SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men.

CONTEXT: Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. OBJECTIVE: To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. DESIGN, SETTING AND PARTICIPANTS: Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years. MAIN OUTCOME MEASURES: Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. RESULTS: Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population. CONCLUSION: In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

Explanatory variables of objectively measured 24-h movement behaviors in people with prediabetes and type 2 diabetes: A systematic review.

AIM: Physical activity (PA), sedentary behavior (SB) and sleep (i.e. 24-h movement behaviors) are associated with health indicators in people with prediabetes and type 2 diabetes (T2D). To optimize 24-h movement behaviors, it is crucial to identify explanatory variables related to these behaviors. This review aimed to summarize the explanatory variables of 24-h movement behaviors in people with prediabetes or T2D. METHODS: A systematic search of four databases (PubMed, Web of Science, Scopus & Embase) was performed. Only objective measurements of 24-h movement behaviors were included in the search strategy. The explanatory variables were classified according to the levels of the socio-ecological model (i.e. intrapersonal, interpersonal and environmental). The risk of bias was assessed using the Joanna Briggs Institute appraisal checklist. RESULTS: None of the 78 included studies investigated 24-h movement behaviors. The majority of the studies investigated PA in isolation. Most studied explanatory variables were situated at the intrapersonal level. Being male was associated with more moderate to vigorous PA but less light PA in people with T2D, and more total PA in people with prediabetes. An older age was associated with a decrease in all levels of PA in people with T2D. HbA1c was positively associated with sleep and SB in both groups. No associations were found at the interpersonal or environmental level. CONCLUSION: The results of this review underscore the lack of a socio-ecological approach toward explanatory variables of 24-h movement behaviors and the lack of focus on an integrated 24-h movement behavior approach in both populations.

Evaluation of the thiazide challenge test to differentiate primary from hypercalciuria-related hyperparathyroidism.

CONTEXT: treatment of primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism due to idiopathic hypercalciuria (SHPT-IH) is markedly different. Robust diagnostic tools to differentiate between both entities are however lacking. OBJECTIVE: evaluate the thiazide challenge test (TCT) in clinical practice, its aid in clinical decision making, evaluate the accuracy (sensitivity, specificity) and potentially useful parameters of the TCT. DESIGN: monocentric observational retrospective cohort study from January 2017 to November 2023. SETTING: outpatient, Ghent University Hospital (Belgium). PATIENTS: 25 adult patients with hypercalciuria, elevated parathyroid hormone (PTH), and high-normal or elevated serum calcium that underwent a TCT. INTERVENTION: TCT. OUTCOME MEASURES: serum, urinary biochemical parameters before and after testing, clinical and imaging outcomes, treatment, and follow-up. RESULTS: patients with a TCT-based working diagnosis of PHPT show greater increases in albumin-adjusted calcium and total serum calcium concentration than patients with SHPT-IH (+0,11 ± 0,10 vs. + 0,0071 ± 0,10mmol/l; p = 0,025 and +0,14 ± 0,12 vs. + 0,012 ± 0,15mmol/l; p = 0,024 respectively). The TCT-based working diagnosis of PHPT has a sensitivity of 81,8%, a specificity of 77,8% and a likelihood ratio of 3,68 of estimating a correct final diagnosis.Urinary calcium excretion, PTH, calcium-phosphorous ratio, PTH-inhibition rate, and parathyroid function index do not differ significantly in patients with PHPT compared to those with SHPT-IH. CONCLUSION: the TCT aids in discriminating patients with PHPT from those with SHPT-IH based on a rise in serum calcium. Other parameters are not different between both groups. Larger prospective trials are necessary to further define the diagnostic potential of the TCT, its most appropriate biochemical outcome variables, and decision cut-offs.

Impaired muscle parameters in adults with mild to severe types of osteogenesis imperfecta: a cross-sectional study.

Impaired muscle parameters may further compromise the already compromised skeleton in individuals with OI. This cross-sectional study aimed to compare muscle function and body composition in adults with various OI types and healthy controls. Sixty-eight adults with OI (mean age 42.2 yr; 27 men) and 68 healthy age- and sex-matched controls were recruited. Maximal isometric muscle force was assessed by handheld dynamometry (hand grip, hip flexors, shoulder abductors, and ankle dorsiflexors), muscle endurance by posture maintenance tests (shoulder abduction, hip flexion, and wall sit), and functional lower limb strength by 30-s chair rise test. In a sub cohort, dynamic muscle function (peak power and force) was assessed by a ground reaction force plate, and lean and fat mass, muscle and fat cross-sectional area (CSA), and muscle density by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Multiple linear regression models were fitted with group (OI type I, III, IV/V, or controls), country, sex, and age in the fixed effects part. Overall, adults with various types of OI had lower isometric, endurance, and functional muscle strength (mean difference [MD] = OI type I: 19-43%, OI type IV/V: 25-68%, OI type III: 20-72%) compared to controls. Furthermore, adults with OI type I had lower dynamic muscle function (peak force [MD = 25-29%] and power [MD = 18-60%]), lean mass (MD = 10-17%), muscle CSA (MD = 9-21%), and muscle density (MD = 2-3%) but higher adiposity indices (MD = 24-42%) compared to controls. Functional lower limb strength and maximal muscle force were significantly different between OI types, whereas muscle endurance was not. To conclude, adults with OI present with markedly impaired muscle function which may partially be explained by their altered body composition. Our findings emphasize the need for proper assessment of various muscle parameters and (research into) appropriate and safe muscle strengthening approaches in this population.

Glycaemic management around postprandial exercise in people with type 1 diabetes: Challenge accepted.

CONTEXT: The precise glycaemic impact and clinical relevance of postprandial exercise in type 1 diabetes has not been clarified yet. OBJECTIVE: Examine acute, subacute and late effects of postprandial exercise on blood glucose (BG). DESIGN: RCT. SETTING: Four lab visits, with 24h follow-up at home. PARTICIPANTS: Adults with type 1 diabetes (n=8), age 44±13 years; BMI: 24±2.1 kg/m2. INTERVENTION: 30 min of rest (CONTROL), walking (WALK), moderate-intensity (MOD), or intermittent high-intensity (IHE) exercise performed 60min after a standardized meal. MAIN OUTCOME MEASURES: BG change during exercise/control (acute), and secondary outcomes included the subacute (≤2h after) and late glycaemic effects (≤24h after). RESULTS: Exercise reduced postprandial glucose (PPG) excursion compared to CONTROL, with a consistent BG decline in all patients for all modalities (mean declines -45±24, -71±39, and -35±21 mg/dL, during WALK, MOD and IHE, respectively (p<0.001). For this decline, clinical superiority was demonstrated separately for each exercise modality vs. CONTROL. Non-inferiority of WALK vs. MOD was not demonstrated, non-inferiority of WALK vs. IHE was demonstrated, and equivalence of IHE vs. MOD was not demonstrated. Hypoglycaemia did not occur during exercise. BG increased in the hour after exercise (more than after CONTROL, p<0.001). More than half of participants showed hyperglycaemia after exercise necessitating insulin correction. There were more nocturnal hypoglycaemic events after exercise vs. CONTROL (p<0.05). CONCLUSIONS: Postprandial exercise of all modalities is effective, safe and feasible if necessary precautions are taken (i.e., prandial insulin reductions), as exercise lowered maximal PPG excursion and caused a consistent and clinically relevant BG decline during exercise while there was no hypoglycaemia during or shortly after exercise. However, there seem two remaining challenges, being subacute post-exercise hyperglycaemia and nocturnal hypoglycaemia.

Cross-sectional associations between 24-hour movement behaviors and cardiometabolic health among adults with type 2 diabetes mellitus: A comparison according to weight status.

OBJECTIVES: Type 2 diabetes mellitus (T2DM) is a chronic disease associated with overweight and obesity. Evidence suggests that 24-hour movement behaviors (24 h-MBs) play a crucial role in cardiometabolic health. However, it is not yet known if 24 h-MBs differ between weight status groups among people with T2DM (PwT2DM) and how 24 h-MBs are associated with their cardiometabolic health. DESIGN: Cross-sectional study. METHODS: Cardiometabolic variables (i.e. Body Mass Index (BMI), waist circumference (WC), HbA1c, fasting glucose, triglycerides, total-cholesterol, HDL-cholesterol, LDL-cholesterol, blood pressure) and 24 h-MBs (accelerometry and sleep-diary) of 1001 PwT2DM were collected. Regression models using compositional data analysis explored differences in 24 h-MBs between weight status groups and analyzed associations with cardiometabolic variables. RESULTS: The 24 h-MBs of PwT2DM being obese consisted of less sleep, light physical activity (LPA) and moderate to vigorous physical activity (MVPA) and more sedentary time (ST) per day as compared to PwT2DM being overweight or normal weight (p < 0.001). Regardless of weight status, the largest associations were found when reallocating 20 min a day from ST into MVPA for BMI (-0.32 kg/m2; [-0.55; -0.09], -1.09 %), WC (-1.44 cm, [-2.26; -0.62], -1.35 %) and HDL-cholesterol (0.02 mmol/l, [0.01, 0.02], +1.59 %), as well as from ST into LPA for triglycerides (-0.04 mmol/l, [-0.05; -0.03], -2.3 %). Moreover, these associations were different when stratifying people by short-to-average (7.7 h/night) versus long sleep (9.3 h/night) period. CONCLUSIONS: This study highlights the importance of 24 h-MBs in the cardiometabolic health of PwT2DM. Shifting time from ST and/or sleep toward LPA or MVPA might theoretically benefit cardiometabolic health among relatively inactive PwT2DM, irrespective of weight status.

Hypertriglyceridemia and its impact on mitotane monitoring in adrenocortical carcinoma.

Summary: Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic-toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10-15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia. Learning points: TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane. Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels. In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated. If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.

Effect of 18 months elexacaftor-tezacaftor-ivacaftor on body mass index and glycemic control in adults with cystic fibrosis.

BACKGROUND & AIMS: Malnutrition and cystic fibrosis related diabetes (CFRD) are common comorbidities in cystic fibrosis (CF). Cystic fibrosis transmembrane regulator (CFTR) modulators have shown beneficial effects on respiratory status. This study aims to determine the effect of elexacaftor-tezacaftor-ivacaftor (ETI) on body mass index (BMI) and glycemic control. METHODS: A retrospective, observational study of a cohort of 17 adult CF patients was conducted at the CF reference center of Ghent University Hospital. BMI evolution was analyzed 18 months before and 0, 3, 6, 12 and 18 months after the start of ETI. The evolution of insulin dependence and the 2 h oral glucose tolerance test (OGTT) results were described until 36 months after start of ETI, in a small subgroup of ten patients with CFRD or impaired glucose tolerance (IGT). RESULTS: A significant increase in mean BMI of 1.2 kg/m2 (±1.3 SD) was observed. Most weight gain was observed in the first 3 months after starting treatment. This effect was sustained during the observed period of 18 months. Six patients had insulin dependent CFRD, of which three were able to stop insulin after starting ETI. Two patients with CFRD treated with dietary measures showed an initial normalization of the 2 h OGTT, but deterioration at 36 month follow-up. CONCLUSIONS: After initiation of ETI an increase in BMI was observed in adults with CF. ETI can have a beneficial impact on glucose metabolism in patients with CFRD, leading to a possible need for reduction or cessation of insulin therapy.

Serum Mg Isotopic Composition Reveals That Mg Dyshomeostasis Remains in Type 1 Diabetes despite the Resolution of Hypomagnesemia.

Hypomagnesemia was historically prevalent in individuals with type 1 diabetes mellitus (T1DM), but contemporary results indicate an incidence comparable to that in the general population, likely due to improved treatment in recent decades, resulting in better glycemic control. However, a recent study found a significant difference between the serum Mg isotopic composition of T1DM individuals and controls, indicating that disruptions to Mg homeostasis persist. Significant deviations were also found in samples taken one year apart. To investigate whether the temporal variability in serum Mg isotopic composition is linked to the transient impact of administered insulin, Mg isotope ratios were determined in serum from 15 T1DM individuals before and one hour after insulin injection/meal consumption using multi-collector inductively coupled plasma-mass spectrometry. Consistent with results of the previous study, significant difference in the serum Mg isotopic composition was found between T1DM individuals and 10 sex-matched controls. However, the average difference between pre- and post-insulin injection/meal T1DM samples of 0.05 ± 0.13‱ (1SD) was not significant. No difference was observed for controls before (-0.12 ± 0.16‱) and after the meal (-0.10 ± 0.13‱) either, suggesting a lack of a postprandial Mg isotopic response within one hour of food consumption, and that the timing of the most recent meal may not require controlling for when determining serum Mg isotopic composition.

Baseline plasma proinsulin response to glucose for predicting therapeutic response to otelixizumab in recent-onset type 1 diabetes.

AIMS: In recent-onset type 1 diabetes, clamp-derived C-peptide predicts good response to anti-CD3. Elevated proinsulin and proinsulin/C-peptide ratio (PI/CP) suggest increased metabolic/inflammatory beta cell burden. We reanalyzed trial data to compare the ability of baseline acutely glucose-stimulated proinsulin, C-peptide and PI/CP to predict functional outcome. METHODS: Eighty recent-onset type 1 diabetes patients participated in the placebo-controlled otelixizumab (GSK; NCT00627146) trial. Hyperglycemic clamps were performed at baseline, 6, 12 and 18 months, involving 3 h of induced euglycemia, followed by acutely raising and maintaining glycemia to ≥ 10 mmol/l for 140 min. Plasma proinsulin, C-peptide and PI/CP were determined after acute (minute 0 at 10 mmol/l; PI0, CP0, PI/CP0) and sustained glucose stimulation (AUC between minutes 60-140). Outcome was assessed as change in AUC60-140 C-peptide from baseline. RESULTS: In multiple linear regression, higher baseline (≥median [P50]) PI0 independently predicted preservation of beta cell function in response to anti-CD3 and interacted significantly with IAA. During follow-up, anti-CD3 tempered a further increase in PI/CP0, but not in PI0. CP0 outperformed PI0 and PI/CP0 for post-treatment monitoring. CONCLUSIONS: In recent-onset type 1 diabetes, elevated acutely glucose-stimulated proinsulin may complement or replace acutely or sustainedly stimulated C-peptide release for identifying good responders to anti-CD3, but not as outcome measure.

The association between newborn cord blood steroids and ambient prenatal exposure to air pollution: findings from the ENVIRONAGE birth cohort.

Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient air pollution and highly accurate measurements of cord blood steroid hormones from the androgenic pathway.This study included 397 newborns born between the years 2010 and 2015 from the ENVIRONAGE cohort in Belgium of whom six cord blood steroid levels were measured: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone, androstenedione, and testosterone. Maternal ambient exposure to PM2.5 (particles with aerodynamic diameter ≤ 2.5 µm), NO2, and black carbon (BC) were estimated daily during the entire pregnancy using a high-resolution spatiotemporal model. The associations between the cord blood steroids and the air pollutants were tested and estimated by first fitting linear regression models and followed by fitting weekly prenatal exposures to distributed lag models (DLM). These analyses accounted for possible confounders, coexposures, and an interaction effect between sex and the exposure. We examined mixture effects and critical exposure windows of PM2.5, NO2 and BC on cord blood steroids via the Bayesian kernel machine regression distributed lag model (BKMR-DLM).An interquartile range (IQR) increment of 7.96 µg/m3 in PM2.5 exposure during pregnancy trimester 3 was associated with an increase of 23.01% (99% confidence interval: 3.26-46.54%) in cord blood levels of 17α-hydroxypregnenolone, and an IQR increment of 0.58 µg/m³ in BC exposure during trimester 1 was associated with a decrease of 11.00% (99% CI: -19.86 to -0.012%) in cord blood levels of androstenedione. For these two models, the DLM statistics identified sensitive gestational time windows for cord blood steroids and ambient air pollution exposures, in particular for 17α-hydroxypregnenolone and PM2.5 exposure during trimester 3 (weeks 28-36) and for androsterone and BC exposure during early pregnancy (weeks 2-13) as well as during mid-pregnancy (weeks 18-26). We identified interaction effects between pollutants, which has been suggested especially for NO2.Our results suggest that prenatal exposure to ambient air pollutants during pregnancy interferes with steroid levels in cord blood. Further studies should investigate potential early-life action mechanisms and possible later-in-life adverse effects of hormonal disturbances due to air pollution exposure.

Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma.

BACKGROUND: Insulinoma is the most common functional pancreatic neuroendocrine tumor and treatment is required to address symptoms associated with insulin hypersecretion. Surgical resection is effective but burdened by high rate of adverse events (AEs). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) demonstrated encouraging results in terms of safety and efficacy for the management of these tumors. However, studies comparing surgery and EUS-RFA are lacking. AIMS: The primary aim is to compare EUS-RFA with surgery in term of safety (overall rate of AEs). Secondary endpoints include: (a) severe AEs rate; (b) clinical effectiveness; (c) patient's quality of life; (d) length of hospital stay; (e) rate of local/distance recurrence; (f) need of reintervention; (g) rate of endocrine and exocrine pancreatic insufficiency; (h) factors associated with EUS-RFA related AEs and clinical effectiveness. METHODS: ERASIN-RCT is an international randomized superiority ongoing trial in four countries. Sixty patients will be randomized in two arms (EUS-RFA vs surgery) and outcomes compared. Two EUS-RFA sessions will be allowed to achieve symptoms resolution. Randomization and data collection will be performed online. DISCUSSION: This study will ascertain if EUS-RFA can become the first-line therapy for management of small, sporadic, pancreatic insulinoma and be included in a step-up approach in case of clinical failure.

The role of 11-oxygenated androgens in prostate cancer.

11-oxygenated androgens are a class of steroids capable of activating the androgen receptor (AR) at physiologically relevant concentrations. In view of the AR as a key driver of prostate cancer (PC), these steroids are potential drivers of disease and progression. The 11-oxygenated androgens are adrenal-derived, and persist after androgen deprivation therapy (ADT), the mainstay treatment for advanced PC. Consequently, these steroids are of particular interest in the castration-resistant prostate cancer (CRPC) setting. The principal androgen of the pathway, 11-ketotestosterone (11KT), is a potent AR agonist and the predominant circulating active androgen in CRPC patients. Additionally, several precursor steroids are present in the circulation which can be converted into active androgens by steroidogenic enzymes present in PC cells. In vitro evidence suggests that adaptations frequently observed in CRPC favour the intratumoral accumulation of 11-oxygenated androgens in particular. Still, apparent gaps in our understanding of the physiology and role of the 11-oxygenated androgens remain. In particular, in vivo and clinical evidence supporting these in vitro findings is limited. Despite recent advances, a comprehensive assessment of intratumoral concentrations has not yet been performed. The exact contribution of the 11-oxygenated androgens to CRPC progression therefore remains unclear. This review will focus on the current evidence linking the 11-oxygenated androgens to PC, will highlight current gaps in our knowledge, and will provide insight into the potential clinical importance of the 11-oxygenated androgens in the CRPC setting based on the current evidence.

Clinical presentation of sporadic and hereditary pheochromocytoma/paraganglioma.

Pheochromocytomas (PHEO) and paragangliomas (PGL) can occur sporadic or within genetic predisposition syndromes. Despite shared embryology, there are important differences between PHEO and PGL. The aim of this study was to describe the clinical presentation and disease characteristics of PHEO/PGL. A retrospective analysis of consecutively registered patients diagnosed with or treated for PHEO/PGL in a tertiary care centre was performed. Patients were compared according to anatomic location (PHEO vs PGL) and genetic status (sporadic vs hereditary). In total, we identified 38 women and 29 men, aged 50 ± 19 years. Of these, 42 (63%) had PHEO, and 25 (37%) had PGL. Patients with PHEO presented more frequently with sporadic than hereditary disease (45 years vs 27 (77%) vs 8 (23%)) than patients with PGL (9 (36%) vs 16 (64%), respectively) and were older at diagnosis (55 ± 17 vs 40 ± 18 years, P = 0.001), respectively). About half of the cases in both PHEO and PGL were diagnosed due to disease-related symptoms. In patients with PHEO, tumour diameter was larger (P = 0.001), metanephrine levels higher (P = 0.02), and there was more frequently a history of cardiovascular events than in patients with PGL. In conclusion, we found that patients with PGL more frequently have a hereditary predisposition than those with PHEO, contributing to the fact that diagnosis is generally made earlier in PGL. Although diagnosis in both PHEO and PGL was mostly due to related symptoms, patients with PHEO more often presented with cardiovascular comorbidities than those with PGL which might relate to a higher number of functionally active tumours in the former.

Extensive profiling of histidine-containing dipeptides reveals species- and tissue-specific distribution and metabolism in mice, rats, and humans.

AIM: Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules with potent antioxidative and carbonyl quenching properties linked to various inflammatory, metabolic, and neurological diseases, as well as exercise performance. However, the distribution and metabolism of HCDs across tissues and species are still unclear. METHODS: Using a sensitive UHPLC-MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n = 26, n = 25, and n = 19 tissues, respectively). RESULTS: Our data show that tissue HCD levels are uniquely produced by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast-twitch skeletal muscle fibres and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analogue N-acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine-like fashion. CONCLUSION: Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.

Physiological declines in sex steroid exposure in relation to changes in body composition in healthy men-a prospective cohort study.

OBJECTIVE: Androgen levels decline from early adulthood and decreases are steeper in men with increasing body mass index. It is, however, unclear to what extent changes in other indices of body composition and metabolism associate with changes in sex steroid levels in healthy men. Therefore, this study investigated longitudinal changes in body composition and metabolic health in relation to sex steroid levels in healthy adult men. DESIGN: This is a longitudinal, population-based study. A total of 676 healthy men aged 24-46 years were measured at baseline and after ±12 years. METHODS: Serum sex hormone-binding globulin (SHBG) was measured by immunoassay, testosterone (T), estradiol (E2), and dihydrotestosterone byliquid chromatography with tandem mass spectrometry (LC-MS/MS), calculated free T and calculated free E2 (cFE2), and homeostasis model assessment for insulin resistance (HOMA-IR) were calculated. Grip strength was measured by hand-grip dynamometry. Body composition was determined using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: Mean fat mass (FM), lean mass (LM), and HOMA-IR increased (all P < .001). Decreasing androgen and SHBG levels was associated with increasing FM, whereas decreasing (cF)E2 levels were associated with decreasing FM (all P < .005). Decreasing (cF)E2 levels and increasing SHBG levels associated with decreasing LM (all P < .002). Changes in sex steroid levels and HOMA-IR or grip strength were not interrelated. CONCLUSION: Aging leads to increases in FM indices and insulin resistance, whereas changes in parameters of LM are less unequivocal. In healthy adult men, physiological changes in sex steroid exposure clearly correlate with changes in adiposity but not so with lean mass, insulin resistance, or grip strength. CLINICAL TRIAL: The SIBEX study was registered on ClinicalTrials.gov (#NVT02997033).

Investigating Levothyroxine Use and Its Association with Thyroid Health in Patients with Hypothyroidism: A Community Pharmacy Study.

Background: To gain maximum therapeutic effect while minimizing side effects, it is imperative for patients with hypothyroidism to use their levothyroxine (LT4) correctly, such as adhering to the prescribed regimen. Little is currently known about how patients actually use LT4 in real life. We investigated the use of LT4, as well as the thyroid health (thyrotropin [TSH] and health-related quality of life [HR-QoL]), and evaluated if proper LT4 use is associated with better thyroid health. Methods: A cross-sectional observational study was conducted in a Belgian community sample of adults using LT4 for hypothyroidism since ≥2 years. Participants completed a self-administered questionnaire on patient characteristics, self-reported adherence to LT4, timing of intake, and co-medication. They also completed the thyroid-specific patient-reported outcome (ThyPRO-39) questionnaire, measuring the HR-QoL. Pharmacy dispensing data were used to calculate the medication possession ratio (MPR). Results: We included 856 participants (mean age 61.4 ± 14.3 years, 86% [740/856] females). Approximately one in four participants (138/563) had out-of-range TSH levels. Generally, ThyPRO-39 scores were in the lower part of the range (indicating better HR-QoL), with the scales "emotional susceptibility" and "tiredness" showing the worst scores. Approximately 28% (178/632) of the participants were classified as non-adherent (MPR <80%), corresponding to at least 73 cumulative days per year without LT4 intake. Twenty-five percent (212/854) of participants self-reported non-adherence, with unintentional non-adherence (forgetfulness) most frequently reported (21.9%, 187/854). Only 39% (329/836) of participants complied with the recommendation of ingesting LT4 ≥ 30 minutes before eating. Additionally, 7% (58/856) of participants concurrently used molecules that bind to LT4, without applying the recommended dosing interval. There was no significant correlation between LT4 usage (adherence, timing of intake, and interaction with complex forming drugs) and TSH or HR-QoL. Conclusions: We found that many participants with hypothyroidism did not use their LT4 as effectively as possible, particularly with respect to timing of administration. However, the participants' HR-QoL seemed largely satisfactory, and there was no significant correlation between correctly using LT4 and thyroid health.

Effects of postprandial exercise on blood glucose levels in adults with type 1 diabetes: a review.

People with type 1 diabetes experience challenges in managing blood glucose around exercise. Previous studies have examined glycaemic responses to different exercise modalities but paid little attention to participants' prandial state, although this is an important consideration and will enhance our understanding of the effects of exercise in order to improve blood glucose management around activity. This review summarises available data on the glycaemic effects of postprandial exercise (i.e. exercise within 2 h after a meal) in people with type 1 diabetes. Using a search strategy on electronic databases, literature was screened until November 2022 to identify clinical trials evaluating acute (during exercise), subacute (≤2 h after exercise) and late (>2 h to ≤24 h after exercise) effects of postprandial exercise in adults with type 1 diabetes. Studies were systematically organised and assessed by exercise modality: (1) walking exercise (WALK); (2) continuous exercise of moderate intensity (CONT MOD); (3) continuous exercise of high intensity (CONT HIGH); and (4) interval training (intermittent high-intensity exercise [IHE] or high-intensity interval training [HIIT]). Primary outcomes were blood glucose change and hypoglycaemia occurrence during and after exercise. All study details and results per outcome were listed in an evidence table. Twenty eligible articles were included: two included WALK sessions, eight included CONT MOD, seven included CONT HIGH, three included IHE and two included HIIT. All exercise modalities caused consistent acute glycaemic declines, with the largest effect size for CONT HIGH and the smallest for HIIT, depending on the duration and intensity of the exercise bout. Pre-exercise mealtime insulin reductions created higher starting blood glucose levels, thereby protecting against hypoglycaemia, in spite of similar declines in blood glucose during activity between the different insulin reduction strategies. Nocturnal hypoglycaemia occurred after higher intensity postprandial exercise, a risk that could be diminished by a post-exercise snack with concomitant bolus insulin reduction. Research on the optimal timing of postprandial exercise is inconclusive. In summary, individuals with type 1 diabetes exercising postprandially should substantially reduce insulin with the pre-exercise meal to avoid exercise-induced hypoglycaemia, with the magnitude of the reduction depending on the exercise duration and intensity. Importantly, pre-exercise blood glucose and timing of exercise should be considered to avoid hyperglycaemia around exercise. To protect against late-onset hypoglycaemia, a post-exercise meal with insulin adjustments might be advisable, especially for exercise in the evening or with a high-intensity component.

Application of NRS2002 to detect malnutrition in a tertiary care centre: agreement between nurse and dietician's screening steps and relation with clinical outcomes.

OBJECTIVE: To evaluate the agreement between nurse and dietician nutritional risk assessments when using the Nutritional Risk Screening 2002 (NRS2002) protocol, and to explore the relations of falsely labeling patients 'not at risk' for malnutrition and the screening time difference (STD) between nurse and dietician with the length of stay (LoS). METHODS: Included are all patients hospitalized in a tertiary care center between January 2017 and December 2019 and screened for malnutrition by both a nurse and a dietician. The inter-rater reliability is evaluated using Cohen's Kappa. The relation between STD and the patient classification (PCET) is assessed by a linear mixed effect model. The relation between the LoS and PCET is evaluated with the Kaplan-Meier method and multivariable Cox regression including STD with pathology group and severity of illness as random effect. RESULTS: 9085 patients are assessed by nurse and dietician. 72% of all assessments agree (Kappa = 0.44 [0.43-0.46]). The dietician is involved later for patients falsely labeled 'not at risk' (1.06 [0.92-1.20] days; p < 0.001). Compared to patients where the dietician is involved within 3 days, the LoS is 7.37 days (Hazard Ratio (HR): 0.51 [0.43-0.61]) longer for patients falsely labeled 'not at risk', while only 3.51 days (HR: 0.72 [0.64-0.80]) longer for patients correctly labeled 'at risk'. CONCLUSIONS: Agreement of screening for malnutrition between nurses and dieticians is weak. Avoiding falsely labeling patients 'not at risk' should be a main concern upon patient admission as later involvement of dieticians is correlated with a longer LoS.

Test-Retest Reliability and Internal Consistency of a Newly Developed Questionnaire to Assess Explanatory Variables of 24-h Movement Behaviors in Adults.

A questionnaire on explanatory variables for each behavior of the 24-h movement behaviors (i.e., physical activity, sedentary behavior, sleep) was developed based on three levels of the socio-ecological model, i.e., the intrapersonal level, interpersonal level and the physical environmental level. Within these levels, different constructs were questioned, i.e., autonomous motivation, attitude, facilitators, internal behavioral control, self-efficacy, barriers, subjective norm, social modeling, social support, home environment, neighborhood, and work environment. The questionnaire was tested for test-retest reliability (i.e., intraclass correlation (ICC)) for each item and internal consistency for each construct (i.e., Cronbach's Alpha Coefficient) among a group of 35 healthy adults with a mean age of 42.9 (±16.1) years. The total questionnaire contained 266 items, consisting of 14 items on general information, 70 items on physical activity, 102 items on sedentary behavior, 45 items on sleep and 35 items on the physical environment. Seventy-one percent of the explanatory items showed moderate to excellent reliability (ICC between 0.50 and 0.90) and a majority of constructs had a good homogeneity among items (Cronbach's Alpha Coefficient ≥ 0.70). This newly developed and comprehensive questionnaire might be used as a tool to understand adults' 24-h movement behaviors.