Vitamin-D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia to review cases with 25-hydroxylase deficiency and to describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from 9 different families who presented with low 25-OH vitamin-D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with heterozygous mutation had hypocalcemic manifestations. 13/18 of homozygous patients and all the heterozygous patients responded to high doses of vitamin-D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. 5/18 of homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzeing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin-D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.
Sarah Bakhamis, Faiqa Imtiaz, Khushnooda Ramzan, Edward De Vol, Osamah AlSagheir, Abdulrahman AlRajhi, Abdullah Alashwal, Bassam Bin Abbas, Nadia Sakati, and Afaf Al-Sagheir
Guang-Ran Yang, Dongmei Li, and Zidian Xie
Objective: There is a lack of consensus on whether a high body mass index (BMI) increases the risk of diabetic retinopathy (DR). We aimed to investigate the association between BMI, overweight, obesity, and DR using the data of diabetes respondents in the 2015 US Behavioral Risk Factor Surveillance System survey.
Methods: Diabetes respondents aged over 18-year-old with complete information as well as undergone fundus examination in the past two years or had been diagnosed with DR were included. Weighted logistic regression analyses were used to identify the association of BMI with DR.
Results: Among the 21,647 diabetes respondents, 4588 respondents had DR with a weighted prevalence of 22.5%. The mean BMI of all diabetes respondents was 31.50±6.95 kg/m2 with18,498 (86.5%) overweight and 11,353 (54.6%) obese. The mean BMI of the DR group (31.83±7.41kg/m2) was significantly higher than that of the non-DR group (31.41±6.81kg/m2, p<0.05). The proportion of obese respondents in the DR group was higher than the non-DR group (54.3%, p<0.001).The weighted prevalence of DR was 0.8%, 13.8%, 29.7%, and 55.7% for the emaciation group, the normal weight group, the overweight group, and the obesity group, respectively (p<0.001). Weighted logistic regression analysis showed that both BMI (adjusted OR=1.004, 95%CI 1.003-1.004) and obesity (adjusted OR=1.051, 95%CI 1.048-1.055) were associated with DR after adjusting for the confounding variables. However, overweight was not significantly associated with DR.
Conclusion: The prevalence of DR in the normal weight, overweight, and obesity groups increased gradually. Obesity, rather than overweight, was significantly associated with increased DR prevalence.
Melinda Kertész, Szilárd Kun, Eszter Sélley, Zsuzsanna Nagy, Tamás Kőszegi, and István Wittmann
Background: Type 2 diabetes is characterized, beyond the insulin resistance, by polyhormonal resistance. Thyroid hormonal resistance has not yet been described in this population of patients. Metformin is used to decrease insulin resistance, and at present it is assumed to influence the effect of triiodothyronine, as well.
Methods: In this open label, pilot, hypothesis generating, follow-up study 21 patients were included, all of them euthyroid with drug naïve, newly diagnosed type 2 diabetes. Before and after four weeks of metformin therapy fructosamine, homeostasis model assessment for insulin resistance (HOMA-IR), thyroid hormones, T3/T4 ratio, and TSH, as well as blood pressure and heart rate using ambulatory blood pressure monitor were measured. We also conducted an in vitro study to investigate the possible mechanisms of T3 resistance, assessing T3 induced Akt phosphorylation among normal (5 mM) and high (25 mM) glucose levels with or without metformin treatment in a human embryonal kidney cell line.
Results: Metformin decreased the level of T3 (p<0.001), the ratio of T3/T4 (p=0.038), fructosamine (p=0.008) and HOMA-IR (p=0.022). All these changes were accompanied by an unchanged TSH, T4, triglyceride, plasma glucose, bodyweight, blood pressure and heart rate. In our in vitro study, T3 induced Akt phosphorylation decreased in cells grown in 25 mM glucose medium compared to those in 5 mM. Metformin could not reverse this effect.
Conclusion: Metformin seems to improve T3 sensitivity in the cardiovascular system in euthyroid, type 2 diabetic patients, the mechanism of which may be supracellular.
Elena V Varlamov, Dan Alexandru Niculescu, Swechya Banskota, Simona Andreea Galoiu, Catalina Poiana, and Maria Fleseriu
Purpose: The number of international acromegaly-related registries is increasing; however, heterogeneity of acromegaly symptoms and signs across countries is not well described. We compared clinical disease manifestations at diagnosis between two large University referral centers from two continents.
Methods: Retrospective, comparative epidemiological study of acromegaly patients at two centers; 1) C. I. Parhon National Institute of Endocrinology, “Carol Davila” University of Medicine and Pharmacy Bucharest, Romania (Parhon), and 2) Pituitary Center, Oregon Health & Science University, Portland, Oregon, United States (OHSU) from approved registries was undertaken. Data were extracted from medical charts and questionnaires. Binary logistic regression analysis was undertaken for the most frequently noted symptoms and clinical signs.
Results: Study included 216 patients (87 Parhon, 129 OHSU). Age, sex and median delay in diagnosis were similar between centers. IGF-1 index was higher in patients at Parhon (3.3 vs 2.1, p < 0.001). The top five symptoms at both centers were; enlarged hands/feet, headache, arthralgia, fatigue, and irregular menses in women. A significant difference was noted for multiple signs and symptoms frequency, often >20 percentage points between centers. Center was a predictor of many signs and symptoms, independent of acromegaly biochemical severity or disease duration.
Conclusion: We show in the first comparative study that differences in medical practice, documentation, and likely cultural differences can influence patients’ symptom(s) reporting and screening patterns in geographically different populations. Pooling data into large multicenter international registries databases may lead to loss of regional characteristics and thus a mixed overall picture of combined cohorts.
Daisuke Watanabe, Satoshi Morimoto, Noriko Morishima, and Atsuhiro Ichihara
Primary aldosteronism (PA) is divided into two major subtypes, aldosterone-producing adenoma (APA) and bilateral idiopathic hyperplasia (IHA) and is associated with a higher risk of cardiovascular events. However, the nature of vascular function in PA patients remains to be determined. The aim of this study was to determine the vascular function and investigate the implications of vascular function assessments in the patients.
Flow-mediated dilation (FMD), as an index of endothelial function, and cardio-ankle vascular index (CAVI), as an index of arterial stiffness, were retrospectively compared between 42 patients with APA, 37 patients with IHA, and 42 patients with essential hypertension (EH). These values were also compared with background factors, KCNJ5 mutation and clinical outcome in terms of blood pressure reduction after adrenalectomy in the APA group.
FMD was significantly lower in the APA group (4.8 ± 2.1%) and IHA group (4.1 ± 1.9%) than in the EH group (5.7 ± 2.1%). CAVI did not differ significantly among groups. Although no significant correlations were seen between FMD and background factors in the IHA group, FMD correlated negatively with BMI and plasma aldosterone concentration in the APA group (rs = −0.313, rs = −0.342, respectively). KCNJ5 mutational status was not associated with FMD value. High FMD was associated with blood pressure normalization after adrenalectomy in the APA group.
Patients with PA displayed impaired endothelial function. Complete clinical success after adrenalectomy was associated with preserved endothelial function. This study provides a better understanding of FMD assessment in patients with PA.
Xiaoli Liu, Lanxiang Liu, Rui Wang, Xiaojiao Jia, Binbin Liu, Ning Ma, and Qiang Lu
We aimed to investigate early arteriosclerosis and its risk factors in populations with prediabetes and new-onset diabetes.
Materials and methods
A total of 148 participants who did not have diabetes mellitus were assigned to three groups through an oral glucose tolerance test: the normal glucose tolerance (NGT) group; the impaired glucose regulation, also known as prediabetes group and the new-onset type 2 diabetes mellitus group. The insulin resistance index was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR). An ELISA was used to determine the level of fibroblast growth factor 21 (FGF21). An arteriosclerosis detector was used to measure the brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). The baPWV, ABI, and FGF21 were used to assess early arteriosclerosis.
Significant differences in age, systolic blood pressure (SBP), fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), 2-h insulin (2hINS), and HOMA-IR were found between the NGT group and the prediabetes and new-onset diabetes groups. All of the above, except 2hINS, showed an increasing trend. Moreover, the FGF21 was higher in the new-onset diabetes group than in the NGT group. The baPWV was higher in the new-onset diabetes group than in the other two groups, but no significant difference was noted in the ABI. Age, SBP, diastolic blood pressure, FPG, 2hPG, and FGF21 were positively correlated with the baPWV. In addition, FPG, SBP, FGF21, and HOMA-IR were independent risk factors for the baPWV.
Patients with prediabetes and new-onset diabetes may have more significant early arteriosclerosis. The blood glucose level and insulin resistance index may be independent risk factors for early arteriosclerosis.
Bharat Kumar, Madhukar Mittal, Maya Gopalakrishnan, Mahendra K Garg, and Sanjeev Misra
Plasma glucose has been correlated with in-hospital mortality among many diseases including infections. We aimed to study the plasma glucose at the admission of hospitalized patients with COVID-19 at a tertiary care referral hospital at Jodhpur, India and its relation with mortality.
A hospital-based clinical study of plasma glucose of COVID-19 patients conducted from May 15 to June 30, 2020 after ethical approval.
Random blood samples at admission were collected for plasma glucose, interleukin-6 (IL6) and high sensitivity C-reactive protein (hsCRP) after written informed consent was obtained. Plasma glucose was analyzed by the automated analyzer, IL6 by chemiluminescent immunoassay and hsCRP by immune-turbidimetric assay.
A total of 386 patients were studied (female 39.6%); 11.1% had severe disease and 4.1% expired. There were 67 (17.4%) patients with known diabetes mellitus (DM). Patients with a history of DM had three times higher mortality (6/67, 9%) than those without DM (10/309, 3.1%). Patients with moderate and severe disease according to ICMR and WHO grading had higher plasma glucose than those with asymptomatic or mild disease (P < 0.0001). Plasma glucose levels at admission were significantly higher in non-survivors when compared to those who survived (297 ± 117 vs 131 ± 73; P < 0.0001). COVID-19 patients showed increased mortality with incremental plasma glucose levels. The hazard ratio for mortality was 1.128 (95% CI 0.86–14.860), 1.883 (95% CI 0.209–16.970), and 4.005 (95% CI 0.503–32.677) in random plasma glucose group of >100–200, >200–300 and >300 mg/dL, respectively, compared to those with random plasma glucose of <100 mg/dL at admission. Plasma glucose was strongly correlated with hsCRP (P < 0.001) and IL6 (P < 0.0001).
Plasma glucose at admission in hospitalized COVID-19 patients is a strong predictor of mortality.
Yardena Tenenbaum-Rakover, Osnat Admoni, Ghadir Elias-Assad, Shira London, Marie Noufi-Barhoum, Hanna Ludar, Tal Almagor, Yoav Zehavi, Charles Sultan, Rita Bertalan, Anu Bashamboo, and Kenneth McElreavey
Disorders of sex development (DSD) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients.
We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology.
The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two atients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A.
Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management – and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.
Christine Rode Andreasen, Andreas Andersen, Filip Krag Knop, and Tina Vilsbøll
Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.
Min Yang, Xiangling Deng, Shunan Wang, Bo Zhou, Wenquan Niu, and Zhixin Zhang
We aimed to identify and characterize potential factors, both individually and jointly as a nomogram, associated with short stature and pre-shortness in Chinese preschool-aged children.
Total of 9501 children aged 3–6 years were recruited from 30 kindergartens in Beijing and Tangshan from September to December 2020 using a stratified random sampling method. Effect-size estimates are expressed as odds ratio (OR) and 95% CI.
The prevalence of short stature and pre-shortness in preschool-aged children was 3.9% (n = 375) and 13.1% (n = 1616), respectively. Factors simultaneously associated with the significant risk for short stature, pre-shortness and both included BMI, paternal height, maternal height, birth weight, birth height, latter birth order (≥2) and less parental patience to children. Besides, breastfeeding duration (≥12 months) was exclusively associated with pre-shortness (OR, 95% CI, P: 1.16, 1.01 to 1.33, 0.037), and childhood obesity with both short stature (3.45, 2.62 to 4.54, <0.001) and short stature/pre-shortness (1.37, 1.15 to 1.64, <0.001). Modeling of significant factors in nomograms had descent prediction accuracies, with the C-index being 77.0, 70.1 and 71.2% for short stature, pre-shortness and both, respectively (all P < 0.001).
Our findings indicate the joint contribution of inherited characteristics, nutrition status from the uterus to childhood, and family psychological environment to short stature and pre-shortness in Chinese preschool-aged children. Further validation in other independent groups is warranted.