RSS 1.0Endocrine and Diabetes
Recent Submissions
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Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes.Background: The dietary supply of methyl donors such as folate, vitamin B12, betaine, methionine, and choline is essential for normal growth, development, and physiological functions through the life course. Both human and animal studies have shown that vitamin B12 deficiency is associated with altered lipid profile and play an important role in the prediction of metabolic risk, however, as of yet, no direct mechanism has been investigated to confirm this. Results: Three independent clinical studies of women (i) non-pregnant at child-bearing age, (ii) in early pregnancy, and (iii) at delivery showed that low vitamin B12 status was associated with higher total cholesterol, LDL cholesterol, and cholesterol-to-HDL ratio. These results guided the investigation into the cellular mechanisms of induced cholesterol biosynthesis due to vitamin B12 deficiency, using human adipocytes as a model system. Adipocytes cultured in low or no vitamin B12 conditions had increased cholesterol and homocysteine levels compared to control. The induction of cholesterol biosynthesis was associated with reduced s-adenosylmethionine (AdoMet)-to-s-adenosylhomocysteine (AdoHcy) ratio, also known as methylation potential (MP). We therefore studied whether reduced MP could lead to hypomethylation of genes involved in the regulation of cholesterol biosynthesis. Genome-wide and targeted DNA methylation analysis identified that the promoter regions of SREBF1 and LDLR, two key regulators of cholesterol biosynthesis, were hypomethylated under vitamin B12-deficient conditions, and as a result, their expressions and cholesterol biosynthesis were also significantly increased. This finding was further confirmed by the addition of the methylation inhibitor, 5-aza-2'-deoxycytidine, which resulted in increased SREBF1 and LDLR expressions and cholesterol accumulation in vitamin B12-sufficient conditions. Finally, we observed that the expression of SREBF1, LDLR, and cholesterol biosynthesis genes were increased in adipose tissue of vitamin B12 deficient mothers compared to control group. Conclusions: Clinical data suggests that vitamin B12 deficiency is an important metabolic risk factor. Regulation of AdoMet-to-AdoHcy levels by vitamin B12 could be an important mechanism by which it can influence cholesterol biosynthesis pathway in human adipocytes.
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Bloom's syndrome in an Indian man in the UKA 17-year-old Indian man was diagnosed with Bloom's syndrome at the age of 3 years. This is the first reported case of Bloom's in an Indian from the UK and the third case report from the British Isles. Bloom's is typically characterised by short stature, photosensitivity, telangiectatic erythema, learning difficulties, immunodeficiency and malignancy. He was born below the 0.4th centile and failed to gain weight as an infant. He presented in clinic with short stature, prominent facial features and hyperpigmented skin patches, which are all defining characteristics of Bloom's syndrome. Other case reports have documented early neoplasms, photosensitivity and learning difficulties in these patients; however, our patient is different, and currently attends a mainstream college, demonstrating little difficulty in coping with the work. To date, he has not presented with any malignancy or characteristic malar rash.
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Simultaneous detection of five one-carbon metabolites in plasma using stable isotope dilution liquid chromatography tandem mass spectrometryDisturbance in one-carbon (1-C) cycle occurs due to nutritional deficiencies (vitamin B12/folate) or specific genetic polymorphisms. This leads to altered levels of key 1-C metabolites such as SAM (s-adenosyl methionine), SAH (s-adenosyl homocysteine), methionine, homocysteine and MMA (methyl malonic acid). These 1-C metabolites are determinants of cellular methylation potential and epigenetic modifications of DNA which impairs metabolic pathways in several pathological diseases and developmental programming. Though methods were able to measure these analytes only independently, none of the methods detect simultaneously. Therefore we developed a method to measure these five 1-C metabolites in a single run using liquid chromatography tandem mass spectrometry (LC-MS/MS). We used stable isotopes dilution LC-MS/MS to measure the 1-C metabolites in human plasma. Blood samples were collected from pregnant women (n=30) at early gestation in the ongoing, multicentre, prospective PRiDE study. Linearity exhibited across the calibration range for all the analytes with the limit of detection (LOD) of 1.005nmol/l for SAM, 0.081nmol/l for SAH, 0.002μmol/l for methionine, 0.046μmol/l for homocysteine and 3.920nmol/l for MMA. The average recovery for SAM was 108%, SAH-110%, methionine-97%, homocysteine-91% and MMA-102%. The inter-assay CV for SAM was 7.3, SAH-5.6%, methionine-3.5%, homocysteine-7.0% and MMA-4.0%. The intra-assay CV for SAM was 8.7%, SAH-4.7%, methionine-5.4%, homocysteine-8.1% and MMA-6.1%. Pregnant women at early gestation with low B12 levels had significantly higher homocysteine, MMA, lower levels of methionine, SAM and SAM:SAH ratio and higher triglycerides. We developed a simple and rapid method to simultaneously quantify 1-C metabolites such as SAM, SAH, methionine, homocysteine and MMA in plasma by stable isotope dilution LC-MS/MS which would be useful to elucidate the epigenetic mechanisms related in the gene-nutrient interactions.
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Low vitamin B12 in pregnancy is associated with adipose-derived circulating miRs targeting PPARγ and insulin resistanceContext: Low vitamin B12 during pregnancy is associated with higher maternal obesity, insulin resistance (IR), and gestational diabetes mellitus. B12 is a key cofactor in one-carbon metabolism. Objective: We hypothesize that B12 plays a role in epigenetic regulation by altering circulating microRNAs (miRs) during adipocyte differentiation and results in an adverse metabolic phenotype. Design, settings, and main outcome measure: Human preadipocyte cell line (Chub-S7) was differentiated in various B12 concentrations: control (500 nM), low B12 (0.15 nM), and no B12 (0 nM). Maternal blood samples (n = 91) and subcutaneous adipose tissue (SAT) (n = 42) were collected at delivery. Serum B12, folate, lipids, plasma one-carbon metabolites, miR profiling, miR expression, and gene expression were measured. Results: Our in vitro model demonstrated that adipocytes in B12-deficient conditions accumulated more lipids, had higher triglyceride levels, and increased gene expression of adipogenesis and lipogenesis. MiR array screening revealed differential expression of 133 miRs involving several metabolic pathways (adjusted P < 0.05). Altered miR expressions were observed in 12 miRs related to adipocyte differentiation and function in adipocytes. Validation of these data in pregnant women with low B12 confirmed increased expression of adipogenic and lipogenic genes and altered miRs in SAT and altered levels of 11 of the 12 miRs in circulation. After adjustment for other possible confounders, multiple regression analysis revealed an independent association of B12 with body mass index (β: -0.264; 95% confidence interval, -0.469 to -0.058; P = 0.013) and was mediated by four circulating miRs targeting peroxisome proliferator-activated receptor γ and IR. Conclusions: Low B12 levels in pregnancy alter adipose-derived circulating miRs, which may mediate an adipogenic and IR phenotype, leading to obesity.
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Bariatric Surgery: A service evaluation of a waiting list initiativeDue to COVID related delays, one NHS hospital sub-contracted patients to another hospital for bariatric surgery with the following selection criteria: minimal comorbidities, BMI <50kg/m² and consenting participant. This project aimed to evaluate surgical outcomes and participant experience.
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Diabetes specialist intervention in general practices in areas of deprivation and ethnic diversity: A qualitative evaluation (QUAL-ECLIPSE)Aim: To assess patients' and healthcare professionals' perspectives of a specialist-led Diabetes Risk-based Assessment Clinic (DIRAC) for people with diabetes at high risk of complications (PWDHRC) in areas of deprivation in Coventry, UK.
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Facial twitching: calcium or concussion conundrum? Hypocalcaemia in a young American football player masking an internal carotid artery dissectionA 30-year-old male American football player presented to the acute medical unit with left-hand and hemifacial spasms. History and examination revealed hemifacial spasms in keeping with seizure-like activity possibly due to symptomatic hypocalcaemia. Subsequent investigations revealed an adjusted calcium of 1.87 mmol/L and, hence, he was managed with intravenous calcium replacement. He presented two further times in a 1-month period, with subjective limb weakness, despite normal adjusted calcium. During his third admission, he developed slurred speech and a marked facial droop, with absence of power in the right upper limb. Imaging revealed acute and old infarctions in the left middle cerebral artery territory and appearances consistent with left internal carotid artery dissection. This presentation of arterial stroke is atypical but with potentially grave consequences if missed. There is limited literature on the presentation of hemifacial spasm, and its association with ischaemic or haemorrhagic stroke represents a key learning point. Keywords: calcium and bone; stroke.
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Emotional eating among adults with healthy weight, overweight and obesity: a systematic review and meta-analysisMEDLINE and APA PsycINFO databases were searched from inception up to January 2022 for studies that reported EE scores from validated questionnaires. The quality of all included studies was assessed using the AXIS tool. Meta-analysis used random effects and standardised mean difference (SMD). Heterogeneity was investigated using I2 statistics and sensitivity analyses.
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Erythroderma (exfoliative dermatitis). Part 2: energy homeostasis and dietetic management strategiesErythroderma (exfoliative dermatitis) is associated with important metabolic changes that include an enhancement in energy expenditure. The key components to total energy expenditure (TEE) include basal metabolic rate (~68% of TEE), physical activity (~22% of TEE) and thermic effect of food (~10% of TEE). In the erythrodermic state, there are likely multiple contributors to the increase in basal metabolic rate, such as 'caloric drain' resulting from increased evaporation of water from enhanced transepidermal water loss, increased activity of the cardiovascular system (including high-output cardiac failure), increased nonshivering thermogenesis and hormonal changes such as hypercortisolaemia. A change in the patient's level of physical activity and appetite as a result of ill health status may further impact on their TEE and energy consumption. In Part 2 of this two-part concise review, we explore the key constituents of energy homeostasis and the potential mechanisms influencing energy homeostasis in erythroderma, and suggest much-needed dietetic management strategies for this important condition.
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Erythroderma (exfoliative dermatitis). Part 1: underlying causes, clinical presentation and pathogenesisErythroderma (exfoliative dermatitis), first described by Von Hebra in 1868, manifests as a cutaneous inflammatory state, with associated skin barrier and metabolic dysfunctions. The annual incidence of erythroderma is estimated to be 1-2 per 100 000 population in Europe with a male preponderance. Erythroderma may present at birth, or may develop acutely or insidiously (due to progression of an underlying primary pathology, including malignancy). Although there is a broad range of diseases that associate with erythroderma, the vast majority of cases result from pre-existing and chronic dermatoses. In the first part of this two-part concise review, we explore the underlying causes, clinical presentation, pathogenesis and investigation of erythroderma, and suggest potential treatment targets for erythroderma with unknown causes.
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Non-Hodgkin lymphoma causing hypopituitarism - can imaging help diagnosis and management?Non-Hodgkin lymphomas of the hypothalamus and pituitary are rare. They usually remain clinically silent until onset of compressive features affecting surrounding structures. When symptomatic, patients most commonly present with diabetes insipidus, headaches, ophthalmoplegia and/or bilateral hemianopia. We report a case of a 67-year-old Caucasian female with a history of B-cell lymphoma in complete remission. She presented with left oculomotor nerve palsy and was subsequently found to have a sellar/suprasellar mass lesion on MRI. Alongside hypocortisolism and hypogonadotropic hypogonadism, she developed transient diabetes insipidus during her illness. Her clinical course was characterized by rapid intracranial progression of the sellar mass. MR spectroscopy suggested a diagnosis of lymphoma. Diagnostic biopsy confirmed high-grade diffuse large B-cell CNS lymphoma; this changed the definitive management from surgical excision to chemotherapy. Despite treatment, she succumbed to her illness within 7 months of initial presentation. This case highlights the aggressive nature of CNS lymphomas and the need for a high index of suspicion in an unusual presentation of sellar/suprasellar mass lesions. Learning points: Novel imaging techniques such as MR spectroscopy might help to differentiate some brain tumours from pituitary macroadenomas, but these are not diagnostic.Tissue diagnosis with biopsy and histopathology is the gold standard for deciding management of pituitary fossa mass lesions with atypical presentation.
