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Benjamin Burggraaf, Nadine M C Pouw, Salvador Fernández Arroyo, Leonie C van Vark-van der Zee, Gert-Jan M van de Geijn, Erwin Birnie, Jeannine Huisbrink, Ellen M van der Zwan, Wouter W de Herder, Monique T Mulder, Patrick C N Rensen, and Manuel Castro Cabezas

Objectives

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) modulate lipid metabolism and improve cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). The exact cardioprotective mechanism of SGLT2i is unclear. We evaluated the effects of SGLT2i on postprandial lipids, lipoprotein concentrations, glucose and fatty acids.

Design

A placebo-controlled randomized, proof-of-concept study.

Methods

Fourteen male patients with T2DM on intensive insulin regimen were randomly and double-blind allocated to 12 weeks dapagliflozin (10 mg) or placebo. Postprandial effects were assessed with an 8-h standardized oral fat loading test.

Results

Mean glycated A1c did not change by dapagliflozin, but the mean daily insulin dose was significantly reduced. Although dapagliflozin did not affect fasting or postprandial levels of glucose and insulin, it increased the postprandial levels of glucagon. While fasting levels of free fatty acids and beta-hydroxybutyrate (bHBA) were unchanged, dapagliflozin significantly increased the postprandial bHBA response. This was seen in the context of increased postprandial glucagon levels by dapagliflozin, without influencing postprandial insulin or glucose levels. Dapagliflozin did not affect fasting or postprandial plasma cholesterol and triglycerides nor postprandial inflammatory markers. Fasting apolipoprotein B48 was decreased without affecting the postprandial response. Markers of inflammation and vascular function did not change.

Conclusion

Treatment with dapagliflozin of patients with T2DM led to a reduction of fasting chylomicron remnants and increased postprandial ketone bodies compared to placebo suggesting enhanced hepatic fatty acid oxidation. The latter may have been caused by decreasing the insulin–glucagon ratio. The beneficial clinical effects seen in the trials using dapagliflozin most likely are not due to effects on postprandial inflammation nor postprandial lipemia.

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Usman Javaid, David Kennedy, Caroline Addison, Vasileios Tsatlidis, and Salman Razvi

Objective

To assess the rationale and frequency of thyroid function testing and to analyse factors that influence serum thyrotropin (TSH) levels.

Patients, design and main outcome measures

Serum TSH levels were evaluated in a hospital laboratory serving a population of 604 000 in 2018. Patients on medications or with conditions affecting thyroid function were excluded. Frequency of thyroid function testing by age and sex was assessed and the relationship between serum TSH with potential predictor variables was analysed using ordinary least square regression analysis allowing for potential non-linearity.

Results

Twenty-eight percent of the local population had their thyroid function tested at least once in 2018 with significant differences by sex (28.2% women vs 23.4% men) and by age groups, with less than 2% of <16-year-old people and more than 50% of >80-year-old people being tested. Most of the symptoms commonly attributed to thyroid dysfunction were not higher in the thyroid dysfunction groups. Serum TSH levels were higher in older people particularly after the age of 60 years, in women (by 0.1 mIU/L), during the early hours of the morning, and in winter and spring seasons. There was remarkable uniformity in the frequency of subclinical thyroid dysfunction, as well as substantial cost savings, if TSH reference intervals were recalculated across sexes, age groups, time-periods and seasons.

Conclusions

Serum TSH is frequently tested in the population but is not a good discriminant of symptoms attributed to thyroid dysfunction. Furthermore, considering the influence of factors on TSH reference limits could significantly impact patient care and resource utilisation.

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Davide Giordano, Cecilia Botti, Simonetta Piana, Andrea Castellucci, Andrea Frasoldati, Michele Zini, Martina Fornaciari, Francesco Maria Crocetta, and Angelo Ghidini

Objective

The aim of this study was to report the rationale and selection criteria for hemithyroidectomy and ipsilateral central neck dissection in patients with selected papillary thyroid cancer and to report the surgical and oncological outcomes.

Design

Single-institution retrospective observational study.

Methods

The clinical records of patients with a histopathological diagnosis of low-risk pT1 papillary thyroid cancer who underwent hemithyroidectomy with or without ipsilateral central neck dissection between March 2000 and April 2018 at a tertiary referral center were retrospectively reviewed. Demographic, clinical, and histopathological data were collected.

Results

During the study period, 176 patients underwent hemithyroidectomy for PTC. Thirteen patients (13/176, 7.39%) were lost to follow-up and 74 patients (74/163 45.40%) underwent completion thyroidectomy within 1 month because they were classified intermediate ATA initial risk based on definitive pathology. The final study group was composed of 89 patients, who had a median follow-up of 5.3 years. The mean follow-up was 6.3 years (range: 36–207 months). Eighty-four patients (94.38%) did not experience recurrence in the follow-up period. A total of 5/89 patients (5.62%) underwent delayed completion thyroidectomy with or without neck dissection for recurrent malignancy in the residual lobe (3/5) or regional lymph nodes (2/5). The median time from surgery to recurrence was 24.8 months (range: 6–60). The follicular variant was an independent risk factor for recurrence.

Conclusions

Hemithyroidectomy with or without prophylactic ipsilateral central neck dissection is a valuable treatment option in selected low-risk papillary thyroid cancers and ensures a low risk of recurrence. Prophylactic ipsilateral central compartment dissection could have a role in improving cancer staging, and accurate ultrasonographic follow-up is essential to identify local recurrence.

Open access

Bu B Yeap, Ross J Marriott, Laurens Manning, Girish Dwivedi, Graeme J Hankey, Frederick C. W. Wu, Jeremy K Nicholson, and Kevin Murray

Objective

Men are at greater risk from COVID-19 than women. Older, overweight men, and those with type 2 diabetes, have lower testosterone concentrations, and poorer COVID-19-related outcomes. We analysed associations of premorbid serum testosterone concentrations, not confounded by effects of acute SARS-CoV-2 infection, with COVID-19-related mortality risk in men.

Design

UK Biobank prospective cohort study of community-dwelling men aged 40-69 years.

Methods

Serum total testosterone and sex hormone-binding globulin (SHBG) were measured at baseline (2006-2010). Free testosterone values were calculated (cFT). Incidence of SARS-CoV-2 infections and deaths related to COVID-19 were ascertained from 16 March 2020-31 January 2021, and modelled using time-stratified Cox regression.

Results

In 159,964 men there were 5,558 SARS-CoV-2 infections and 438 COVID-19 deaths. Younger age, higher body mass index, non-white ethnicity, lower educational attainment, and socio-economic deprivation were associated with incidence of SARS-CoV-2 infections, but total testosterone, SHBG, and cFT were not. Adjusting for potential confounders, higher total testosterone was associated with COVID-19-related mortality risk (overall trend P=0.008; hazard ratios, HR [95% confidence intervals] quintile 1, Q1 vs Q5 [reference]: 0.84 [0.65-1.12], Q2:Q5 0.82 [0.63-1.10], Q3:Q5 0.80 [0.66-1.00], Q4:Q5 0.82 [0.75-0.93]). Higher SHBG was also associated with COVID-19 mortality risk (P=0.008), but cFT was not (P=0.248).

Conclusions

Middle-aged to older men with the highest premorbid serum total testosterone and SHBG concentrations are at greater risk of COVID-19-related mortality. Men could be advised that having relatively high serum testosterone concentrations does not protect against future COVID-19-related mortality. Further investigation of causality and potential underlying mechanisms is warranted.

Open access

Esra Arslan Ates, Mehmet Eltan, Bahadir Sahin, Busra Gurpinar Tosun, Tuba Seven Menevse, Bilgen Bilge Geckinli, Andy Greenfield, Serap Turan, Abdullah Bereket, and Tulay Guran

Background

The human INHA gene encodes the inhibin subunit alpha protein, which is common to both inhibin A and B. The functional importance of inhibins in male sex development, sexual function, and reproduction remain largely unknown.

Objective

We report for the first time two male siblings with homozygous INHAmutations.

Methods

The medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods.

Results

Two brothers complained of gynecomastia, testicular pain, and had a history of hypospadias. Biochemistry revealed low serum testosterone, high gonadotropin and anti-Mullerian hormone, and very low/undetectable inhibin concentrations, where available. Both patients had azoospermia in the spermiogram. We have identified a homozygous 2 bp deletion (c.208_209delAG, R70Gfs*3) variant, which leads to a truncated INHA protein in both patients, and confirmed heterozygosity in the parents. The external genital development, pubertal onset and progression, reproductive functions, serum gonadotropins, and sex hormones of mother and father, who were heterozygous carriers of the identified mutation, were normal.

Conclusion

Homozygosity for INHA mutations causes decreased prenatal and postnatal testosterone production and infertility in males, while the heterozygous female and male carriers of INHA mutations do not have any abnormality in sex development and reproduction.

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Charlotte Brøns, Anne Cathrine Baun Thuesen, Line Ohrt Elingaard-Larsen, Louise Justesen, Rasmus Tanderup Jensen, Nicolai Stevns Henriksen, Helene Bæk Juel, Joachim Størling, Mathias Ried-Larsen, Lauren M Sparks, Gerrit van Hall, Else Rubæk Danielsen, Torben Hansen, and Allan Vaag

Objective

Ectopic liver fat deposition, resulting from impaired subcutaneous adipose tissue expandability, may represent an age-dependent key feature linking low birth weight (LBW) with increased risk of type 2 diabetes (T2D). We examined whether presumably healthy early middle-aged, non-obese LBW subjects exhibit increased liver fat content, whether increased liver fat in LBW is associated with the severity of dysmetabolic traits and finally whether such associations may be confounded by genetic factors.

Methods

Using 1H magnetic resonance spectroscopy, we measured hepatic fat content in 26 early middle-aged, non-obese LBW and 22 BMI-matched normal birth weight (NBW) males. Endogenous glucose production was measured by stable isotopes, and a range of plasma adipokine and gut hormone analytes were measured by multiplex ELISA. Genetic risk scores were calculated from genome-wide association study (GWAS) data for birth weight, height, T2D, plasma cholesterol and risk genotypes for non-alcoholic fatty liver disease (NAFLD).

Results

The LBW subjects had significantly increased hepatic fat content compared with NBW controls (P= 0.014), and 20% of LBW vs no controls had overt NAFLD. LBW subjects with NAFLD displayed widespread metabolic changes compared with NBW and LBW individuals without NAFLD, including hepatic insulin resistance, plasma adipokine and gut hormone perturbations as well as dyslipidemia. As an exception, plasma adiponectin levels were lower in LBW subjects both with and without NAFLD as compared to NBW controls. Genetic risk for selected differential traits did not differ between groups.

Conclusion

Increased liver fat content including overt NAFLD may be on the critical path linking LBW with increased risk of developing T2D in a non-genetic manner.

Open access

Clement N Kufe, Lisa K Micklesfield, Maphoko Masemola, Tinashe Chikowore, Andre P Kengne, Fredrik Karpe, Shane A Norris, Nigel J Crowther, Tommy Olsson, and Julia H Goedecke

Aims

Despite a higher prevalence of overweight/obesity in Black South African women compared to men, the prevalence of type 2 diabetes (T2D) does not differ. We explored if this could be due to sex differences in insulin sensitivity, clearance and/or beta-cell function and also sex-specific associations with total and regional adiposity.

Methods

This cross-sectional study included 804 Black South African men (n = 388) and women (n = 416). Dual-energy X-ray absorptiometry was used to measure total and regional adiposity. Insulin sensitivity (Matsuda index), secretion (C-peptide index) and clearance (C-peptide/insulin ratio) were estimated from an oral glucose tolerance test.

Results

After adjusting for sex differences in the fat mass index, men were less insulin sensitive and had lower beta-cell function than women (P  < 0.001), with the strength of the associations with measures of total and central adiposity being greater in men than women (P  < 0.001 for interactions). Further, the association between total adiposity and T2D risk was also greater in men than women (relative risk ratio (95% CI): 2.05 (1.42–2.96), P  < 0.001 vs 1.38 (1.03–1.85), P = 0.031).

Conclusion

With increasing adiposity, particularly increased centralisation of body fat linked to decreased insulin sensitivity and beta-cell function, Black African men are at greater risk for T2D than their female counterparts.

Open access

Connar S J Westgate, Keira Markey, James L Mitchell, Andreas Yiangou, Rishi Singhal, Paul Stewart, Jeremy W Tomlinson, Gareth G Lavery, Susan P Mollan, and Alexandra J Sinclair

Context

Idiopathic intracranial hypertension (IIH) is a disease of raised intracranial pressure (ICP) of unknown aetiology. Reductions in glucocorticoid metabolism are associated with improvements in IIH disease activity. The basal IIH glucocorticoid metabolism yet to be assessed.

Objective

To determine the basal glucocorticoid phenotype in IIH and assess the effects of weight loss on the IIH glucocorticoid phenotype.

Design

A retrospective case-control study and a separate exploratory analysis of a prospective randomised intervention study.

Methods

The case-control study compared female IIH patients to body mass index, age, and sex-matched controls. The randomised intervention study, different IIH patients were randomized to either a community weight management intervention, or bariatric surgery, with patients assessed at baseline and 12 months. Glucocorticoid levels were determined utilising 24-hour urinary steroid profiles alongside the measurement of adipose tissue 11β-HSD1 activity.

Results

Compared to control subjects, patients with active IIH had increased systemic 11β-hydroxysteroid dehydrogenase (11β-HSD1) and 5α-reductase activity. The intervention study demonstrated that weight loss following bariatric surgery reduced systemic 11β-HSD1 and 5α-reductase activity. Reductions in these were associated with reduced ICP. Subcutaneous adipose tissue explants demonstrated elevated 11β-HSD1 activity compared to samples from matched controls.

Conclusion

We demonstrate that in IIH, there is a phenotype of elevated systemic and adipose 11β-HSD1 activity in excess to that mediated by obesity. Bariatric surgery to induce weight loss was associated with reductions in 11β-HSD1 activity and decreased ICP. These data reflect new insights into the IIH phenotype and further point towards metabolic dysregulation as a feature of IIH.

Open access

Christina Wenzek, Anita Boelen, Astrid M Westendorf, Daniel R Engel, Lars C Moeller, and Dagmar Führer

Over the past few years, growing evidence suggests direct crosstalk between thyroid hormones (THs) and the immune system. Components of the immune system were proposed to interfere with the central regulation of systemic TH levels. Conversely, THs regulate innate and adaptive immune responses as immune cells are direct target cells of THs. Accordingly, they express different components of local TH action, such as TH transporters or receptors, but our picture of the interplay between THs and the immune system is still incomplete. This review provides a critical overview of current knowledge regarding the interaction of THs and the immune system with the main focus on local TH action within major innate and adaptive immune cell subsets. Thereby, this review aims to highlight open issues which might help to infer the clinical relevance of THs in host defence in the context of different types of diseases such as infection, ischemic organ injury or cancer.

Open access

Lisa M Shepherd, Kelly Ann Schmidtke, Jonathan M Hazlehurst, Eka Melson, Janine Dretzke, Noel Hawks, Wiebke Arlt, Abd A Tahrani, Amelia Swift, and Debbie M Carrick-Sen

Abstract

Objective: The incidence of adrenal crisis remains high, particularly for people with primary adrenal insufficiency, despite the introduction of behavioural interventions. The present study aimed to identify and evaluate available evidence of interventions aiming to prevent adrenal crisis in primary adrenal insufficiency.

Design: Systematic review of literature and theoretical mapping.

Methods: MEDLINE, MEDLINE in Process, EMBASE, ERIC, Cochrane CENTRAL, CINAHL, PsycINFO, the Health Management Information Consortium (HMIC) and trial registries were searched from inception to November 2021. Three reviewers independently selected studies and extracted data. Two reviewers appraised the studies for risk of bias.

Results: Seven observational or mixed methods studies were identified where interventions were designed to prevent adrenal crisis in adrenal insufficiency. Patient education was the focus of all interventions and utilised the same two behaviour change techniques, instruction on how to perform a behaviour’ and ‘pharmacological support’. Barrier and facilitator themes aiding or hindering the intervention included: knowledge, behaviour, emotions, skills, social influences and environmental context and resources. Most studies did not measure effectiveness and assessment of knowledge was variable across studies. Study quality was moderate.

Conclusion: This is an emerging field with limited studies available. Further research is required in relation to the development and assessment of different behaviour change interventions to prevent adrenal crisis.

Systematic review registration PROSPERO (International prospective register of systematic reviews) CRD 42019137412