Worsening of unrecognized tumour-induced osteomalacia with inadvertent use of recombinant human parathyroid hormone

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GENETIC SUSCEPTIBILITY OF TRANSCRIPTION FACTOR 7-LIKE 2 GENE VARIANT AND RISK OF TYPE 2 DIABETES IN ASIAN INDIANS

Background: The variants of transcription factor 7-like 2 (TCF7L2) gene have been shown to be associated with type 2 diabetes mellitus (T2DM) and its related complications. Objectives: We aimed to explore the possible association of rs7903146 (C/T) variant in TCF7L2 with the risk of T2DM in the North Indian population. Methods: The present case–control study included a total of 638 human subjects (318 T2DM subjects and 320 healthy controls). Various anthropometric, biochemical, and genetic parameters were studies in all the subjects. Genotyping of TCF7L2 gene was carried out using allele-specific polymerase chain reaction method. Results: The results of this study indicate significantly higher values of body mass index, waist circumference, waist-to-hip ratio, and body fat (%) in T2DM subjects than controls (p≤0.001). Dyslipidemia represented by higher levels of triglycerides and reduced values of high-density lipoprotein was more predominant in diabetic subjects compared to healthy subjects. The frequency of risk genotype (TT) frequency was significantly higher in T2DM subjects (16.4%) compared to controls (11.6%). The “T” allele was more dominant in diabetic subjects than controls. Logistic regression analysis of the data revealed a significant association of TT genotype with 2-fold (odds ratio with 95% of confidence interval; 2.09 [1.29–3.42] p=0.003) and CT genotype with 1.7-fold (1.73 [1.23–2.44] p=0.002) increased risk of developing T2DM. Conclusions: The present study demonstrated a significant association of rs7903146 (C/T) variant in TCF7L2 with the augmented risk of T2DM in North Indian population

Metabolic syndrome and risk of major coronary events among the urban diabetic patients: North Indian Diabetes and Cardiovascular Disease Study-NIDCVD-2

Objective: The present study aimed at estimating the prevalence of metabolic syndrome (MetS) and prospectively, evaluating cardiovascular events among Asian Indians type 2 diabetic subjects. Methods: The sample comprised 1522 type 2 diabetic mellitus (T2DM) subjects aged 25-91. years, who participated in the North Indian Diabetes and Cardiovascular Disease Study (NIDCVD). The participants were screened for hypertension, dyslipidemia, obesity and cardiovascular events. Anthropometric, clinical and biochemical measurements were done in all subjects. The prevalence of MetS was estimated in all the subjects according to the harmonized criteria of 2009. Results: The prevalence of MetS among urban Indian diabetic subjects was 71.9% and was significantly higher in females (86%) as compared to males (57.9%). To determine the independent predictors of the MetS in diabetic sample, binary logistic regression analyses were performed using demographic and biochemical parameters. Significant differences in the indices of generalized and abdominal obesity and lipids (total cholesterol, high density lipoprotein) were observed (p <. 0.01) in male:female and MetS and non-MetS comparisons. Regression analysis for prediction of CAD showed that family history, age, body mass index (BMI), SBP, physical inactivity and hypertension independently and significantly predicted the disease outcome. Binary logistic regression analysis revealed that MetS may be an independent risk/predictor of CAD (odd ratio (OR) = 3.44, CI 1.31-9.01, p = 0.012) along with higher age groups, BMI and hypertension in Indian population. Conclusion: The study demonstrated that the high prevalence of MetS and its different components were positively associated with a higher risk of CAD in north Indian diabetic subjects. Nevertheless, MetS is a major health problem in India, comprehensive population studies are warranted for estimation of incidence and prevalence, and education should be provided on its prevention and control to reduce the diabetes-related morbidity and mortality

GCM2 Silencing in Parathyroid Adenoma is associated with Promoter Hypermethylation and Gain of Methylation on Histone 3

PURPOSE: Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of parathyroid glands. We sought to identify if the epigenetic alterations in the GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices. EXPERIMENTAL DESIGN: mRNA and protein expression of GCM2 were analyzed by RT-qPCR and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of GCM2 promoter were measured by bisulfite sequencing and ChIP-qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in PTH-C1 cells by treating with 5-aza 2\u27deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels. RESULTS: mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P\u3c0.001) and higher H3K9me3 levels in GCM2 promoter (P\u3c0.04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a non-significant change in GCM2 transcription. CONCLUSION: These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be promising avenues of research for parathyroid adenoma therapeutics

Large parathyroid adenomas: Potential mechanisms to reconcile adenoma size and disease phenotype

Parathyroid adenomas weighing more than 3.5 g are reported variously as atypical , large or giant parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the \u3e3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 510 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC

Can fingernail quality predict bone damage in Type 2 diabetes mellitus? a pilot study

Type 2 diabetes mellitus (T2DM) adversely affects the normal functioning, intrinsic material properties, and structural integrity of many tissues, including bone. It is well known that the clinical utility of areal bone mineral density (aBMD) is limited to assess bone strength in individuals with T2DM. Therefore, there is a need to explore new diagnostic techniques that can better assist and improve the accuracy of assessment of bone tissue quality. The present study investigated the link between bone and fingernail material/compositional properties in type 2 diabetes mellitus (T2DM). For that, femoral head and fingernail samples were obtained from twenty-five adult female patients (with/without T2DM) with fragility femoral neck fractures undergoing hemi/total hip arthroplasty. Cylindrical cores of trabecular bone were subjected to micro-CT, and lower bone volume fraction was observed in the diabetic group than the non-diabetic group due to fewer and thinner trabeculae in individuals with T2DM. The material and compositional properties of bone/fingernail were estimated using nanoindentation and Fourier Transform Infrared Spectroscopy, respectively. Both bone/fingernails in T2DM had lower reduced modulus (Er), hardness (H), lower Amide I and Amide II area ratio (protein content), higher sugar-to-matrix ratio, and relatively high carboxymethyl-lysine (CML) content compared with non-diabetic patients. Sugar-to-matrix ratio and relative CML content were strongly and positively correlated with HbA1c for both bone/fingernail. There was a positive correlation between bone and fingernail glycation content. Our findings provide evidence that the degradation pattern of bone and fingernail properties go hand-in-hand in individuals with T2DM. Hence, the fingernail compositional/material properties might serve as a non-invasive surrogate marker of bone quality in T2DM; however, further large-scale studies need to be undertaken

ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia with metabolic syndrome in Asian Indians

Background: Ectonucleotide pyrophosphatase/phosphodiesterase1 (ENPP1/PC-1) is a key modulator of the insulin signaling pathway, and its common variant, K121Q, increases the susceptibility to diabetes and cardiovascular diseases. Objectives: The main objective of the present study was to investigate the association of ENPP1 K121Q polymorphism with the pathophysiology of metabolic syndrome (MetS) in a north Indian population. Methods: A total of 567 participants (303 MetS subjects and 264 healthy controls) were examined for ENPP1 genotypes and various clinical parameters, including body mass index (BMI), waist circumference (WC), systolic and diastolic blood pressures (SBP/DBP), fasting blood glucose (FBG), cholesterol, triglycerides (TG), highdensity lipoprotein, and insulin. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Statistical analysis of the data was done using SPSS. Results: Significant increases in BMI, WC, SBP, DBP, FBG, TG, low-density lipoprotein, insulin, and Homeostasis Model Assessment of insulin resistance (HOMAIR) and of beta-cell function (HOMA-BF) were observed in MetS patients compared to healthy controls. Logistic regression analysis of data demonstrated a nonsignificant association of QQ and KQ+QQ genotypes with increased risk of MetS (OR [95% CI], 1.583 [0.455–5.507], p = 0.470 for QQ genotypes and 1.097 [0.784–1.540], p = 0.587 for KQ+QQ genotypes). Moreover, MetS subjects carrying Q alleles had significantly higher levels of TG, insulin, body fat percentage, and insulin resistance as evident by higher values of HOMAIR. Conclusions: We conclude that ENPP1 K121Q functional variant enhances susceptibility to insulin resistance and dyslipidemia in MetS subjects of an Asian Indian population

Tumor-induced osteomalacia: experience from three tertiary care centers in India

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by recalcitrant hypophosphatemia. Reports from the Indian subcontinent are scarce, with most being single center experiences involving few patients. Herein, we conducted a retrospective analysis of 30 patients of TIO diagnosed at three tertiary care hospitals in India. Patients with persistent hypophosphatemia (despite correction of hypovitaminosis D), normocalcemia, elevated alkaline phosphatase, low TmP/GFR and elevated or ‘inappropriately normal’ FGF23 levels were labeled as having TIO. They were sequentially subjected to functional followed by anatomical imaging. Patients with a well-localized tumor underwent excision; others were put on phosphorous and calcitriol supplementation. The mean age at presentation was 39.6 years with female:male ratio of 3:2. Bone pain (83.3%) and proximal myopathy (70%) were the chief complaints; 40% of cases had fractures. The mean delay in diagnosis was 3.8 years. Tumors were clinically detectable in four patients (13.3%). The mean serum phosphate was 0.50 mmol/L with a median serum FGF23 level of 518 RU/mL. Somatostatin receptor-based scintigraphy was found to be superior to FDG-PET in tumor localization. Lower extremities were the most common site of the tumor (72%). Tumor size was positively correlated with serum FGF23 levels. Twenty-two patients underwent tumor resection and 16 of them had phosphaturic mesenchymal tumors. Surgical excision led to cure in 72.7% of patients whereas disease persistence and disease recurrence were seen in 18.2% and 9.1% of cases, respectively. At the last follow-up, serum phosphate in the surgically treated group was significantly higher than in the medically managed group

FRAX: Facts and Fantasy

FRAX is an important web based tool to assess fragility fracture risk in osteoporosis. It has many important limitations too. Good clinical judgement is needed to interpret the results of FRAX. With increasing use we can improvise this tool further