VITAMIN D RECEPTOR GENE POLYMORPHISMS AND HAPLOTYPE ANALYSIS IN TYPE 2 DIABETES MELLITUS PATIENTS FROM NORTH INDIA

  Objective: Vitamin D receptor (VDR) mediated Vitamin D signaling is important for expression of insulin gene and glucose transporters, which help in glucose uptake by cells. Current evidence suggests that four common polymorphisms (FokI, BsmI, ApaI, TaqI) of VDR gene are associated with Type 2 diabetes mellitus (T2DM) in different populations. However, there is a scarcity of data on VDR polymorphisms from Indian population.Methods: In the current study, total genomic DNA was isolated from 100 well-characterized T2DM patients and 100 healthy controls. We investigated the prevalence of FokI and ApaI polymorphisms in VDR gene of these patients by polymerase chain reaction-restriction fragment length polymorphism-based method. Taking help of our previous published data on TaqI and BsmI polymorphisms in same patients, the haplotype study was also conducted. Statistical analysis of data was performed using SPSS 21.0 software. Haplotype and linkage disequilibrium analysis was performed by Haploview software.Results: Both the wild (TT) and mutant (CC) genotype of FokI polymorphism showed a significant difference between patients and controls (p<0.001 and p<0.001, respectively). The frequency of mutant allele (C) was also significantly higher in T2DM patients than the controls (p<0.001). In case of ApaI, frequency of wild (GG) and mutant (CC) genotype was significantly different in patients and controls (p=0.017 and p=0.034). As per haplotype analysis, the CACT haplotype was predicted to be of significance in patients and consists of mutant alleles of three polymorphisms (FokI, BsmI, ApaI). Conclusion: Our study supports the association of FokI and ApaI polymorphism in T2DM. The haplotype analysis also indicates that the combinations of mutant allele of different VDR polymorphisms are probably responsible for increased susceptibility of these individuals toward T2DM

Effect of vitamin D supplementation on insulin kinetics and cardiovascular risk factors in polycystic ovarian syndrome: a pilot study

To assess the effect of vitamin D supplementation on parameters of Insulin Sensitivity/Resistance (IS/IR) and insulin secretion in subjects with Polycystic Ovarian Syndrome (PCOS). A prospective double-blind randomized control trial was conducted to assess the effect of vitamin D on insulin kinetics in women with PCOS. The trial was conducted in a tertiary care research hospital. A total of 36 subjects with PCOS, aged 18–35 years, were included in this study. Vitamin D3 4000  IU/day versus placebo was given once a month for 6 months and both groups received metformin. IS (by whole-body IS index or Matsuda index), IR (by homeostasis model assessment IR (HOMA-IR)) and insulin secretion (by insulinogenic index; II30) were the main outcome measures. Secondary outcome included Blood Pressure (BP), lipid profile, Disposition Index (DI) and vascular stiffness. Out of 36 subjects who consented, 32 completed the study. Subjects were randomized into two groups: group A (n = 15; metformin and vitamin D 4000  IU/day) or group B (n = 17; metformin and placebo). Oral glucose tolerance tests with 75 g glucose were carried out at baseline and 6 months after supplementation. Hypovitaminosis D was observed in 93.8% of all subjects with mean serum 25 hydroxy vitamin D level of 7.30 ± 4.45 ng/ml. After 6 months of vitamin D supplementation, there was no significant difference in any of the parameters of IS/IR (area under curve (AUC)–glucose, AUC–insulin, insulin:glucose ratio, HOMA-IR, Matsuda index, insulinogenic index and DI), II30 and cardiovascular risk factors between the two groups. Supplementation of vitamin D, at a dose of 4000  IU/day for 6 months, did not have any significant effect on parameters of IS/IR and insulin secretion in subjects with PCOS

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta- Analysis

Background-—Low 25-hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. Methods and Results-—We conducted a systematic review and individual participant meta-analysis to examine the effect of vitamin D supplementation on flow-mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo-controlled randomized trials of at least4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial-level metaanalysis was performed using random-effects models; individual participant meta-analyses used a 2-stage analytic strategy, examining effects in prespecified subgroups. 31trials (2751 participants) were included; 29 trials (2641participants) contributed data to trial-level meta-analysis, and24trials (2051 participants) contributed to individual-participant analyses. VitaminD3daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to12 months. Trial-level meta-analysis showed no significant effect of supplementation on macrovascularmeasures(flow-mediateddilatation,0.37%[95%confidenceinterval, 0.23to0.97]; carotid-femoralpulsewavevelocity, 0.00 m/s [95% confidence interval, 0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial-level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. Conclusions-—Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis

Rationale and protocol for estimating the economic value of a multicomponent quality improvement strategy for diabetes care in South Asia.

BACKGROUND: Economic dimensions of implementing quality improvement for diabetes care are understudied worldwide. We describe the economic evaluation protocol within a randomised controlled trial that tested a multi-component quality improvement (QI) strategy for individuals with poorly-controlled type 2 diabetes in South Asia. METHODS/DESIGN: This economic evaluation of the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) randomised trial involved 1146 people with poorly-controlled type 2 diabetes receiving care at 10 diverse diabetes clinics across India and Pakistan. The economic evaluation comprises both a within-trial cost-effectiveness analysis (mean 2.5 years follow up) and a microsimulation model-based cost-utility analysis (life-time horizon). Effectiveness measures include multiple risk factor control (achieving HbA1c < 7% and blood pressure < 130/80 mmHg and/or LDL-cholesterol< 100 mg/dl), and patient reported outcomes including quality adjusted life years (QALYs) measured by EQ-5D-3 L, hospitalizations, and diabetes related complications at the trial end. Cost measures include direct medical and non-medical costs relevant to outpatient care (consultation fee, medicines, laboratory tests, supplies, food, and escort/accompanying person costs, transport) and inpatient care (hospitalization, transport, and accompanying person costs) of the intervention compared to usual diabetes care. Patient, healthcare system, and societal perspectives will be applied for costing. Both cost and health effects will be discounted at 3% per year for within trial cost-effectiveness analysis over 2.5 years and decision modelling analysis over a lifetime horizon. Outcomes will be reported as the incremental cost-effectiveness ratios (ICER) to achieve multiple risk factor control, avoid diabetes-related complications, or QALYs gained against varying levels of willingness to pay threshold values. Sensitivity analyses will be performed to assess uncertainties around ICER estimates by varying costs (95% CIs) across public vs. private settings and using conservative estimates of effect size (95% CIs) for multiple risk factor control. Costs will be reported in US$ 2018. DISCUSSION: We hypothesize that the additional upfront costs of delivering the intervention will be counterbalanced by improvements in clinical outcomes and patient-reported outcomes, thereby rendering this multi-component QI intervention cost-effective in resource constrained South Asian settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01212328

The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis.

BACKGROUND: It is uncertain which simple measures of childhood obesity are best for predicting future obesity-related health problems and the persistence of obesity into adolescence and adulthood. OBJECTIVES: To investigate the ability of simple measures, such as body mass index (BMI), to predict the persistence of obesity from childhood into adulthood and to predict obesity-related adult morbidities. To investigate how accurately simple measures diagnose obesity in children, and how acceptable these measures are to children, carers and health professionals. DATA SOURCES: Multiple sources including MEDLINE, EMBASE and The Cochrane Library were searched from 2008 to 2013. METHODS: Systematic reviews and a meta-analysis were carried out of large cohort studies on the association between childhood obesity and adult obesity; the association between childhood obesity and obesity-related morbidities in adulthood; and the diagnostic accuracy of simple childhood obesity measures. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and a modified version of the Quality in Prognosis Studies (QUIPS) tool. A systematic review and an elicitation exercise were conducted on the acceptability of the simple measures. RESULTS: Thirty-seven studies (22 cohorts) were included in the review of prediction of adult morbidities. Twenty-three studies (16 cohorts) were included in the tracking review. All studies included BMI. There were very few studies of other measures. There was a strong positive association between high childhood BMI and adult obesity [odds ratio 5.21, 95% confidence interval (CI) 4.50 to 6.02]. A positive association was found between high childhood BMI and adult coronary heart disease, diabetes and a range of cancers, but not stroke or breast cancer. The predictive accuracy of childhood BMI to predict any adult morbidity was very low, with most morbidities occurring in adults who were of healthy weight in childhood. Predictive accuracy of childhood obesity was moderate for predicting adult obesity, with a sensitivity of 30% and a specificity of 98%. Persistence of obesity from adolescence to adulthood was high. Thirty-four studies were included in the diagnostic accuracy review. Most of the studies used the least reliable reference standard (dual-energy X-ray absorptiometry); only 24% of studies were of high quality. The sensitivity of BMI for diagnosing obesity and overweight varied considerably; specificity was less variable. Pooled sensitivity of BMI was 74% (95% CI 64.2% to 81.8%) and pooled specificity was 95% (95% CI 92.2% to 96.4%). The acceptability to children and their carers of BMI or other common simple measures was generally good. LIMITATIONS: Little evidence was available regarding childhood measures other than BMI. No individual-level analysis could be performed. CONCLUSIONS: Childhood BMI is not a good predictor of adult obesity or adult disease; the majority of obese adults were not obese as children and most obesity-related adult morbidity occurs in adults who had a healthy childhood weight. However, obesity (as measured using BMI) was found to persist from childhood to adulthood, with most obese adolescents also being obese in adulthood. BMI was found to be reasonably good for diagnosing obesity during childhood. There is no convincing evidence suggesting that any simple measure is better than BMI for diagnosing obesity in childhood or predicting adult obesity and morbidity. Further research on obesity measures other than BMI is needed to determine which is the best tool for diagnosing childhood obesity, and new cohort studies are needed to investigate the impact of contemporary childhood obesity on adult obesity and obesity-related morbidities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005711. FUNDING: The National Institute for Health Research Health Technology Assessment programme

The impact of inflammation on bone mass in children

Bone is a dynamic tissue. Skeletal bone integrity is maintained through bone modeling and remodeling. The mechanisms underlying this bone mass regulation are complex and interrelated. An imbalance in the regulation of bone remodeling through bone resorption and bone formation results in bone loss. Chronic inflammation influences bone mass regulation. Inflammation-related bone disorders share many common mechanisms of bone loss. These mechanisms are ultimately mediated through the uncoupling of bone remodeling. Cachexia, physical inactivity, pro-inflammatory cytokines, as well as iatrogenic factors related to effects of immunosuppression are some of the common mechanisms. Recently, cytokine signaling through the central nervous system has been investigated for its potential role in bone mass dysregulation in inflammatory conditions. Growing research on the molecular mechanisms involved in inflammation-induced bone loss may lead to more selective therapeutic targeting of these pathological signaling pathways

A review of the growing risk of vitamin D toxicity from inappropriate practice

Vitamin D is a particularly important sterol hormone, with evidence emerging of its beneficial effects well beyond bone. In consequence of this and increased global recognition of vitamin D deficiency in the general population, there has been a resurgence in treatment with vitamin D preparations. However, the increasing use of vitamin D treatments has also seen a substantial increase in the number of reports of vitamin D intoxication, with the majority (75%) of reports published since 2010. Many of these cases are a consequence of inappropriate prescribing, and the use of high‐dose over‐the‐counter preparations or unlicensed preparations. This review highlights that the majority of cases were preventable and discusses the inappropriate use of poorly formulated, and unlicensed vitamin D preparations

Endocrine abnormalities in dilated cardiomyopathy

Background: Progress has been made in the understanding of cellular and molecular mechanisms of hormone action and its effects on the cardiac tissue. There is evidence from observational studies that patients with postpartum cardiomyopathy improve after inhibition of release of prolactin from the pituitary by bromocriptine. This has renewed interest in the role of hormones in the pathogenesis of cardiomyopathy, especially in women. We intended to assess the hormonal changes in female patients with dilated cardiomyopathy (DCM). Methods: Twenty female patients aged 20-40 years old (mean age 29 ΁ 5.6 years) with a diagnosis of idiopathic DCMP with left ventricular ejection fraction [EF] <35% and a stable clinical course in the last 3 months were included in the study. All the patients were in New York Heart Association (NYHA) Class II or III. All the patients underwent clinical evaluation followed by blood sampling for hormonal analysis. Blood was taken after overnight fasting and analyzed for thyroid stimulating hormone (TSH), T3, T4, insulin-like growth factor I (IGF-I), prolactin, insulin, parathyroid hormone (PTH), and 25 (OH) Vitamin D. The results were compared with twenty age and sex matched controls. Results: The mean EF of the twenty patients was 24.4 ΁ 5.3% and duration of symptoms was 29.1 ΁ 24 months. Insulin growth factor 1 levels were significantly lower than normal. Fifty percent of the patients had levels lower than normal, but there was no correlation of IGF-I with NYHA class and EF. Testing of the thyroid hormones revealed that TSH levels were similar between patient and controls though 40% of the patients had elevated TSH levels. Of these patients, 5% (1) had hypothyroid. In addition to this, 10% (2) had isolated low T3, suggestive of the low T3 syndrome. None of the thyroid abnormalities showed a correlation with NYHA class or EF. All other hormone concentrations were comparable in both groups. Conclusion: In this cohort of female patients with DCM, circulating concentrations of IGF-I was significantly lower than in healthy controls, most likely as a result of chronic disease. Some patients had serum evidence of hypothyroidism and some with isolated low T3 levels. Other hormone levels were normal including blood glucose, insulin, and prolactin