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

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

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

Progression of puberty after initiation of androgen therapy in patients with idiopathic hypogonadotropic hypogonadism

Background: Onset of puberty in boys usually occurs by 14 years of age. Some boys may exhibit delayed sexual maturation till about 17-18 years of age. However, pubertal onset beyond 18 years of age is exceedingly rare. Materials and Methods: Patients diagnosed as idiopathic hypogonadotropic hypogonadism (IHH) who had onset of puberty (increase in testicular volume >10 ml) while on androgen therapy were studied. These patients were evaluated prospectively. Results: There were nine subjects that were included in the study. The pre-therapy testicular volumes ranged from 3 to 6 ml. Luteinizing hormone (LH) levels increased from 1.2 ± 0.96 to 2.8 ± 1.0 IU/L, follicular stimulating hormone (FSH) levels increased from 1.5 ± 0.79 to 3.5 ± 1.9 IU/L, and testosterone increased from 0.36 ± 0.16 to 3.4 ± 2.1 ng/ml. Three out of nine patients had testosterone levels below 3 ng/ml. Conclusion: Our present study indicates that pubertal development can occur in patients presenting with hypogonadotropic hypogonadism after 18 years of age. However, acquired pubertal status may be subnorma

ACTH resistance syndrome: An experience of three cases

The term adrenocorticotropin (ACTH) resistance syndrome is used for a group of rare inherited disorders, which present with primary adrenal insufficiency during childhood. The syndrome includes two disorders inherited in an autosomal recessive fashion – familial glucocorticoid deficiency and triple A syndrome. Herein, we report our experience of three cases with ACTH resistance syndrome, highlighting the approach to diagnosis and management in such patients

Acromegaly with no pituitary adenoma and no evidence of ectopic source

More than 99% of patients with acromegaly harbor a growth hormone (GH) secreting pituitary adenoma. As the time from onset of signs/symptoms to diagnosis of acromegaly is long (symptom onset to diagnosis is often 4–10 years), pituitary adenomas that cause GH excess are often large and are nearly always visible on conventional magnetic resonance imaging (MRI). However, in rare circumstances, acromegalic patients without an ectopic source will not have imaging evidence of a pituitary adenoma. Management of these patients poses special challenge, and once ectopic source of GH/growth-hormone-releasing hormone (GHRH) is ruled out, an exploration of pituitary might be useful. We herein report a case of acromegaly with imaging evidence of sellar floor osteoma, but no pituitary adenoma, and negative work up for an ectopic source of GH/GHRH tumor, and on surgical exploration pituitary adenoma could be identified and removed and confirmed on histopathologic examination

Assessment of iodine nutrition in pregnant north Indian subjects in three trimesters

Objective: The cross-sectional study was carried out to assess the iodine status of pregnant women, using median urinary iodine concentration (MUI) as the measure of outcome, to document the impact of advancing gestation on the MUI in normal pregnancy. Materials and Methods: The present study assessed the MUI in casual urine samples from 50 pregnant subjects of each trimester and 50 age-matched non-pregnant controls. Results: The median (range) of urinary iodine concentration (UIC) in pregnant women was 304 (102-859) μg/L and only 2% of the subjects had prevalence of values under 150 μg/L (iodine insufficiency). With regard to the study cohort, median (range) UIC in the first, second, and third trimesters was 285 (102-457), 318 (102-805), and 304 (172-859) μg/L, respectively. Differences between the first, second, and third trimesters were not statistically significant. The MUI in the controls (305 μg/L) was not statistically different from the study cohort. Conclusion: The pregnant women had no iodine deficiency, rather had high median urinary iodine concentrations indicating more than adequate iodine intake. Larger community-based studies are required in iodine-sufficient populations, to establish gestation-appropriate reference ranges for UIC in pregnancy

Study of pituitary morphometry using MRI in Indian subjects

Aim: To establish normative measurements of pituitary gland in Indian population. Material and Methods: In this cross-sectional study, we measured dimensions of pituitary gland in 482 (213 females and 269 males) Indian subjects with apparently normal pituitary gland function. Mid-sagittal T1-weighted image (T1-WI) on magnetic resonance imaging (MRI) was used to measure height and length of pituitary gland. Pituitary gland width was measured using coronal T1-WI and pituitary gland volume was calculated. Results: Mean height, length and calculated volume of pituitary gland was significantly higher in females compared to males (p = <0.001, P = 0.03 and P = <0.001, respectively) when all age groups were combined but pituitary gland width was not statistically different in male and female subjects. When subjects were divided into different age groups, except for 10–14 years age group where pituitary height was significantly higher in females as compared to male, no significant difference was observed between male and female in any of the parameters (height, length, width and volume). The mean pituitary gland height was 5.80 ± 1.32 mm and 5.37 ± 1.25 mm in female and male subjects, respectively. Females achieved peak pituitary gland height in 10 to 14-year age group, while males achieved their peak pituitary gland height in 15 to 19-year age group. Conclusion: Our study provides age and sex wise normative data for pituitary measurements derived from Indian population

Efficacy and safety of 90,000 IU versus 300,000 IU single dose oral Vitamin D in nutritional rickets: A randomized controlled trial

Aim: To compare efficacy and safety of 90,000 IU versus 300,000 IU oral single dose vitamin D for treatment of nutritional rickets. Study Design: Randomized controlled trial. Setting: Tertiary care hospital. Participants: One hundred ten children (6 months to 5 years, median age 10.5 months) with rickets. Exclusion criteria were disease affecting absorption, intake of calcium/vitamin D preparation in last 6 months, abnormal renal function, and rickets other than nutritional. Intervention: Vitamin D3 as a single oral dose 90,000 IU (group A, n = 55) or 300,000 IU (group B, n = 55). Methodology: Severity of rickets was scored on knee and wrist X-ray as per Thacher's radiographic score. Baseline serum levels of calcium, SAP, 25(OH)D, iPTH were measured. Follow up was done at 1 week, 4 weeks, and 12 weeks. Outcome Variable: Primary – Radiographic score at 3 months. Secondary – Serum levels of 25(OH)D, SAP, and iPTH at 3 months, clinical and biochemical adverse effects. Results: Eighty-six subjects (43 in each group) completed the study. The radiographic score reduced from 6.90 to 0.16 in group A and from 6.93 to 0.23 in group B. The levels of 25(OH)D, ALP, and PTH were similar between the groups at baseline and follow up. Hypercalciuria and hypercalcemia were seen more often in group B as was hypervitaminosis D. There were no clinical adverse events. Conclusions: Single oral dose vitamin D3 90,000 IU is safe and effective in achieving healing of rickets