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The article presents the Virtual Annual Meeting in September 2020, the European Association for the Study of Diabetes has launched a series of videos on its e-Learning platform with the catchy title of Around the Diabetes World in 80 Days. Topics include the videos consisted of messages from leaders in diabetes care from different countries around the world, and the national representatives were asked to summarise the challenges and opportunities in diabetes care and research in their region.

Introduction: Ankle Brachial Index (ABI), a useful tool in diagnosingperipheral arterial disease (PAD), maygive falsely high values in sclerosed & calcified arteries. Toe Brachial Index (TBI) offers an alternative approach here, as digital arteries are unaffected by atherosclerotic changes and medial calcification. Aim: To find out the sensitivity and specificity of ABI and TBI in diagnosing PAD in T2D compared to CT angiography (CTA) as a non-invasive gold standard. Methods: 175 subjects with T2D, >50 years or >40 yearswith diabetes duration >10 years, were included. ABI&TBI were measured with an automated vascular Doppler XT 6 ports (Hadeco Inc. Japan). ABI < 0.9 & TBI < 0.6 was considered abnormal. USG Color Doppler& CTA of lower limb arterial system was performed. Arterial stenosis >50% on CTA was taken as evidence of PAD. Statistical analysis was performed by using IBM-SPSS statistics version 26 & GraphPad Prism Software version 9.0e. Results: Theprevalence of PAD was 24%. The sensitivity& NPV of 38% and 80% respectively for ABI (<0.9) reflect an increased risk of failure to diagnose existing disease. The sensitivity of TBI was 90% indicating that TBI was quite likely to accurately detect PAD. The specificity of ABI and TBI were 90% and 85% respectively suggesting both were relatively unlikely to falsely detect PAD. ROC analysis showed ABI at 0.9950 has sensitivity 60% and specificity 70%, TBI at 0.6 has sensitivity 88% & specificity 86%. Conclusion: The prevalence of PAD in T2D is much higher in our study population compared to previous studies. We showed, TBI has much greater sensitivity and comparable specificity to ABI in participants at risk of PAD making it a useful tool for vascular assessment in people with T2D. The existing TBI cutoff is satisfactory and the ABI cutoff needs to be re-evaluated.{Table 1} [ABSTRACT FROM AUTHOR]

The article offers the author's insights on the critical intervention at prediabetes stage to control epidemic among Asian Indians. Topics mentioned include the use of lifestyle intervention and metformin drug in preventing type-2 diabetes (T2DM), the challenge in implementing lifestyle intervention in India which has limited population awareness, and the multiple risk factors in Asian Indians. It also suggested a multi-centric trial on the benefits of metformin.

Managing precocious puberty (PP) has been a challenge due to lack of standardized definition, gonadotrophins assay, gonadotrophin stimulation, timings for blood sampling, and parameters for assessing outcomes. This review evaluated available literature to simplify the algorithm for managing gonadotrophin dependent/central PP (CPP), with an Indian perspective. CPP is one of the commonest forms of PP and mimics the normal course of puberty, at an age <8 and 9 years for girls and boys respectively. Basal and post gonadotrophin hormone releasing hormone analog (GnRHa) luteinizing hormone (LH) ≥0.3-0.6 IU/L and ≥4-5 IU/L (30-60 min after GnRH/GnRHa administration) respectively, using modern ultrasensitive automated chemiluminescence assays, can be considered positive for central puberty initiation. Uterine length of >3.5 cm and uterine volume of >1.8 ml are two most specific indicators for true CPP. Therapy is indicated in children with CPP with accelerated bone age, height advancement, or psychosocial stress. Treatment goal is to halt puberty progression to a socially acceptable age, allowing the child to attain optimal height potential. GnRHa is the treatment of choice, with best height outcomes when initiated <6 years age. Treatment is recommended till 11 years age. LH suppression to <3 U/L may be a reasonable target in patients on GnRHa therapy. Medroxyprogesterone acetate holds an important place in managing PP in India, cause of high costs associated with GnRHa therapy. There is an urgent need for clinical trials from India, for establishing Indian cut-off for diagnosis, treatment and follow-up of children with PP. [ABSTRACT FROM AUTHOR]

Uncontrolled cell growth and tissue invasion define the characteristic features of cancer. Several growth factors regulate these processes by inducing specific signaling pathways. We show that FGF16, a novel factor, is expressed in human ovary, and its expression is markedly increased in ovarian tumors. This finding indicated possible involvement of FGF16 in ovarian cancer progression. We observed that FGF16 stimulates the proliferation of human ovarian adenocarcinoma cells, SKOV-3 and OAW-42. Furthermore, through the activation of FGF receptor-mediated intracellular MAPK pathway, FGF16 regulates the expression ofMMP2,MMP9, SNAI1, and CDH1 and thus facilitates cellular invasion. Inhibition of FGFR as well as MAPK pathway reduces the proliferative and invasive behavior of ovarian cancer cells. Moreover, ovarian tumors with up-regulated PITX2 expression also showed activation of Wnt/β-catenin pathway that prompted us to investigate possible interaction among FGF16, PITX2, and Wnt pathway. We identified that PITX2 homeodomain transcription factor interacts with and regulates FGF16 expression. Furthermore, activation of the Wnt/β-catenin pathway induces FGF16 expression. Moreover, FGF16 promoter possesses the binding elements of PITX2 as well as T-cell factor (Wnt-responsive), in close proximity, where PITX2 and β-catenin binds to and synergistically activates the same. A detail study showed that both PITX2 and T-cell factor elements and the interaction with their binding partners are necessary for target gene expression. Taken together, our findings indicate that FGF16 in conjunction with Wnt pathway contributes to the cancer phenotype of ovarian cells and suggests that modulation of its expression in ovarian cells might be a promising therapeutic strategy for the treatment of invasive ovarian cancers. [ABSTRACT FROM AUTHOR]

Background: The A1 chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from West Bengal, India. Results: A total of 1133 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 897), insulin detemir (n = 94), insulin aspart (n = 90), basal insulin plus insulin aspart (n = 28) and other insulin combinations (n = 19). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.5%) and insulin user (mean HbA1c: 8.9%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naïve: -1.3%, insulin users: -1.6%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Background: Cushing's syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) and/or ectopic corticotropic releasing hormone (CRH) secretion accounts for <10% of all CS. Neuroendocrine carcinomas rarely cause CS. These carcinomas have been found to secrete either ACTH or rarely CRH. Herein we report a case of neuroendocrine carcinoma originating from the thyroid as the source of ACTH-dependent CS. Summary: A 30-year-old woman with features of CS presented with severe respiratory distress. Six months before that, she was diagnosed with primary hypothyroidism and started on levothyroxine (LT4) therapy. Biochemical evaluation was done, and nonsuppressed serum cortisol levels following dexamethasone with high ACTH confirmed a diagnosis of ACTH-dependent CS. Magnetic resonance imaging of the brain showed a bulky pituitary gland. Adrenal imaging showed bilateral adrenal hyperplasia. A computerized tomography scan showed a large anterior mediastinal mass arising from the neck and extending behind the transverse aortic arch. She underwent emergency thoracotomy due to rapidly progressive superior mediastinal syndrome and left vocal cord palsy. At surgery, the mass was seen originating from the thyroid and the thymus was compressed posteriorly. Near total thyroidectomy and thymectomy with removal of pericardial seedlings were done. Histopathology revealed sheets, cords, and nests of round or oval tumor cells with hyperchromatic nuclei and scant cytoplasm with local invasion and lymphovascular embolization suggestive of a neuroendocrine carcinoma arising from thyroid, staining positive for cytokeratin, synaptophysin, and chromogranin-A, and negative for calcitonin and carcinoembryonic antigen. Conclusions: Here we report a case of a neuroendocrine tumor of the thyroid causing ACTH-dependent CS. The tumor was negative for calcitonin staining, indicating that this was not a medullary carcinoma of the thyroid. Neuroendocrine carcinomas originating from the thyroid gland are very rare. A thyroid tumor of neuroendocrine origin causing ACTH-dependent CS has not been reported previously. [ABSTRACT FROM AUTHOR]

Aims/Introduction Materials and Methods Results Conclusions Deficiency of neurotropic factors is implicated in diabetic neuropathy (DN). Netrin‐1 is a neurotropic factor, but its association with DN has not been explored. We have assessed the association between serum netrin‐1 levels and early diabetic neuropathy assessed by quantifying corneal nerve fiber loss using corneal confocal microscopy.A total of 72 participants with type 2 diabetes, without and with corneal nerve fiber loss (DN− n = 42, DN+ n = 30), and 45 healthy controls were studied. Serum netrin‐1 levels were measured by enzyme‐linked immunosorbent assay, and corneal nerve morphology was assessed using corneal confocal microscopy.Corneal nerve fiber density, branch density, fiber length and serum netrin‐1 levels were significantly lower in the DN− and DN+ groups compared with controls (P < 0.001). Netrin‐1 levels correlated with corneal nerve fiber length in the DN+ group (r = 0.51; P < 0.01). A receiver operating characteristic curve analysis showed that a netrin‐1 cut‐off value of 599.6 (pg/mL) had an area under the curve of 0.85, with a sensitivity of 76% and specificity of 74% (P < 0.001; 95% confidence interval 0.76–0.94) for differentiating patients with and without corneal nerve loss.Serum netrin‐1 levels show a progressive decline with increasing severity of small nerve fiber damage in patients with diabetes. Netrin‐1 could act as a biomarker for small nerve fiber damage in DN. [ABSTRACT FROM AUTHOR]

Purpose: To collate the effect of SGLT2 inhibitors (SGLT2i) on adverse gout events in people with type 2 diabetes mellitus (T2DM). Methods: PubMed/MEDLINE, Embase, and Web of Science databases were systematically searched using appropriate keywords/MeSH/Emtree terms till January 25, 2022, to identify observational studies, randomized controlled trials (RCTs) or post hoc analysis reporting incident gout events and/or commencement of anti-gout drug in people with T2DM receiving SGLT2i versus those not receiving SGLT2i. Subgroup analyses were performed using comparators as placebo/other antidiabetic drugs and presence/absence of baseline hyperuricemia (uric acid ≥ 7 or < 7 mg/dl). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Results: We identified 5 studies (3 observational, 2 post hoc analysis of RCTs) pooling data retrieved from 568,010 people with T2DM. Pooled analysis showed that SGLT2i use was associated with 30% reduction in incident gout events/gout flares (HR 0.70, 95% CI: 0.59, 0.84, p < 0.001, I2 = 84%). Sensitivity analysis after excluding the retrospective observational study showed similar estimates (HR 0.65, 95% CI: 0.60, 0.70, p < 0.001, I2 = 0%). Subgroup analysis of data retrieved only from RCTs also showed significant benefits (HR 0.74, 95% CI: 0.55, 0.98, p = 0.03, I2 = 0%). Pooled analysis of data from 2 studies showed that SGLT2i use led to a significant reduction in the need for commencement of new anti-gout drug (pooled HR 0.58, 95% CI: 0.48, 0.71, p < 0.001, I2 = 0%). Consistent benefits were also observed for subgroup without baseline hyperuricemia (pooled HR 0.65, 95% CI: 0.47, 0.89, p < 0.01, I2 = 0%). Conclusions: SGLT2i may potentially prevent gout-related adverse events in people with T2DM. [ABSTRACT FROM AUTHOR]

Background: Non-invasive clinic-based tools for assessing PAD are not without limitations. Therefore, costly tests like Doppler study, CT angiography and MR angiography are often required to make a diagnosis. Ankle brachial index (ABI), commonly used for assessment of PAD, has high false positivity rates in sclerosed, calcified arteries which render them non-compressible. Toe brachial index (TBI) can be an alternative, as digital arteries are relatively unaffected by these changes. Aim: To compare the reliability of ABI and TBI in diagnosing PAD in type 2 diabetes using CT angiography (CTA) as the reference. Methods: 175 adults with T2D were selected. ABI &TBI were measured with an automated vascular Doppler XT 6 ports bilaterally for all subjects. For any subject, the limb with lower ABI and TBI was included for analysis. ABI < 0.9 & TBI < 0.6 were taken as evidence of PAD. CTA showing > 50% narrowing was taken as evidence of PAD. Results: 24% of our study subjects had CTA confirmed PAD. ABI has low sensitivity of 35.29% (95% CI 0.21–0.52) compared to TBI being 82.35% (95% CI 0.66–0.92). The specificity however was similar. ABI < 0.9 was able to detect CTA confirmed PAD, but ABI > 0.9, including the so-called normal ABI (0.9–1.3) was unable to detect PAD. ROC showed ABI at 1.005 has sensitivity 64.71% (95% CI 0.48- 0.79) and specificity 61.7% (95% CI 0.53–0.69) and TBI at 0.6 has sensitivity 82.35% (95% CI 0.66–0.92) & specificity 92% (95% CI 0.87–0.96). Utilizing Cohen's Kappa, the reliability of ABI with respect to CTA showed fair agreement (K = 0.225, p = 0.001), whereas the reliability of TBI with respect to CTA showed substantial agreement (K = 0.759, p < 0.0001). Conclusion: ABI < 0.9 detects PAD reliably, but presence of PAD in patients with ABI > 9.0 including the normal of ABI (0.9–1.3) can be confirmed with TBI, which correlated strongly with CTA. TBI is also non-inferior for PAD detection, when ABI < 0.9. TBI and not ABI can be utilized for initial assessment of PAD in subjects with T2D. [ABSTRACT FROM AUTHOR]

Background: Gestational Diabetes Mellitus (GDM) is a public health problem in India with implications well pronounced in pregnancy and beyond. Biomarkers like Glycated Albumin (G.A.) can well monitor the glycaemic status and evaluate the transient hyperglycaemic spikes, which account for the diabetic complications. Aims and Objectives: In this study, we intend to study urinary G.A. excretion with respect to urinary albumin excretion expressed as UGA% in gestational diabetes mellitus. Materials and Methods: A prospective observational study was conducted for a period of 16 months on 177 pregnant women who attended antenatal clinics for the first time at a single centre.Among the surveyed population, 26 pregnant women subsequently developed GDM, and 31 healthy pregnant women who did not develop GDM were included in the study. Results: The UGA% between GDM and healthy mothers showed an increase in GDM with a p value <0.05 during the first and second trimesters. Pearson’s correlation coefficient at 5% interval showed moderate to strong correlation for fasting plasma glucose (FBS) vs UGA% in 1st trimester(r= 0.61) and 3rd trimester(r=0.54).Conclusion: The higher UGA% in GDM mothers in the early trimester may help monitor glycaemic status efficiently and timely. Long term follows up would be worthwhile to predict future progression to nephropathy, retinopathy, and neuropathy. Henceforth, UGA being a non-invasive marker may emerge as a more patient-friendly marker reducing the hassles of innumerable invasive tests to monitor the well-being of a mother as well as a foetus during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Adult women with Turner syndrome (TS) have high rates of miscarriage, presumably due to the abnormal size and shape of the uterus. There is a paucity of data regarding the determinants of uterine volume (UtVol) in young girls with TS before the initiation of oestrogen replacement therapy (ERT). Methods: We performed a cross‐sectional study on premenarchal girls with TS, aged 5–15 years, pubertal stage B1–B3, not having received ERT (n = 73) and 50 age‐matched healthy controls. Anthropometric parameters and a history of growth hormone (GH) therapy (≥1 year) were noted. Uterine length (UtL), UtVol, and mean‐ovarian‐volume (MOV) standard‐deviation scores (SDS) were determined from transabdominal ultrasonography data. Results: Girls with TS had lower median UtVol‐SDS (−1.07 vs. 0.86; p <.001), UtL‐SDS (−3.72 vs. −0.41; p <.001) and MOV‐SDS (−5.53 vs. 1.96; p <.001) compared to age‐matched controls. Among TS girls, recipients of GH (n = 38) had higher UtVol‐SDS (−0.63 vs. −1.39; p =.0001), UtL‐SDS (−1.73 vs. −6.49; p <.0001) but similar MOV‐SDS compared to nonrecipients (n = 35). Those with normal uterine volume for age (NUVA, n = 29) had earlier initiation (7.8 vs. 9.3 years; p =.03) and a longer duration of GH (3.71 vs. 2.14 years; p =.002) than those with low UtVol for age (n = 44). UtVol‐SDS correlated with duration of GH (ρ = 0.411, p =.01) and negatively with age at GH initiation (ρ = −0.479, p =.003). In a model adjusted for pubertal status, karyotype and height‐SDS, GH use could independently predict having NUVA (odds ratio: 5.09, confidence interval: 1.63–15.94, p =.005). Conclusion: GH therapy has a stimulatory effect on uterine dimensions in pre‐and peripubertal girls with TS. Earlier initiation and longer duration of GH is important in TS girls before ERT. [ABSTRACT FROM AUTHOR]

Background: Diabetic foot ulcer (DFU) is a major complication of diabetes often impacted by polymicrobial infection in the wound site. Diabetic patients are immunocompromised in nature and hence vulnerable to infection once the skin barrier is breached. Microbiological culture-based methods show that Staphylococcus aureus (SA) is the most frequently isolated bacteria from the DFU wounds. SA and its most clinically important antibiotic resistant variant methicillin-resistant S. aureus (MRSA) are commonly found in the nasal vestibule and colonization of SA as well as MRSA in any wound site can aggravate the condition. We hypothesize that the presence of nasal MRSA carriage can serve as a potential risk factor contributing to the emergence of antibiotic resistance in diabetic foot ulcer wounds. Methods: In the present study, we have compared the carriage of SA and MRSA in nasal cavity and foot skin among DFU patients (D+F+, n = 50), diabetic patients without any ulcer (D+F-, n = 50), and healthy controls (D-F-, n = 40) by using bacterial culture and PCR based methods. The D+F+, D+F- and D-F-individuals were further categorized based on the presence or absence of MRSA and clinical parameters were compared between MRSA+ ve and MRSA-ve individuals in each of the three groups mentioned above. Results: Our results show that, (a) nasal MRSA carriage is significantly higher (p < 0.05) in D+F+ group than the D+F- and D-F- and significantly associated with wound MRSA carriage in D+ F+ individuals (O.R. = 4.09; 95% C.I. = 1.12–15.05) and (b) the HbA1C level is significantly higher (p < 0.02) in wound MRSA positive, compared to MRSA negative D+F+ patients. Interestingly more than half of the MRSA (64%) isolated from DFU wound were identified to be multidrug resistant. Conclusion: These findings strongly suggest that nasal MRSA carriage can act as a risk factor for development of antibiotic resistance in diabetic foot ulcers and it is therefore important to screen nasal and wound sites of these patients regularly. We have also developed a rapid multiplex PCR assay to detect MRSA from clinical isolates or microbial DNA isolated from clinical samples in the hospital settings. [ABSTRACT FROM AUTHOR]

Aims: To pool the effects of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors on gout and to investigate the association of these effects with baseline serum uric acid (SUA), SUA lowering, and underlying conditions, such as type 2 diabetes mellitus (T2DM)/heart failure (HF). Methods: PubMed, Embase, Web of Science, Cochrane Library and clinical trial registry websites were searched for randomized controlled trials (RCTs) or post hoc analyses (≥1‐year duration; PROSPERO:CRD42023418525). The primary outcome was a composite of gouty arthritis/gout flares and commencement of anti‐gout drugs (SUA‐lowering drugs/colchicine). Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using a generic inverse‐variance method with a random‐effects model. Mixed‐effects model univariate meta‐regression analysis was performed. Results: Five RCTs involving 29 776 patients (T2DM, n = 23 780) and 1052 gout‐related events were identified. Compared to placebo, SGLT2 inhibitor use was significantly associated with reduced risk of composite gout outcomes (HR 0.55, 95% CI 0.45‐0.67; I2 = 61%, P < 0.001). Treatment benefits did not differ between trials being conducted exclusively in baseline HF versus those conducted in patients with T2DM (P‐interaction = 0.37), but were greater with dapagliflozin 10 mg and canagliflozin 100/300 mg (P < 0.01 for subgroup differences). Sensitivity analysis excluding trials that evaluated the effects of empagliflozin 10/25 mg (HR 0.68, 95% CI 0.57‐0.81; I2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between‐trial heterogeneity (HR 0.46, 95% CI 0.39‐0.55; I2 = 0%). Univariate meta‐regression found no impact of baseline SUA, SUA lowering on follow‐up, diuretic use, or other variables on their anti‐gout effects. Conclusion: We found that SGLT2 inhibitors significantly reduced the risk of gout in individuals with T2DM/HF. Lack of an association with SUA‐lowering effects suggests that metabolic and anti‐inflammatory effects of SGLT2 inhibitors may predominantly mediate their anti‐gout benefits. [ABSTRACT FROM AUTHOR]

Introduction: Pancytopenia is a rare complication of Graves' disease with few case reports being available in literature. The authors depict a typical case of Graves' disease which was complicated by pancytopenia. Case Report: A 47-year-old female presented with complaints of 'bulging eyes,' episodic palpitations and increased sweating for last one year. Examination revealed a regular pulse rate of 116/min and loud S1. Bilateral exophthalmos with slightly decreased extraocular movement in upward gaze but with preserved vision and normal fundi was found. Diffuse thyroid enlargement with audible bruitwas noted. Complete blood count showed tri-lineage depression-Hb-8.2 g/dl; total WBC count- 3300/cmm (N-56%; L-35%) and platelet - 66000/cmm. Bone marrow aspirate with trephine biopsy showed normal cellular marrowwith no abnormal cell. Thyroid function test showed increased FT4: 4.2 ng/dl (N: 0.8-1.9) and TT3: 431 ng/dl (N: 60-200) with depressed TSH0.03 uIU/ml (N: 0.35-5.5 uIU/ml). 99m Technitium thyroid scan showed increased homogenous tracer uptake. A diagnosis of Graves' disease complicated by thyroid associated ophthalmopathy (TAO) and pancytopenia was made. Patient was started on carbimazole (30 mg/day). Follow-up at 6 months revealed improvement of Graves' disease, both clinically and biochemically, associated with marked recovery in haematological parameters: Hb-11.5 g/dl; TLC-6100/ cmm: N-73%; L-26% and platelet -- 188000/cmm. Discussion: Usually marrow depression in Graves' disease is treatment - related due to anti-thyroid drugs which may cause agranulocyosis. The index patient developedpancytopenia prior to administration of carbimazole. The causal effect of thyrotoxicosis in pancytopenia is best exemplified by the normalization of blood counts following reversal of thyrotoxic state. The mechanism may be shared autoimmune mechanism leading to reduced life span of blood cells or disturbances in maturation and differentiation of the pluripotent stem cells. Routine hematologic evaluation should be performed before administration of anti-thyroid drugs to differentiate pancytopenia related to Graves' disease itself from the marrow depression induced by these drugs. [ABSTRACT FROM AUTHOR]

Background: Lithium is the gold standard for the treatment of bipolar affective disorder and is associated with a number of biochemical and hormonal changes with use. In the absence of sufficient data from this part of the country, this study was planned. Objectives: Prevalence of biochemical (specially glycemic status and calcium) and hormonal (specially thyroid function) in patients on lithium. Method: This was a cross sectional study planned on adult patients taking lithium for at least 6 months and were not on thiazides, bisphosphonates or had history of prior thyroid or parathyroid disease or surgery. A total of 40 patients were taken. Data was managed in Excel 2016 and exported to SPSS 25 software for statistical analysis. Level of significance was set at p < 0.05. Result: Mean age of patients was 40 ± 13.9 yrs, with 30 females. Most patients were in age gr 30-40 yrs and hypertension present in 30%. Mean serum calcium was 8.6 mg/dl with a prevalence of thyroid dysfunction at 46%. Discussion/Conclusions: Lithium use is associated with hypothyroidism predominantly. [ABSTRACT FROM AUTHOR]

The authors comment on an article by E. Lontchi-Yimagou and colleagues in which they describe diabetes in individuals with low body mass index (BMI) from India. Topics discussed include comparison between type 2 diabetes (T2D) in White Caucasians and T2D in Asian Indians, metabolic characteristics of lean diabetes noted by Lontchi-Yimagou and colleagues, and criteria needed for individuals with diabetes to be grouped into a specific diagnostic category.

A letter to the editor is presented in response to the article "Incidence of diabetes and prediabetes and predictors of progression among Asian Indians: 10-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES)" by Anjana R.M. and colleagues in a 2015 issue.

Background: Individuals with Turner syndrome (TS) have a high risk for prediabetes/type 2 Diabetes Mellitus (T2DM). There is scarce data regarding risk factors for prediabetes in TS, specially from South Asia. Methods: We conducted a cross-sectional study on girls with TS aged 12-30 years who had achieved pubertal stage B3 and above--spontaneously or with oestrogen. Anthropometric measurements and biochemical tests were conducted, and medical records were reviewed for details about pubertal onset and progression, growth hormone (GH) and oestrogen therapy. Results: Out of 129 patients with TS in our database, 99 met the criteria for inclusion, mean age 18.33+/-3.78 years and mean BMI 20.57+/-3.71 kg/m2. Prevalence of prediabetes was 23.23%. Plasma-glucose measured after 75 g-oral-anhydrous-glucose-load (OGTT-PPG) identified five additional prediabetes cases, who had normal fasting plasma glucose (FPG) or HbA1c%. Compared to those without prediabetes, TS with prediabetes (n = 23) had higher mean body weight, BMI, waist circumference (WC) [42.02+/-5.83 vs 36.22+/-8.07, 22.77+/-2.78 vs 19.91+/- 3.72, 85.26+/- 3.52 vs 81.08+/- 4.59, pall < 0.03], higher median WC-to-height ratio (WHtR) and WC-to-hip ratio (WHR) ((0.64 [0.6-0.69] vs 0.59[0.56- 0.66], 0.9[0.84-1.12] vs 0.85[0.75-1.01], pboth < 0.02), and higher LDL-cholesterol, triglycerides, and greater prevalence of hepatosteatosis (47.1% vs 21.1%, P < 0.01). Among GH recipients (n = 36), those with prediabetes had delayed initiation and shorter duration of GH therapy. There were no differences in cardiometabolic parameters or the prevalence of diabetes between different karyotypic variants of TS. BMI, WC and WHR had significant positive correlation with FBG, OGTT-PPG and HbA1c% (pall < 0.004). Delay in oestrogen initiation had a significant correlation with OGTT-PPG (Spearman's-rho = 0.69, P < 0.004). BMI, WHR and pubertal status were independent predictors for prediabetes (OR: 1.27 [1.03-1.57]), 1.18 [1.04-1.34]) and 0.09[0.02-0.38], respectively, pall < 0.02), but karyotype was not. BMI had the highest sensitivity [cut-off: 21.04 kg/m2 (sensitivity: 82.6%, specificity: 62.2%) and WHR had the highest specificity [cut-off: 0.89 (sensitivity: 73.9%, specificity 78.4%)] for predicting prediabetes. Conclusion: Indian girls with TS have a high risk for prediabetes, irrespective of underlying karyotype and should be screened with oral glucose challenge to identify prediabetes. Timely intervention against central obesity and early initiation of GH and oestrogen should be ensured in TS. Late presenting girls should be closely monitored for dysglycaemia before and during treatment with GH and/or oestrogen. [ABSTRACT FROM AUTHOR]

A surfeit of mitochondrial reactive oxygen species (ROS) and inflammation serve as obligatory mediators of lipid-associated hepatocellular maladies. While retinoid homeostasis is essential in restoring systemic energy balance, its role in hepatic mitochondrial function remains elusive. The role of lecithin-retinol acyltransferase (LRAT) in maintenance of retinoid homeostasis is appreciated earlier; however, its role in modulating retinoic acid (RA) bioavailability upon lipid-imposition is unexplored. We identified LRAT overexpression in high-fat diet (HFD)-fed rats and palmitate-treated hepatoma cells. Elevation in LRAT expression depletes RA production and deregulates RA signaling. This altered RA metabolism enhances fat accumulation, accompanied by inflammation that leads to impaired mitochondrial function through enhanced ROS generation. Hence, LRAT inhibition could be a novel approach preventing lipid-induced mitochondrial dysfunction in hepatoma cells. [ABSTRACT FROM AUTHOR]

A case study of 43-year-lady with goiter for 9 years is presented, who had undergone diffuse tattooing of the goiter as a treatment option, however the lady's condition worsening heaviness, dysphagia and dyspnea for last one year.

The presentation of primary hyperparathyroidism (PHPT) is variable throughout the world. The present study explored retrospective data submitted to the Indian PHPT registry ( http://www.indianphptregistry.com ) between July 2005 and June 2015 from 5 centres covering four different geographical regions. The clinical, biochemical, radiological and histopathological characteristics of PHPT patients across India were analysed for similarity and variability across the centres. A total of 464 subjects (137 men and 327 women) with histopathologically proven PHPT were analysed. The mean age was 41 ± 14 years with a female:male ratio of 2.4:1. The majority (95%) of patients were symptomatic. Common clinical manifestations among all the centres were weakness and fatigability (58.7%), bone pain (56%), renal stone disease (31%), pancreatitis (12.3%) and gallstone disease (11%). Mean serum calcium, parathyroid hormone and inorganic phosphorus levels were 11.9 ± 1.6 mg/dL, 752.4 ± 735.2 pg/mL and 2.8 ± 0.9 mg/dL, respectively. Sestamibi scanning had better sensitivity than ultrasonography in the localisation of parathyroid adenoma; however, when these two modalities were combined, 93% of the cases were correctly localised. Mean parathyroid adenoma weight was 5.6 ± 6.5 g (0.1-54 g). It was concluded that the majority of PHPT patients within India are still mainly symptomatic with >50% of patients presenting with bone disease and one-third with renal impairment. Compared to Western countries, Indian patients with PHPT are younger, biochemical abnormalities are more severe, and adenoma weight is higher. As our observation is largely derived from a tertiary care hospital (no routine screening of serum calcium level), the results do not reflect racial differences in susceptibility to PHPT. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 (DPP-IV) is a ubiquitous proteolytic enzyme that cleaves incretin hormones, such as glucagon-like peptide 1 (GLP1) and gastric inhibitory protein (GIP), leading to reduced glucose stimulated insulin secretion from the pancreatic beta cells. The functionally active enzyme is present in a membrane bound form in several cell types as well as in a soluble form in the circulation. The present report deals with DPP-IV expression and its regulation in the pancreatic beta cells in presence of free fatty acids (FFAs) and Fetuin-A, a circulatory glycoprotein associated with insulin resistance in humans and animals. FFA and Fetuin-A individually or in combination trigger DPP-IV expression in MIN6 cells. Islets isolated from high fat diet fed (HFD) mice (16 weeks) showed higher levels of DPP-IV expression than standard diet (SD) fed mice. Fetuin-A increased DPP-IV expression in HFD mice (4 weeks). Inhibition of TLR4 or NFkB prevented palmitate-Fetuin-A mediated DPP-IV expression in MIN6. It has been seen that Fetuin-A alone also could trigger DPP-IV expression in MIN6 cells via NFkB. Additionally, palmitate treatment exhibited reduced level of soluble DPP-IV in the media of MIN6 culture, which corroborated with the expression pattern of its protease, KLK5 that cleaves and releases the membrane bound DPP-IV into the secretion. Our results demonstrate that FFA-Fetuin-A upregulates DPP-IV expression in the pancreatic beta cells through the TLR4-NFkB pathway. • FFA-Fetuin-A induces DPP-IV expression in the pancreatic beta cells. • Fetuin-A-palmitate mediated DPP-IV expression occurs through the activation of the TLR4-NFkB pathway. • Palmitate reduces the cleavage of membrane bound DPP-IV in MIN6 via KLK5 protease. [ABSTRACT FROM AUTHOR]

Background & objectives: Although polymicrobial infections involving both aerobic and anaerobic bacteria are very common in diabetic foot ulcers, in many centres of developing countries, anaerobes are rarely isolated due to technical difficulties. This can be overcome by using a new simple, innovative technique of a combination of candle combustion and use of acidified copper-coated steel wool, as reported here. Methods: In-house developed method was used in a prospective clinico-microbiological study for anaerobes from randomly selected 43 patients with diabetic foot ulcers along with conventional method of anaerobic culture in GasPak system and aerobic culture by standard laboratory procedures. For primary isolation of anaerobes, Brucella blood agar supplemented with hemin (5 μg/ml) and menadione (1 μg/ml) was used. Antibiotic sensitivity tests were performed by the standard disc diffusion method for aerobes and E-test method for anaerobes. Results: All the 43 samples were culture positive, of which aerobic Gram-negative bacteria (GNB) predominated, followed by Staphylococcus aureus, Enterococcus and diphtheroids. Anaerobes isolated from 21 samples were Peptostreptococcus, Bacteroides, Porphyromonas, Veillonella spp. and Clostridium perfringens by both GasPak and in-house developed and modified candle jar techniques. Imipenem and metronidazole were most sensitive while clindamycin, penicillin and cefoxitin were least sensitive drugs for anaerobes. Aerobic GNB were found to be multidrug resistant, especially to penicillin and cephalosporins. The most sensitive drug was piperacillin-tazobactam. Interpretation & conclusions: For isolation of anaerobes from clinical specimens such as diabetic foot ulcers, modified candle jar technique was found to be as reliable as GasPak system. This modified technique needs to be tested for many other clinical materials which are not yet evaluated. [ABSTRACT FROM AUTHOR]

World is now experiencing a major health calamity due to the coronavirus disease (COVID‐19) pandemic, caused by the severe acute respiratory syndrome coronavirus clade 2. The foremost challenge facing the scientific community is to explore the growth and transmission capability of the virus. Use of artificial intelligence (AI), such as deep learning, in (i) rapid disease detection from x‐ray or computed tomography (CT) or high‐resolution CT (HRCT) images, (ii) accurate prediction of the epidemic patterns and their saturation throughout the globe, (iii) forecasting the disease and psychological impact on the population from social networking data, and (iv) prediction of drug–protein interactions for repurposing the drugs, has attracted much attention. In the present study, we describe the role of various AI‐based technologies for rapid and efficient detection from CT images complementing quantitative real‐time polymerase chain reaction and immunodiagnostic assays. AI‐based technologies to anticipate the current pandemic pattern, prevent the spread of disease, and face mask detection are also discussed. We inspect how the virus transmits depending on different factors. We investigate the deep learning technique to assess the affinity of the most probable drugs to treat COVID‐19. This article is categorized under:Application Areas > Health CareAlgorithmic Development > Biological Data MiningTechnologies > Machine Learning [ABSTRACT FROM AUTHOR]

Introduction: The studies in animal models of cirrhosis suggest that dipeptidyl peptidase type 4 (DPP-4) enzymes play a crucial role in disease pathogenesis. In this clinical observational study, activity of DPP-4 and related gene expression were analysed in chronic liver disease patients. Objectives: To understand the DPP-4 enzyme activity variation in the common types of chronic liver disease by assessing plasma and peripheral blood mononuclear cell (PBMC) DPP-4 activity and comparing with healthy controls and to explore DPP-4 gene expression in PBMC. Methods: We recruited 130 study subjects in four cohorts—46 nonalcoholic fatty liver disease (NAFLD), 23 non-alcoholic cirrhosis (NAC) excluding viral aetiology, 21 alcoholic liver disease (ALC), and 40 control subjects. Blood samples were analysed for relevant biochemical parameters and plasma DPP-4 activity. PBMC fraction was used for the DPP-4 activity assay and gene expression analysis. Results: We found that lower plasma DPP-4 activity among patient cohorts but this was not statistically significant. The PBMC DPP-4 activity was significantly lower in NAFLD cohort. In the same cohort, DPP-4 gene expression in PBMC fraction was significantly increased (P < 0.05). There was significant correlation between plasma DPP-4 activity and liver injury marker alanine aminotransferase (ALT) among NAFLD (rho = 0.459, P < 0.01), NAC (rho = 0.475, P < 0.05), and ALC (rho = –0.572, P < 0.01) patients. Plasma DPP-4 activity modestly predicted ALT plasma level (beta coefficient = 0.489, P < 0.01). Conclusions: The PBMC DPP-4 activity and DPP-4 gene expression gets significantly altered in NAFLD patients. Plasma DPP-4 activity also shows correlation with ALT levels in CLD patients. The role of DPP-4 in disease pathology in NAFLD and other forms of CLD needs to be explored. [ABSTRACT FROM AUTHOR]

Objective: To compare the clinical profile of long-term survivors and nonsurvivors with type 1 diabetes (T1D) in India. Research Design and Methods: This is a retrospective study of 76 individuals with T1D who had survived for at least 40 years ("survivors") and 51 individuals with T1D who had died with shorter duration of diabetes ("non-survivors"), from diabetes clinics in different cities of India. Prevalence of complications in both groups and causes of death of the nonsurvivors were analyzed. Retinopathy was diagnosed by retinal photography; chronic kidney disease (CKD) by urinary albumin excretion (micro-or macroalbuminuria) and estimated glomerular filtration rate; peripheral vascular disease (PVD) by doppler measurement of ankle-brachial pressure index; coronary artery disease (CAD) based on history of myocardial infarction or coronary revascularization, and neuropathy by biothesiometry. Results: Mean glycated hemoglobin (8.4% ± 1.5% vs. 10.7% ± 2.2%, P < 0.001), serum low-density lipoprotein cholesterol (91 ± 29 mg/dL vs. 107 ± 22 mg/dL, P = 0.004), and systolic blood pressure (135 ± 16 mmHg vs. 153 ± 37 mmHg, P = 0.003) were lower, and high-density lipoprotein cholesterol (51 ± 11 mg/dL vs. 43 ± 15 mg/dL, P = 0.002) higher, among survivors compared to nonsurvivors. Diabetic retinopathy, CKD, neuropathy, PVD, and CAD were more frequent among nonsurvivors. CAD [25.5%] and renal failure [23.5%] were the most frequent causes of death. Conclusions: In this first report of long-term survivors with T1D from India, we report that survivors had better glycemic and blood pressure control, more favorable lipid profiles and lower prevalence of complications compared to nonsurvivors. However, there could be other protective factors as well, which merit further studies. [ABSTRACT FROM AUTHOR]

Infectious diseases of the central nervous system (CNS) are increasingly being recognized as important causes of hypopituitarism. Although tuberculosis is the most common agent involved, non-mycobacterial agents like viruses, bacteria, fungus, and protozoa are important causes in our country. Involvement post infections could be due to a strategically located tuberculoma, or pituitary abscess, or meningoencephalitis. Although it might not be reasonable to screen all patients with CNS infections for hypopituitarism, awareness of the possibility and clinical follow-up for suggestive symptoms is required. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia. [Display omitted] • Vildagliptin downregulates DPP-4 and fetuin-A expression in MIN6 and palmitate treated pancreatic islets • DPP-4 inhibition in MIN6 cell line suppresses TLR4-NFkB activation • Vildagliptin lowers high fat and fetuin-A mediated lipid accumulation and improves insulin secretion in pancreatic beta cells [ABSTRACT FROM AUTHOR]

A letter to the editor about the treatment of invasive giant prolactinoma with short term low dose cabergoline is presented.

Background: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and elevated risk of cardiovascular disease and diabetes. Chronic inflammation has been observed in PCOS in several studies but there is also opposing evidence and a dearth of research in Indians. Objective: To estimate chronic inflammation in PCOS and find its relationship with appropriate anthropometric and biochemical parameters. Materials and Methods: Chronic inflammation was assessed in 30 women with PCOS (Group A) and 30 healthy controls (Group B) with highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), and platelet microparticles (PMP). In group A, the relationship of chronic inflammation with insulin resistance, waist hip ratio (WHR) serum testosterone, and serum glutamate pyruvate transaminase (SGPT) were examined. Results: In group A, the hsCRP, TNFα, and PMP were significantly elevated compared to group B. However, IL-6 level was similar between the groups. In group A, PMP showed a significant positive correlation with waist-hip ratio and serum testosterone. IL-6 showed a significant positive correlation with insulin sensitivity and significant negative correlation with insulin resistance and serum glutamate pyruvate transaminase. Conclusion: PCOS is associated with chronic inflammation and PMP correlates positively with central adiposity and biochemical hyperandrogenism in women with PCOS. [ABSTRACT FROM AUTHOR]

Introduction: Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries, but are rarely reported in India. Therefore, we report here a case of hypophosphatemic rickets. Aim and objective: To report a case of hypophosphatemic rickets presenting with recurrent pathological fractures. Material and Methods: A 34-year-old premenopausal lady presented with recurrent pathological fractures, bone pain, and muscle weakness since 14 years of age. A thorough history was taken followed by clinical examination, and relevant biochemical and radiological investigations were done. Results: Height was 125 cm, arm span 145 cm, body weight 30 kg, and body mass index (BMI) 19.2 kg/m². Dental caries, kyphoscoliosis, shortening of left lower limb, bilateral coxa vara deformity of knee, muscle weakness, and bone tenderness were present. Calcium was 9.4 mg/dL, phosphorus: 1.8 mg/dL, albumin: 4.0 gm/dL, alkaline phosphatase: 360 U/L, creatinine: 0.4 mg/dL, a normal ammonium chloride (NH4 Cl) loading test,24-hour urine calcium excretion: 102 mg/day, 25-hydroxyvitamin D3 [25(OH)D3]: 21.6 ng/mL, intact parathyroid hormone (PTH): 43.74 pg/mL, fraction excretion of phosphate (PO4): 40%, tubular maximum reabsorption of phosphate per unit of glomerular filtrate (TmP/GFR): 0.65 mg/dL, and fibroblast growth factor (FGF)23: 321.4 RU/mL. Skeletal X-rays showed multiple old fractures and pseudofractures. Magnetic resonance imaging (MRI) of the whole body showed no evidence of tumor. Fludeoxyglucose ( 18 F)- positron emission tomography (FDG-PET) computed tomography (CT) scan revealed metabolically active marrow with multiple areas of fracture and FDG-avid lesions in both lungs but no CT-based findings. Conclusion: Hypophosphatemic rickets or osteomalacia, possibly hereditary, is a rare cause of recurrent pathological fractures. [ABSTRACT FROM AUTHOR]

Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1.Mechanistically, we showthat p300- mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND OR CONTEXT: Pituitary adenoma (PA) is the most common pathology of the pituitary gland. Pituitary tumors were historically considered benign, however, from recent advances in pathological and molecular analyses, numerous prognostic markers have been identified, allowing a better characterization of tumor behavior and prediction of response to treatment and recurrences. AIMS AND OBJECTIVES: Evaluation of the epidemiological occurrence of pituitary tumors in our center and prediction of the benign, aggressive, or malignant nature of the tumor with the help of immunohistochemical markers (IHC) Ki-67, P53, and O-6-methylguanine-DNA methyltransferase (MGMT) along with radiology. MATERIALS AND METHODS: A prospective study was done in 33 cases. Patients with clinically suspected pituitary tumors and related symptoms and signs are referred from the endocrine outpatient department and subsequently operated at the neurosurgery department were selected. We have studied the clinical features, radiology, histopathology, and IHC with the help of Ki-67, P53, and MGMT of PA over 2 years. RESULTS: We have 94% (31/33) cases of PA among them 94% (29/31) cases are macroadenoma. The IHC was conducted on 30 cases (excluding 1 case of pituitary apoplexy) where Ki-67, p53, and MGMT have been used for IHC in order to analyze the prognosis of the PA, irrespective of the immunological subtype of the PA. In our study, only 13% (4 patients) had MGMT score 0 and 2 patients, among these 4 patients having above cutoff level of Ki-67 and p53 value, considered as aggressive (in case of Ki-67 >3% and >50% in case of p53). When comparing MGMT expression with recurrence, a high degree of significance was found (Mann–Whitney U-test, P = 0.0038). Most of the recurrent tumors (6/9) had MGMT score 1 or below and most of the nonrecurring tumor had MGMT score 2 or above. When comparing MGMT expression with aggressiveness, a high degree of significance was found (Mann–Whitney U-test, P < 0.0001). Finally, combining the radiological Ki-67, p53, and MGMT values, two cases of aggressive adenoma have been seen in our study, the remaining being benign adenomas (WHO classification 2004). We did not encounter any case of pituitary carcinoma. MGMT did not show any significant correlation with radiological grading and histology. CONCLUSION: The benign, aggressive, or malignant nature of PA can be effectively predicted with the help of IHC, such as Ki-67, p53, and MGMT. This helps in better patient management and predicts recurrences and prognosis. [ABSTRACT FROM AUTHOR]

Insulin Resistance (IR) plays a key role in pathogenesis of type 2 diabetes. NAFLD, considered by some as the hepatic manifestation of IR, leads to NASH, cirrhosis and rarely hepatocellular carcinoma. Hepatic Cirrhosis secondary to NAFLD is an emerging public health tsunami. IR is known to impair lipid induced hepatic Retinoid metabolism. Lecithin: Retinol Acyl Transferase (Lrat) plays a crucial role in retinoid homeostasis. Studies have shown the involvement of all-trans Retinoic Acid (atRA) in mitochondrial biogenesis; it functions mainly through PPAR-α and RXR. We identified overexpression of LRAT in liver of HFD-fed rats, hepG2 and huh7 cell lines. Lipid (Palmitic acid-PA) induced over expression of Lrat was associated with a significant reduction in RA production; thereby impairing PPAR-α mediated fatty acid oxidation (FAO) and fat accumulation in hepatocytes. PA induced overexpression of hepatic Lrat was accompanied by excess lipid influx into the mitochondria resulting in impaired mitochondrial biogenesis and bioenergetics, characterized by loss of membrane potential, elevated ROS generation and impaired FAO. Knockdown of Lrat gene restored reduced levels of PPARα resulting from overexpression of Lrat upon PA treatment. Silencing of hepatic Lrat abrogated neutral fat accumulation in PA treated liver tissue and cell lines. Lipid induced mitochondrial dysfunction and resulting elevation in ROS levels was associated with increased mitochondrial fragmentation and decreased membrane potential; Lrat silencing reversed this process. Taken together our study unravels a novel role of PA induced Lrat overexpression in neutral fat accumulation in the liver that may potentially lead to development of NAFLD and NASH in the short term and cirrhosis and rarely, HCC in the long term. This brings to the fore Lrat silencing as a future drug target to prevent and/or treat fat accumulation in the liver in setting of Insulin Resistance. Disclosure: E. Karmakar: None. N. Das: None. S. Mukhopadhyay: None. S. Roy: None. [ABSTRACT FROM AUTHOR]

Introduction: Rickets due to renal tubular acidosis is not uncommon, but rarely diagnosed. We describe four cases of proximal renal tubular acidosis presenting with short stature and rickets. After excluding nutritional, calcipenic and commoner causes of rickets, proximal renal tubular dysfunction was diagnosed in all cases. Case 1: Our first case is a 7-year-old boy with pathological fracture, protuberant abdomen and radiological features of rickets. The boy had phosphaturia, glucosuria, and proteinuria. Genetic testing confirmed a diagnosis of Fanconi- Bickel syndrome with mutation in SLC2A2. He is on phosphate and calcitriol replacement. Case 2: The second case is that of a short girl with lower limb deformity. She had phosphaturia, metabolic acidosis, aminoaciduria hypokalaemia, crystals on the cornea and hypothyroidism. Leucocyte cysteine levels were elevated. Genetic analysis revealed nephropathic cystinosis. Case 3: The next case is a 2-year-old female presenting with delayed development, polyuria and widening of wrists and ankles. There was profound hypophosphatemia, phosphaturia, metabolic acidosis, glucosuria, aminoaciduria and multiple liver nodules on Ultrasonography. Mass spectrometry analysis of blood and urine gave a diagnosis of tyrosinemia type1. Case 4: Our fourth case is 10-year-old boy presenting with diminution of vision and short stature. There was severe metabolic acidosis with adequate urinary acidification and delayed bone age. Eye examination showed a band shaped corneal opacity in both eyes. The overall picture was suggestive of Sodium bicarbonate cotransporter (NBC) defect in the proximal tubule. [INLINE:1] Discussion: These cases represent four rare and difficult to diagnose causes of short stature and rickets due to proximal renal tubular involvement. Short stature, metabolic acidosis, varying degrees of proximal tubular defect are common to all these cases with unique overtones. Renal phosphate wasting is seen in most. Oral phosphate, active vitamin D3, alkali form the cornerstone of management with individualisations. [ABSTRACT FROM AUTHOR]

Accumulation and polarization of anti-inflammatory M2 to proinflammatory M1 macrophage in the adipose tissue of obese diabetic mice is an important pathogenic signature. It worsens lipid induced inflammation and insulin resistance. Here we demonstrate that a small molecule, a peroxyvanadate compound i.e. DmpzH [VO(O 2 ) 2 (dmpz)] or dmp, could robustly decrease macrophage infiltration, accumulation and their polarization in high fat diet (HFD) induced obese diabetic mice. In searching the underlying mechanism it was revealed that SIRT1 level was strikingly low in the inflamed adipose tissue of HFD mice as compared to mice fed with standard diet (SD). Administration of dmp markedly increased SIRT1 level by inducing its gene expression with a consequent decrease in macrophage population. Elevation of SIRT1 coincided with the decrease of MCP1, Fetuin-A (FetA) and IFNγ. Since MCP1 and FetA drive macrophage to inflamed adipose tissue and IFNγ promotes M2 to M1 transformation, both recruitment and M1 induced inflammation were found to be significantly repressed by dmp. In addressing the question about how dmp induced excess SIRT1 could reduce MCP1, FetA and IFNγ levels, we found that it was due to the inactivation of NFκB because of its deacetylation by SIRT1. Since NFκB is the transcriptional regulator of these molecules, their expressions were significantly suppressed and that caused sharp decline in macrophage recruitment and their polarity to M1. This effected a marked fall in proinflammatory cytokine level which significantly improved insulin sensitivity. dmp is likely to be the first molecule that rescues inflammatory burden contributed by macrophage in obese diabetic mice adipose tissue which causes significant increase in insulin sensitivity therefore it may be a meaningful choice to treat type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background and Objectives: Nonalcoholic fatty liver disease (NAFLD) and dysglycemia are public health challenges. There is urgent need for anthropometric surrogates for NAFLD screening. This study evaluated role of neck circumference (NC) and neck-height ratio (NHtR) as predictors of liver stiffness measure (LSM) in individuals with prediabetes (IPD). Methods: In a cross-sectional study, 188 IPD from 1130 screened individuals underwent anthropometry, ultrasonography, Fibroscan® for LSM, dyslipidemia, insulin resistance (IR), and fetuin-A assessment. Results: Hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), metabolic syndrome (MetS), NAFLD, and significant liver stiffness (SLS) (LSM >8.5kPa) were observed in 53.7%, 31.4%, 71.3%, 73.9%, 24.5%, and 11.2% prediabetes individuals, respectively. Prediabetes with NAFLD had significantly higher body mass index (BMI), NC, NHtR, glycated hemoglobin, triglycerides, fatty liver index (FLI), and LSM. Prediabetes in highest NHtR quartile had significantly higher BMI, hypertension, MetS, fasting glucose, glycated hemoglobin, homeostatic model assessment-IR, NAFLD, LSM, SLS, and lower HDL-C. Stepwise forward linear regression revealed that NHtR, FLI, and LDL-C were best predictors of LSM, at baseline (Model-1), after adjusting for age and sex (Model-2), and adjusting model-2 plus systolic and diastolic blood pressure (Model-3). NHtR and NC (in females) and NHtR and BMI (in males) had largest area under the curves for predicting LSM, NAFLD, and MetS. NHtR ≥21.54 cm/m (sensitivity: 90%; specificity: 52.5%; females) and ≥21.62 cm/m (sensitivity: 80%; specificity: 49.4%; males) was best predictor of SLS. Interpretation and Conclusion: NHtR is a reliable tool for community screening of NAFLD and liver stif fness in prediabetes. [ABSTRACT FROM AUTHOR]

Background: L-theanine is a natural bioactive amino acid present in tea (Camellia sinensis [L.] O. Kuntze) and consumed worldwide through tea decoction. Objective: The present work aims at evaluation of the insulin secretion and cytoprotective efficacy of L-theanine, a bioactive amino acid present in tea, on pancreatic β-cell line, RIN-m5F. Methods: RIN m5F cell were treated with L-theanine alone or prior to hydrogen peroxide (200 um) treatment and subsequently cell viability, cellular morphology, insulin secretion and insulin gene expression were analyzed. Results: Studies have shown that L-theanine dose dependently (0-300 μm) increases the β-cell mass as well as increases insulin production by RIN-m5F cell. It was also observed that pretreatment of the cell with L-theanine partially protected the oxidative stress of β-cells that were evident from cell viability, cellular morphology, and restoration of insulin-secreting ability. Conclusion: Results suggest that L theanine is an insulinotropic agent as well as effective in giving partial protection to pancreatic β-cells in oxidatively stressed condition. L-theanine can be used in the prevention or treatment of diabetes. [ABSTRACT FROM AUTHOR]

Although several reports demonstrated that accumulation of excess lipid in adipose tissue produces defects in adipocyte which leads to the disruption of energy homeostasis causing severe metabolic problems, underlying mechanism of this event remains yet unclear. Here we demonstrate that FetuinA (FetA) plays a critical role in the impairment of two metabolic sensors, SIRT1 and AMPK, in inflamed adipocytes of high fat diet (HFD) mice. A linear increase in adipocyte hypertrophy from 10 to 16 week was in tandem with the increase in FetA and that coincided with SIRT1 cleavage and decrease in pAMPK which adversely affects PGC1α activation. Knock down (KD) of FetA gene in HFD mice could significantly improve this situation indicating FetA's contribution in the damage of energy sensors in inflamed adipocyte. However, FetA effect was not direct, it was mediated through TNF-α which again is dependent on FetA as FetA augments TNF-α expression. FetA being an upstream regulator of TNF-α, its suppression prevented TNF-α mediated Caspase-1 activation and cleavage of SIRT1. FetA induced inactivation of PGC1α due to SIRT1 cleavage decreased PPARϒ, adiponectin, NRF1 and Tfam expression. All these together caused a significant fall in mitochondrial biogenesis and bioenergetics that disrupted energy homeostasis resulting loss of insulin sensitivity. Taken together, our findings revealed a new dimension of FetA, it not only induced inflammation in adipocyte but also acts as an upstream regulator of SIRT1 cleavage and AMPK activation. Intervention of FetA may be worthwhile to prevent metabolic imbalance that causes insulin resistance and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Islets of type 2 diabetes patients display inflammation, elevated levels of cytokines and macrophages. The master regulator of inflammation in the islets is free fatty acids (FFA). It has already been reported that FFA and TLR4 stimulation induces pro-inflammatory factors in the islets. In this report we demonstrate that excess lipid triggers Fetuin-A (FetA) secretion from the pancreatic β-cells. Palmitate treatment to MIN6 cells showed significantly elevated FetA levels in respect to their controls. Fatty acid induces the FetA gene and protein expression in the pancreatic β-cells via TLR4 and over-expression of NF-κB. In the NF-κB knocked down MIN6 cells palmitate could not trigger FetA release into the incubation medium. These results suggest that NF-κB mediates palmitate stimulated FetA secretion from the pancreatic β-cells. Blocking the activity of TLR4 by CLI-095 incubation or TLR4 siRNA restored insulin secretion which confirmed the role of TLR4 in FFA-FetA mediated pancreatic β-cell dysfunction. Palmitate mediated expression of NF-κB enahnced inflammatory response through expression of cytokines such as IL-1β and IL-6. These results suggest that FFA mediated FetA secretion from pancreatic β-cells lead to their dysfunction via FFA-TLR4 pathway. FetA thus creates an inflammatory environment in the pancreatic islets that can become a possible cause behind pancreatic β-cell dysfunction in chronic hyperlipidemic condition. [ABSTRACT FROM AUTHOR]

Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic β-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17μM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy. [ABSTRACT FROM AUTHOR]

Adiponectin secreted from adipocytes is an anti-diabetic and anti-atherogenic adipokine. Adiponectin level is known to fall significantly in obesity induced type 2 diabetes which worsen insulin sensitivity because of aberrant lipid management. However, underlying mechanism of adiponectin decrease in obese diabetic condition is yet unclear. We report here that lowering of plasma adiponectin coincided with the higher Fetuin A (FetA) level in high fat diet (HFD) induced obese diabetic mice. Knock down of FetA gene (FetA KD ) elevated adiponectin level markedly in HFD mice, while reinforcement of FetA into FetA KD HFD mice reduced its level again. These results indicate FetA's involvement in the lowering of adiponectin level in obesity induced diabetic mice. Our findings to understand how FetA could affect adiponectin decrease demonstrated that FetA could enhance Wnt3a expression in the adipocyte of HFD mice. FetA addition to 3T3L1 adipocyte incubation elevated Wnt3a expression in a dose dependent manner. Overexpression of Wnt3a by FetA inhibited PPARγ and adiponectin. FetA failed to reduce PPARγ and adiponectin in Wnt3a gene knocked down 3T3L1` adipocytes. All these suggest that FetA mediate its inhibitory effect on adiponectin through Wnt3a–PPARγ pathway. Inhibition of adiponectin expression through FetA and Wnt3a significantly compromised with the activation of AMPK and its downstream signalling molecules which adversely affected lipid management causing loss of insulin sensitivity. Downregulation of adiponectin in inflamed adipocyte by FetA through the mediation of Wnt3a and PPARγ is a new report. [ABSTRACT FROM AUTHOR]

Introduction: Glycated hemoglobin (HbA1c) can be altered in different conditions. We hypothesize that HbA1c levels may change due to altered thyroid status, possibly due to changes in red blood cell (RBC) turnover. Objectives: The objective of this study was to determine the effects of altered thyroid status on HbA1c levels in individuals without diabetes, with overt hyper- and hypo-thyroidism, and if present, whether such changes in HbA1c are reversed after achieving euthyroid state. Methods: Euglycemic individuals with overt hypo- or hyper-thyroidism were selected. Age- and sex-matched controls were recruited. Baseline HbA1c and reticulocyte counts (for estimation of RBC turnover) were estimated in all the patients and compared. Thereafter, stable euthyroidism was achieved in a randomly selected subgroup and HbA1c and reticulocyte count was reassessed. HbA1c values and reticulocyte counts were compared with baseline in both the groups. Results: Hb A1c in patients initially selected was found to be significantly higher in hypothyroid group. HbA1c values in hyperthyroid patients were not significantly different from controls. HbA1c reduction and rise in reticulocyte count were significant in hypothyroid group following treatment without significant change in glucose level. Hb A1c did not change significantly following treatment in hyperthyroid group. The reticulocyte count, however, decreased significantly. Conclusion: Baseline HbA1c levels were found to be significantly higher in hypothyroid patients, which reduced significantly after achievement of euthyroidism without any change in glucose levels. Significant baseline or posttreatment change was not observed in hyperthyroid patients. Our study suggests that we should be cautious while interpreting HbA1c data in patients with hypothyroidism. [ABSTRACT FROM AUTHOR]