could mimic IBS symptoms.
Xin He, Qin Yan, Chazhen Liu, Zhengyuan Wang, Ping Liao, Tong Liu, Zehuan Shi, Qi Song, Xueying Cui, Wenjing Wang, and Jiajie Zang
This study aimed to explore the relationship between thyroid function and autoimmunity and adverse birth outcomes. Serum levels of thyroid function were detected by electrochemiluminescence assay. Urine iodine concentration was detected using the acid digestion method. We used multiple linear regression to assess the correlation between thyroid function indicators and birth weight according to trimester stratification and binary logistic regression to evaluate the correlation between thyroid dysfunction and adverse birth outcomes. Reference ranges for trimester-specific thyroid hormones were established in our 2564 pregnant women cohort with mild iodine deficiency. The higher the maternal thyroid-stimulating hormone in the first trimester (B = 0.09, P = 0.048) and total triiodothyronine (TT3) in the third trimester (B = 0.16, P < 0.001) of TPOAbnegative women, the higher the birth weight Z-score, whereas in the second trimester, free-thyroxine of mothers with TPOAb negative was lower (B = −0.10, P = 0.026) and the birth weight Z-score was higher. Pregnant women with overt and subclinical hyperthyroidism had a higher risk of preterm births than euthyroid women (11.9% vs 4.5%; odds ratio (OR): 2.84; P = 0.009). Women with higher TT3 had a higher risk of preterm (17.0% vs 4.5%; OR: 4.19; P < 0.001) and LGA (34.0% vs 11.1%; OR: 3.70; P < 0.001) births than euthyroid women. In conclusion, thyroid function during pregnancy could affect birth weight and birth outcome.
Wang-shu Liu, Ling-yan Hua, Su-xiang Zhu, Feng Xu, Xue-qin Wang, Chun-feng Lu, Jian-bin Su, and Feng Qi
The aim of the study was to explore whether plasma stromal cell-derived factor 1 (SDF-1) levels are associated with the EZSCAN score and its derived indicators in patients with type 2 diabetes (T2D).
From July 2020 to December 2020, a total of 253 patients with T2D were consecutively recruited. Serum SDF-1 levels were measured by sandwich ELISA. EZSCAN test was applied to evaluate the sudomotor function of each patient, and based on the results, EZSCAN score, cardiac autonomic neuropathy risk score (CANRS) and cardiovascular risk score (CVDRS) were calculated by particular algorithms. In addition, other relevant clinical data were also collected.
With increasing tertiles of serum SDF-1 levels, the CANRS and CVDRS significantly increased (both Pfor trend <0.001), while the EZSCAN score significantly decreased (Pfor trend <0.001). Moreover, serum SDF-1 levels were significantly and positively correlated with the CANRS and CVDRS (r = 0.496 and 0.510, respectively, both P < 0.001), and negatively correlated with the EZSCAN score (r = −0.391, P < 0.001). Furthermore, multivariate linear regression analyses were constructed, and after adjusting for other clinical covariates, serum SDF-1 levels were independently responsible for EZSCAN score (β = −0.273, t = −3.679, P < 0.001), CANRS (β = 0.334, t = 5.110, P < 0.001) and CVDRS (β = 0.191, t = 4.983, P = 0.003).
SDF-1 levels in serum were independently associated with the EZSCAN score and its derived indicators, such as CANRS and CVDRS in patients with T2D.
Sarantis Livadas, Christina Bothou, Justyna Kuliczkowska-Płaksej, Ralitsa Robeva, Andromahi Vryonidou, Jelica Bjekic Macut, Ioannis Androulakis, Milica Opalic, Zadalla Mouslech, Andrej Milewicz, Alessandra Gambineri, Dimitrios Panidis, and Djuro Macut
Polycystic ovary syndrome (PCOS) is considered a risk factor for the development of type 2 diabetes mellitus (T2DM). However, which is the most appropriate way to evaluate dysglycemia in women with PCOS and who are at increased risk are as yet unclear.
Aim of the study
To determine the prevalence of T2DM, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in PCOS women and potential factors to identify those at risk.
Subjects and methods
The oral glucose tolerance test (OGTT), biochemical/hormonal profile, and ovarian ultrasound data from 1614 Caucasian women with PCOS and 362 controls were analyzed in this cross-sectional multicenter study. The data were categorized according to age and BMI.
Dysglycemia (T2DM, IGT, and IFG according to World Health Organization criteria) was more frequent in the PCOS group compared to controls: 2.2% vs 0.8%, P = 0.04; 9.5% vs 7.4%, P = 0.038; 14.2% vs 9.1%, P = 0.002, respectively. OGTT was essential for T2DM diagnosis, since in 88% of them basal glucose values were inconclusive for diagnosis. The presence of either T2DM or IFG was irrespective of age (P = 0.54) and BMI (P = 0.32), although the latter was associated with IGT (P = 0.021). There was no impact of age and BMI status on the prevalence of T2DM or IFG. Regression analysis revealed a role for age, BMI, fat deposition, androgens, and insulin resistance for dysglycemia. However, none of the factors prevailed as a useful marker employed in clinical practice.
One-third of our cohort of PCOS women with either T2DM or IGT displayed normal fasting glucose values but without confirming any specific predictor for dysglycemic condition. Hence, the evaluation of glycemic status using OGTT in all women with PCOS is strongly supported.
Panisa Hantrakun, Rattanaporn Sekararithi, Thidarat Jaiwongkam, Sirinart Kumfu, Chatree Chai-adisaksopha, Nipon Chattipakorn, Theera Tongsong, and Phudit Jatavan
To evaluate the effect of metformin in improving platelet dysfunction in women with gestational diabetes mellitus (GDM).
Patients and methods
A randomized controlled trial was conducted on pregnant women diagnosed with GDM. Singleton low-risk pregnancies meeting the inclusion criteria were randomly allocated at 27–31 weeks to receive metformin and placebo through the rest of pregnancy. Thirty-seven and 39 cases were recruited into the metformin group and the placebo group, respectively. MPVs, P-selectin, and 8-isoprostane levels were determined at the time of allocation and 6 weeks after treatment. Obstetric and neonatal outcomes were also assessed.
Most baseline characteristics of the two groups were comparable. The levels of P-selectin after 6 weeks of treatment were significantly higher in the metformin group (68.9 ± 14.4 vs 60.6 ± 11.3; P-value = 0.006), indicating more platelet activation. All of the obstetric and neonatal outcomes were comparable except that birth weight was significantly lower in the metformin group (3018 ± 364 g vs 3204 ± 393 g; P-value = 0.037).
Metformin, in addition to diet and lifestyle modifications, does not improve or worsen oxidative stress and platelet dysfunction in women with GDM. Nevertheless, metformin significantly reduces fetal weight in women with GDM, theoretically preventing macrosomia.
Katrine M Lauritsen, Jens Hohwü Voigt, Steen Bønløkke Pedersen, Troels K Hansen, Niels Møller, Niels Jessen, Lars C Gormsen, and Esben Søndergaard
SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P = 0.03) and mRNA content (P = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.