Trabecular bone score in adults with type 1 diabetes: a meta-analysis.

Type 1 diabetes mellitus (T1DM) is associated with a disproportionately high fracture rate despite a minimal decrease in bone mineral density. Though trabecular bone score (TBS), an indirect measure of bone architecture, is lower in adults with T1DM, the modest difference is unlikely to account for the large excess risk and calls for further exploration. INTRODUCTION: Fracture rates in type 1 diabetes mellitus (T1DM) are disproportionately high compared to the modestly low bone mineral density (BMD). Distortion of bone microarchitecture compromises bone quality in T1DM and is indirectly measured by trabecular bone score (TBS). TBS could potentially be used as a screening tool for skeletal assessment; however, there are inconsistencies in the studies evaluating TBS in T1DM. We performed this meta-analysis to address this knowledge gap. METHODS: An electronic literature search was conducted using PubMed, Scopus, and Web of Science resources (all-year time span) to identify studies relating to TBS in T1DM. Cross-sectional and retrospective studies in adults with T1DM were included. TBS and BMD data were extracted for pooled analysis. Fracture risk could not be analyzed as there were insufficient studies reporting it. RESULT: Data from six studies were included (T1DM: n = 378 and controls: n = 286). Pooled analysis showed a significantly lower TBS [standardized mean difference (SMD) = - 0.37, 95% CI - 0.52 to - 0.21; p < 0.00001] in T1DM compared to controls. There was no difference in the lumbar spine BMD (6 studies, SMD - 0.06, 95% CI - 0.22 to 0.09; p = 0.43) and total hip BMD (6 studies, SMD - 0.17, 95% CI - 0.35 to 0.01; p = 0.06) in the case and control groups. CONCLUSIONS: Adults with T1DM have a lower TBS but similar total hip and lumbar spine BMD compared to controls. The risk attributable to the significant but limited difference in TBS falls short of explaining the large excess propensity to fragility fracture in adults with T1DM. Further studies on clarification of the mechanism and whether TBS is suited to screen for fracture risk in adults with T1DM are necessary.

Prandial Insulins: A Person-Centered Choice.

PURPOSE OF REVIEW: Postprandial hyperglycemia, or elevated blood glucose after meals, is associated with the development and progression of various diabetes-related complications. Prandial insulins are designed to replicate the natural insulin release after meals and are highly effective in managing post-meal glucose spikes. Currently, different types of prandial insulins are available such as human regular insulin, rapid-acting analogs, ultra-rapid-acting analogs, and inhaled insulins. Knowledge about diverse landscape of prandial insulin will optimize glycemic management. RECENT FINDINGS: Human regular insulin, identical to insulin produced by the human pancreas, has a slower onset and extended duration, potentially leading to post-meal hyperglycemia and later hypoglycemia. In contrast, rapid-acting analogs, such as lispro, aspart, and glulisine, are new insulin types with amino acid modifications that enhance their subcutaneous absorption, resulting in a faster onset and shorter action duration. Ultra-rapid analogs, like faster aspart and ultra-rapid lispro, offer even shorter onset of action, providing better meal-time flexibility. The Technosphere insulin offers an inhaled route for prandial insulin delivery. The prandial insulins can be incorporated into basal-bolus, basal plus, or prandial-only regimens or delivered through insulin pumps. Human regular insulin, aspart, lispro, and faster aspart are recommended for management of hyperglycemia during pregnancy. Ongoing research is focused on refining prandial insulin replacement and exploring newer delivery methods. The article provides a comprehensive overview of various prandial insulin options and their clinical applications in the management of diabetes.

Long-Term Impact on Offspring (5 to 11 Years of Age) of Metformin Use in Pregnancy in Mothers With Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Data are scant on the impact of metformin use in gestational diabetes mellitus/diabetes in pregnancy on long-term outcomes in children and mothers beyond 5 years of childbirth. This systematic review and meta-analysis aimed to evaluate the long-term impact of metformin use in pregnancy on children and their mothers. METHODS: Electronic databases were searched for studies evaluating metformin compared with insulin for managing gestational diabetes mellitus/diabetes in pregnancy. The primary outcome was the change in body mass index (BMI) in children at the ages of 5 to 11 years. The secondary outcomes were alterations in other anthropometric measures, obesity, and changes in the levels of lipids and adipocytokines in children and mothers. RESULTS: Children at the age of 9 years born to mothers who were treated with metformin during pregnancy had similar BMI (mean difference [MD], 1.09 kg/m2 [95% confidence interval {CI}, -0.44 to 2.62]; P = .16; I2 = 16%), waist circumference-to-height ratio (MD, 0.13 [95% CI, -0.05 to 0.30]; P = .16; I2 = 94%), dual-energy X-ray absorptiometry (DXA) total fat mass (MD, 0.68 kg [95% CI, -2.39 to 3.79]; P = .66; I2 = 70%), DXA total fat percent (MD, 0.04% [95% CI, -3.44 to 3.51]; P = .98; I2 = 56%), DXA total fat-free mass (MD, 0.81 kg [95% CI, -0.96 to 2.58]; P = .37; I2 = 55%), magnetic resonance imaging visceral adipose tissue volume (MD, 80.97 cm3 [95% CI, -136.47 to 298.41]; P = .47; I2 = 78%), and magnetic resonance spectroscopy liver fat percentage (MD, 0.27% [95% CI, -1.26 to 1.79]; P = .73; I2 = 0%) to those born to mothers who were treated with insulin. Serum adiponectin, leptin, alanine aminotransferase, and ferritin were comparable among groups. In children between the ages of 9 and 11 years, the occurrence of obesity, diabetes, or challenges in motor and social development were comparable between the 2 groups. After 9 years of childbirth, BMI and the risk of developing diabetes were similar between the 2 groups of women. CONCLUSION: Metformin use in pregnancy did not show any adverse effects compared with insulin on long-term outcomes in children and their mothers.

Role of Resmetirom, a Liver-Directed, Thyroid Hormone Receptor Beta-Selective Agonist, in Managing Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis.

BACKGROUND: Resmetirom, a liver-directed, thyroid hormone receptor beta-selective agonist, has recently been approved to treat nonalcoholic steatohepatitis (NASH). This meta-analysis aimed to summarize the efficiency and safety of resmetirom in treating NASH. METHODS: Electronic databases were searched for randomized controlled trials (RCTs) of resmetirom vs placebo in patients with NASH. The primary outcomes were the changes from baseline in hepatic fat content, liver histology, including NASH resolution, and noninvasive markers of hepatic fibrosis. RESULTS: Three randomized controlled trials (n = 2231) met the inclusion criteria. Compared to placebo, resmetirom achieved greater reductions from baseline in hepatic fat content assessed by magnetic resonance imaging proton density fat fraction (for resmetirom 80 mg: MD -27.76% [95%CI: -32.84, -22.69]; for resmetirom 100 mg: MD -36.01% [95%CI: -41.54, -30.48]; P < .00001 for both) and FibroScan controlled attenuation parameter (for resmetirom 80 mg: MD -21.45 dBm [95%CI: -29.37, -13.52]; for resmetirom 100 mg: MD -25.51 dBm [95%CI: -33.53, -17.49]; P < .00001 for both). Resmetirom 80 mg outperformed placebo in NASH resolution and ≥2-point nonalcoholic fatty liver disease activity score reduction. Moreover, resmetirom 80 mg and 100 mg were superior to placebo in cytokeratin-18 (M30) reduction. Greater reductions in liver enzymes, lipids, and reverse triiodothyronine were observed in the resmetirom arms with no impact on triiodothyronine. Nausea and diarrhea were more common with resmetirom than with placebo; other adverse events were comparable. CONCLUSION: Resmetirom improves hepatic fat content, liver enzymes, and fibrosis biomarkers in NASH patients. Resmetirom generally does not affect thyroid function and is well-tolerated.

Role of Teplizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Managing Newly Diagnosed Type 1 Diabetes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Teplizumab has emerged as a potential disease-modifying drug in type 1 diabetes (T1D). This meta-analysis sought to summarize the therapeutic effect of teplizumab in newly diagnosed patients with T1D. METHODS: Randomized controlled trials involving patients with T1D receiving teplizumab in the intervention arm and placebo (or no active intervention) in the control arm were searched throughout the electronic databases. The primary outcome was the change in area under the curve of C-peptide levels from baseline. RESULTS: Seven reports from 6 studies involving 834 subjects met the inclusion criteria. Compared to teplizumab, greater reductions in area under the curve of C-peptide from the baseline values were observed in the control group after 6 months (mean difference [MD] 0.07 nmol/L [0.01, 0.13], P = .02), after 12 months (MD 0.07 nmol/L [0.04, 0.11], P = .0001), after 18 months (MD 0.10 nmol/L [0.06, 0.14], P < .00001), and after 24 months (MD 0.07 nmol/L [0.01, 0.14], P = .03) of interventions. Moreover, fewer patients treated with teplizumab had a decreased C-peptide response after 6 months (odds ratio [OR] 0.21), after 12 months (OR 0.17), after 18 months (OR 0.30), and after 24 months (OR 0.12) of treatment. The preservation of endogenous insulin production was supported by reduced use of exogenous insulin with maintenance of comparable glycemic control for up to 18 months post-treatment. Teplizumab imparted higher risks of grade 3 or higher adverse events, adverse events leading to study medication discontinuation, nausea, rash, and lymphopenia. CONCLUSION: The results of the meta-analysis support teplizumab as a promising disease-modifying therapy for newly diagnosed T1D.

Hyperprolactinemia Due to Prolactinoma has an Adverse Impact on Bone Health with Predominant Impact on Trabecular Bone: A Systematic Review and Meta-Analysis.

BACKGROUND: No meta-analysis has holistically analysed and summarized the effect of prolactin excess due to prolactinomas on bone mineral metabolism. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for studies having patients with hyperprolactinemia due to prolactinoma and the other being a matched control group. The primary outcome was to evaluate the differences in BMD Z-scores at different sites. The secondary outcomes of this study were to evaluate the alterations in bone mineral density, bone mineral content and the occurrence of fragility fractures. RESULTS: Data from 4 studies involving 437 individuals was analysed to find out the impact of prolactinoma on bone mineral metabolism. Individuals with prolactinoma had significantly lower Z scores at the lumbar spine [MD -1.08 (95 % CI: -1.57 - -0.59); P < 0.0001; I2 = 54 % (moderate heterogeneity)] but not at the femur neck [MD -1.31 (95 % CI: -3.07 - 0.45); P = 0.15; I2 = 98 % (high heterogeneity)] as compared to controls. Trabecular thickness of the radius [MD -0.01 (95 % CI: -0.02 - -0.00); P = 0.0006], tibia [MD -0.01 (95 % CI: -0.02 - -0.00); P=0.03] and cortical thickness of the radius [MD -0.01 (95 % CI: -0.19 - -0.00); P = 0.04] was significantly lower in patients with prolactinoma as compared to controls. The occurrence of fractures was significantly higher in patients with prolactinoma as compared to controls [OR 3.21 (95 % CI: 1.64 - 6.26); P = 0.0006] Conclusion: Bone mass is adversely affected in patients with hyperprolactinemia due to prolactinoma with predominant effects on the trabecular bone.

Impact of pheochromocytoma or paraganglioma on bone metabolism: A systemic review and meta-analysis.

INTRODUCTION: Preclinical and animal studies have suggested that excess catecholamines can lead to bone mineral loss. However, to date, no systematic review is available that has analyzed the impact of catecholamine excess in the context of pheochromocytoma/paraganglioma (PPGL) on bone metabolism. We conducted this meta-analysis to address this knowledge gap. METHODS: Electronic databases were searched for studies evaluating bone metabolism, including assessments of bone mineral density (BMD), quantitative computed tomography (qCT), trabecular bone score (TBS), or bone turnover markers in patients with PPGL. These markers included those of bone resorption, such as tartrate-resistant acid phosphatase 5b (TRACP-5b) and cross-linked C-telopeptide of type I collagen (CTx), as well as markers of bone formation, such as bone-specific alkaline phosphatase (BS ALP). RESULTS: Out of the initially screened 1614 articles, data from six studies published in four different patient cohorts with PPGL that met all criteria were analysed. Individuals with PPGL had significantly lower TBS [Mean Difference (MD) -0.04 (95% CI: -0.05--0.03); p < 0.00001; I2 = 0%], higher serum CTx [MD 0.13 ng/ml (95% CI: 0.08-0.17); p < 0.00001; I2 = 0%], and higher BS-ALP [MD 1.47 U/L (95% CI: 0.30-2.64); p = 0.01; I2 = 1%]. TBS at 4-7 months post-surgery was significantly higher compared to baseline [MD 0.05 (95% CI: 0.02-0.07); p < 0.0001]. A decrease in CTx has been documented post-surgery. CONCLUSION: Bone health deterioration is a major concern in patients with PPGL. In addition to providing a definitive cure for catecholamine excess, monitoring and treating osteoporosis is essential for individuals with secondary osteoporosis due to PPGL. Long-term studies on bone health outcomes in PPGL are warranted.

Treatment options in people with COVID19: Selecting the best armamentarium against the novel virus.

Novel coronavirus disease (COVID-19) infection is a global pandemic, of high infectivity, variable mortality, with currently no established treatment. This review summarizes different molecules which are being evaluated for COVID19 treatment. PubMed and Medline, search for articles published to March 2020 was done using terms "COVID19" OR "corona-virus 2019" OR "2019-nCoV" or "severe acute respiratory syndrome coronavirus" AND "treatment". As of today, we have >350 RCTs happening with different agents. COVID19 treatment agents can be broadly classified into immuno-modulators (prevent hyperimmune-activation and cytokine storm) and anti-viral therapies (prevent virus entry, replication or viricidal). Hydroxychloroquine/chloroquine, Interferon-l, glucocorticoids, interleukin antagonists, Ulinastatin, intravenous immunoglobulins, plasmapheresis are main immunomodulators showing initial positive outcomes. Umifenovir. Lopinavir/Ritonavir, Ribavirin, remdesivir and Ravipiravir are some of the major antiviral agents showing initial encouraging results. It may be concluded that the most successful regimen is going to be multi-drug therapy, a combination of immunomodulatory agent with anti-viral agent.

The diabetic knee.

Diabetes is a multisystemic and multifaceted syndrome, and its clinical impact is wide ranging and varied. The musculoskeletal complications of diabetes, too cover a broad spectrum of joints and presentations. Relatively less attention is paid, however, to the diabetic knee. This communication describes the bidirectional relationship between diabetes and the knee, and the potential influence this may have on therapy.

Increased trunk fat along with decreased peripheral fat as an important predictor of hypertriglyceridaemia & hypercholesterolaemia in Indians with HIV infection.

BACKGROUND & OBJECTIVES: Dyslipidaemia is a major contributor to cardiovascular morbidity, which is increased in HIV. Data on dyslipidaemia in Indians with HIV are scant. This study was undertaken to determine the predictors of dyslipidaemia and lipoatrophy in Indians with HIV infection and their relation with body composition parameters. METHODS: A total of 382 consecutive patients with HIV infection were screened, of whom 257 clinically stable patients, without any acute comorbidity, having at least one year follow up underwent biochemical and DEXA analysis. RESULTS: The most common dyslipidaemia was hypertriglyceridaemia (47.08%), followed by hypercholesterolaemia [total cholesterol (TC)] (38.91%) and low high-density lipoprotein (HDL) cholesterol (38.52%), in patients having median age 37 (32-42) yr and HIV duration 57 (33-101) months. Patients with at least one dyslipidaemia (78.99%) had significantly higher insulin resistance (IR), per cent body fat, per cent trunk fat (PTF) and trunk limb fat ratio (TLFR). Baseline CD4 count and delta CD4 count (change in CD4 count 6-12 months following ART) had significant inverse correlation with triglycerides and TC. Patients with highest triglycerides and cholesterol quartiles had significantly higher immune reconstitution, metabolic syndrome, IR, trunk fat mass (FM), PTF and TLFR, with comparable total FM. Logistic regression revealed that body mass index, HIV duration and PTF were independent predictors of hypertriglyceridaemia, with only PTF being significant predictor of hypercholesterolaemia. Every unit increase in PTF was associated with 13 and 4.1 per cent increased hypertriglyceridaemia and hypercholesterolaemia. Lipoatrophy was present in 8.57 per cent patients and was a poor predictor of dyslipidaemia. INTERPRETATION & CONCLUSIONS: : High occurrence of dyslipidaemia was observed in patients with HIV on anti retroviral therapy. Central adiposity (TFM) was the most important predictor of dyslipidaemia in these patients.

Occurrence & predictors of osteoporosis & impact of body composition alterations on bone mineral health in asymptomatic pre-menopausal women with HIV infection.

Background & objectives: Data on bone mineral density (BMD) and sarcopenia are scant from young females with HIV. This study was conducted to determine occurrence, predictors and impact of body composition alterations on osteoporosis in pre-menopausal women with HIV. Methods: A total of 214 females with serologically documented HIV infection were screened, of whom 103 pre-menopausal women, 25-45 yr age, clinically stable, having at least one year follow up data, underwent hormonal and dual-energy X-ray absorptiometry analysis for BMD and body composition. Seventy five matched controls were also evaluated. Results: Females with HIV had significantly lower BMD and. Z: -score at lumbar spine (LS), total femur, neck of femur (NOF), and radius ultra-distal (UD) compared to controls. Osteoporosis at least at one site was observed in 34.95 per cent patients, compared to eight per cent in controls (P<0.001). Most common site of osteoporosis in females with HIV was radius UD (24.27%), followed by radius 33 per cent (17.48%), radius total (15.53%) and greater trochanter, NOF and LS (6.80% each). HIV patients had significantly lower bone mineral content, lean mass (LM), fat per cent, android (A) fat, gynoid (G) fat, and A/G ratio. LM and fat mass (FM) were -15.65 and -11.54 per cent lower in HIV patients, respectively. Osteoporosis patients had significantly higher use of antiretroviral therapy and lower LM, FM and fat per cent. On logistic regression, LM followed by A/G ratio and BMI were the best predictors of osteoporosis. Sarcopenia was observed in 17.5 per cent patients. Interpretation & conclusions: Our results showed that osteoporosis and sarcopenia were significant problems in young women with HIV. HIV was associated with greater LM loss, which was critical for bone health. Sarcopenia may predict low BMD in HIV.

Presence, patterns & predictors of hypocortisolism in patients with HIV infection in India.

BACKGROUND & OBJECTIVES: : Adrenal insufficiency (AI) is rarely diagnosed in patients with HIV infection, in spite of autopsy studies showing very high rates of adrenal involvement. This study was aimed to determine the presence, patterns and predictors of AI in patients with HIV infection. METHODS: : Consecutive HIV patients, 18-70 yr age, without any severe co-morbid state, having at least one-year follow up at the antiretroviral therapy clinic, underwent clinical assessment and hormone assays. RESULTS: : From initially screened 527 patients, 359 patients having good immune function were analyzed. Basal morning cortisol <6 µg/dl (<165 nmol/l; Group 1), 6-11 µg/dl (165-300 nmol/l; Group 2), 11-18 µg/dl (300-500 nmol/l; Group 3) and ≥18 µg/dl (500 nmol/l; Group 4) were observed in 13, 71, 199 and 76 patients, respectively. Adrenocorticotropic hormone (ACTH) stimulation test revealed 87 patients (24.23%) to have AI. AI in groups 1-4 was 100, 56.34, 17.09 and 0 per cent, respectively. AI patients were more likely to be females (P< 0.05), having longer disease duration (P< 0.05), immune reconstitution inflammatory syndrome, hyperkalaemia (P< 0.01), lower fasting glucose (P< 0.01), dehydroepiandrosterone sulphate (DHEAS) and vitamin D. Regression analysis revealed morning cortisol and DHEAS to be best predictors of AI (P=0.004 and 0.028, respectively). INTERPRETATION & CONCLUSIONS: : AI is a significant problem in HIV-infected individuals, observed in nearly a quarter of patients. Diagnosis warrants high index of suspicion and low threshold for screening, especially in those having low DHEAS and hyperkalaemia. Morning cortisol is a reasonable screening test, with ACTH stimulation warranted to confirm diagnosis, especially in patients with morning cortisol <11 µg/dl (300 nmol/l).

Occurrence, patterns & predictors of hypogonadism in patients with HIV infection in India.

BACKGROUND & OBJECTIVES: Data on hypogonadism among human immunodeficiency virus (HIV)-infected Indians are not available. This study was aimed to evaluate the occurrence, pattern and predictors of hypogonadism in HIV-infected Indians. METHODS: Consecutive stable HIV-infected patients, 18-70 yr age, without any severe comorbid state, having at least one year follow up data at the antiretroviral therapy clinic, underwent clinical assessment and hormone assays. RESULTS: From initially screened 527 patients, 359 patients (225 males; 134 females), having disease duration of 61.44±39.42 months, 88.58 per cent on highly active antiretroviral therapy (HAART), 40.67 per cent having tuberculosis history and 89.69 per cent with vitamin D insufficiency were analyzed. Testosterone <300 ng/dl was documented in 39.11 per cent males. Primary, hypogonadotropic hypogonadism (HypoH) and compensated hypogonadism were observed in 7.56, 31.56 and 12.44 per cent males, respectively. Males with hypogonadism were significantly older (P=0.009), and had higher opportunistic infections (P<0.001) with longer disease duration (P=0.05). Menstrual abnormalities were observed in 40.3 per cent females, who were significantly older (P<0.001), had lower CD4 count (P=0.038) and higher tuberculosis history (P=0.005). Nearly 46.3, 16.2 and 13 per cent women with menstrual abnormalities were in peri-/post-menopausal state, premature ovarian insufficiency (POI) and HypoH, respectively. Age, CD4 count at diagnosis and 25(OH)D were best predictors of male hypogonadism. Age and CD4 count increment in first 6-12 months following HAART were the best predictors of POI. INTERPRETATION & CONCLUSIONS: Hypogonadism was observed to be a significant problem in HIV-infected men and women in India, affecting 39 and 29 per cent patients, respectively. HypoH was the most common form in males whereas ovarian failure being the most common cause in females.

Malaria and diabetes.

Both malaria and diabetes are more common in the developing world, and are major public health challenges. A direct relationship between these 2 conditions has not been evaluated. This review article assessed the literature guaging the relationship between these two conditions, and suggests a pragmatic approach to management. References for this review were identified through searches of PubMed, Medline, and Embase for articles published to October 2016 using the terms "diabetes" [MeSH Terms] AND "malaria" [All Fields]. The reference lists of the articles thus identified were also searched. The search was not restricted to English-language literature. Malaria has been documented to be more common in diabetes, in several studies from Africa. Malarial infection during pregnancy is an important cause of low birth weight and anaemia, and may contribute to the intra-uterine hypothesis explanation for the diabetes epidemic. Prevention and timely/effective management of malaria during pregnancy may therefore be viewed as a primordial preventive strategy against diabetes. Patients with diabetes have atypical malaria presentations. Glucose-6-phosphate dehydrogenase deficiency, which is associated with primaquine failure for radical cure is also associated with dysglycaemia. Type 2 Diabetic mice infected with malaria are more efficient at infecting mosquitoes. A similar synergy in humans warrants evaluation, which would then make "diabetic malaria" a public health problem. Metformin has well known anti-malarial properties. There is significant literature available highlighting the link between diabetes and malaria, an area warranting active further research. Metformin as a prophylactic agent for malaria prevention warrants evaluation.

Role of NF-κB activation and VEGF gene polymorphisms in VEGF up regulation in non-proliferative and proliferative diabetic retinopathy.

The present study was aimed to investigate the relation between nuclear factor kappa beta (NFκB) activation and downstream up-regulation of vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR). Moreover the study was intended to evaluate the role of VEGF gene single nucleotide polymorphisms (SNPs) in DR occurrence and to investigate the functional relevance of VEGF gene SNPs in terms of VEGF expression in DR. Serum level of VEGF, VEGF R1 (receptor 1), VEGF R 2 (receptor 2) and NFκB (p50/65) activity was measured by enzyme linked immune sorbent assay. Genotyping and allelic composition of different SNPs i.e., rs2010963, rs3025039, rs1570360 and rs 2071559 were investigated by Taqman SNP genotyping assay. VEGF, NFκB p50/p65, and VEGF R1 & R2 gene expressions were quantified by real time quantitative polymerase chain reaction. Increased NFκB p50/p65 activity and expressions were observed in non proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) subjects compared to type 2 diabetes mellitus without retinopathy (DNR) group. Significantly elevated levels of serum VEGF and highest VEGF expression were found among PDR subjects compared to DNR or NPDR subjects. CC genotype and C allele of rs2010963 and TT genotype and T allele of rs3025039 were significantly over represented among PDR subjects compared to DNR group. Increased activation of NFκß in NPDR and PDR subjects might involve increased up regulation of VEGF. VEGF SNPs i.e., rs2010963 C allele and rs3025039 T allele might be associated with PDR occurrence and in turn regulates VEGF expression among PDR subjects.

Increased Soluble TNF Receptor-1 and Glutathione Peroxidase may Predict Carotid Intima Media Thickness in Females with Cushing Syndrome.

OBJECTIVE: Cardiovascular events are the most common cause of mortality in Cushing syndrome (CS). This study aimed to evaluate the impact of novel factors on atherosclerosis in endogenous CS. METHODS: A total of 22 female patients with CS and 33 normal female controls underwent evaluation of fibrinogen, high-sensitivity C-reactive protein (hsCRP), inflammatory cytokines (interleukin [IL]-6, IL-1ß, soluble tumor necrosis factor receptor [sTNFR]-1, and sTNFR2), glutathione peroxidase (GPx; measure of oxidative stress), carotid intima media thickness (CIMT; a measure of atherosclerosis), and percent change in flow-mediated vasodilation (%FMV) of the brachial artery, a measure of endothelial dysfunction. Stepwise multiple linear regressions were done after adjusting for variables in models 1 through 3 to evaluate their role in predicting CIMT and %FMV. Model 1 consisted of age and body mass index (BMI). Model 2 consisted of model 1 plus blood pressure (BP), fasting blood glucose (FBG), and 2-hour postglucose blood glucose (2hPGBG). Model 3 consisted of model 2 plus triglycerides and low- and high-density lipoprotein. RESULTS: Females with CS had significantly higher BMI, BP, FBG, 2hPGBG, total cholesterol, triglycerides, fibrinogen, IL-6, IL-1ß, sTNFR1, and GPx. CIMT and %FMV were significantly higher and lower, respectively, in CS patients. Regression analyses revealed sTNFR1 to be a consistent predictor of CIMT after adjusting for model 1 (ß = 0.656; P = .004), model 2 (ß = 0.571; P = .047), and model 3 (ß = 0.683; P =.026). GPx was a predictor of CIMT after adjusting for model 1 (ß = 0.565; P = .033) and model 3 (ß = 0.756; P= .038). CONCLUSION: This study highlights increased CIMT and endothelial dysfunction in CS, associated with an altered inflammatory milieu. sTNFR1 and GPx may predict CIMT in females with CS.

Occurrence of osteoporosis & factors determining bone mineral loss in young adults with Graves' disease.

BACKGROUND & OBJECTIVES: There is a paucity of data with conflicting reports regarding the extent and pattern of bone mineral (BM) loss in Graves' disease (GD), especially in young adults. Also, interpretation of BM data in Indians is limited by use of T-score cut-offs derived from Caucasians. This study was aimed to evaluate the occurrence of osteoporosis in active treatment naive patients with GD and determine the factors predicting BM loss, using standard T-scores from Caucasians and compare with the cut-offs proposed by the Indian Council of Medical Research (ICMR) for diagnosing osteoporosis in Indians. METHODS: Patients with GD, >20 yr age without any history of use of anti-thyroid drugs, and normal controls without fracture history, drugs use or co-morbidities underwent BM density (BMD) assessment at lumbar spine, hip and forearm, thyroid function and calcium profile assessment. Women with menopause or premature ovarian insufficiency and men with androgen deficiency were excluded. RESULTS: p0 atients with GD (n=31) had significantly lower BMD at spine (1.01±0.10 vs. 1.13±0.16 g/cm 2 ), hip (0.88±0.10 vs. 1.04±0.19 g/cm 2 ) and forearm (0.46±0.04 vs. 0.59±0.09 g/cm 2 ) compared with controls (n=30) (P<0.001). Nine (29%) and six (19.3%) patients with GD had osteoporosis as per T-score and ICMR criteria, respectively. None of GD patients had osteoporosis at hip or spine as per ICMR criteria. Serum T 3 had strongest inverse correlation with BMD at spine, hip and femur. Step-wise linear regression analysis after adjusting for age, BMI and vitamin D showed T 3 to be the best predictor of reduced BMD at spine, hip and forearm, followed by phosphate at forearm and 48 h I 131 uptake for spine BMD in GD. INTERPRETATION & CONCLUSIONS: Osteoporosis at hip or spine is not a major problem in GD and more commonly involves forearm. Diagnostic criterion developed from Caucasians tends to overdiagnose osteoporosis in Indians. T 3 elevation and phosphate are important predictors of BMD. Baseline I 131 uptake may have some role in predicting BMD.

Proinflammatory and antiinflammatory attributes of fetuin-a: a novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome.

OBJECTIVE: Fetuin-A is a novel hepatokine. The number of biologic roles attributed to fetuin-A has increased exponentially in the past decade. The objective of this review is to discuss the pathophysiology of fetuin-A action, its proinflammatory and antiinflammatory attributes in different biological systems throughout the body, and pharmacologic interventions that modulate fetuin-A levels. METHODS: PubMed, Medline, and Embase search for articles published to July 2014, using the terms "alpha-2-hs-glycoprotein" [MeSH Terms] OR "alpha-2-hs-glycoprotein" [All Fields] OR "fetuin a" [All Fields]. RESULTS: Fetuin-A is the endogenous ligand for Toll-like receptor-4 activation, for lipid-induced insulin resistance. Fetuin-A has inverse interaction with adiponectin. Increased fetuin-A is a risk factor for diabetes and fatty liver disease in normoglycemia and prediabetes. Fetuin-A is a negative acute-phase reactant in sepsis and endotoxemia, promotes wound healing, and is neuroprotective in Alzheimer's disease. Decreased fetuin-A predicts increased disease activity in obstructive lung disease, Crohn's disease, and ulcerative colitis. Both elevated and reduced fetuin-A may be linked with increased cardiovascular events. CONCLUSION: Fetuin-A is a pleotropic molecule with diverse (sometimes even contradictory) effects in different systems, brought about by interaction with a variety of receptors, including the insulin, transforming growth factor-ß, and a plethora of Toll-like receptors. As a proinflammatory molecule, fetuin-A contributes to insulin resistance and is an important link between liver, adipose tissue, and muscles. Fetuin-A is neuroprotective and plays an important antiinflammatory role in sepsis and autoimmune disorders. Pharmacologic options are limited in modulating serum fetuin-A, but salsalates, curcumin, and vitamin D are promising agents of the future.