A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans

Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance

Social anxiety increases visible anxiety signs during social encounters but does not impair performance

Background: Preliminary evidence suggests that impairment of social performance in socially anxious individuals may be specific to selective aspects of performance and be more pronounced in females. This evidence is based primarily on contrasting results from studies using all-male or all-female samples or that differ in type of social behaviour assessed. However, methodological differences (e.g. statistical power, participant population) across these studies means it is difficult to determine whether behavioural or gender-specific effects are genuine or artefactual. The current study examined whether the link between social anxiety and social behaviour was dependent upon gender and the behavioural dimension assessed within the same study under methodologically homogenous conditions. Methods: Ninety-three university students (45 males, 48 females) with a mean age of 25.6 years and varying in their level of social anxiety underwent an interaction and a speech task. The speech task involved giving a brief impromptu presentation in front of a small group of three people, while the interaction task involved “getting to know” an opposite-sex confederate. Independent raters assessed social performance on 5 key dimensions from Fydrich’s Social Performance Rating Scale. Results: Regression analysis revealed a significant moderate association of social anxiety with behavioral discomfort (e.g., fidgeting, trembling) for interaction and speech tasks, but no association with other performance dimensions (e.g., verbal fluency, quality of verbal expression). No sex differences were found. Conclusions: These results suggest that the impairing effects of social anxiety within the non-clinical range may exacerbate overt behavioral agitation during high demand social challenges but have little impact on other observable aspects of performance quality

Zinc-alpha2-glycoprotein, dysglycaemia and insulin resistance: a systematic review and meta-analysis

To systematically review the current literature investigating associations between zinc-alpha2-glycoprotein (ZAG) and dysglycaemia (including type 2 diabetes (T2DM), poly-cystic-ovary syndrome (PCOS), pre-diabetes or insulin resistance). This included relationships between ZAG and continuous measures of insulin and glucose. Additionally, we performed a meta-analysis to estimate the extent that ZAG differs between individuals with or without dysglycaemia; whilst examining the potential influence of adiposity. A systematic search was performed on four databases for studies on circulating ZAG concentrations in adult human populations, comparing healthy controls to individuals with dysglycaemia. Key characteristics, including the mean ZAG concentrations (mg∙L−1), and any correlational statistics between ZAG and continuous measures of glucose, glycated haemoglobin (HbA1c) or insulin were extracted. Meta-analyses were performed to compare metabolically healthy controls to cases, and on studies that compared controls and cases considered overweight or obese (body mass index (BMI) ≥25 kg.m2). 1575 papers were identified and 14 studies (16 cohorts) were considered eligible for inclusion. Circulating ZAG was lower in individuals with dysglycaemia compared to metabolically healthy controls (−4.14 [−8.17, −0.11] mg.L−1; I2 = 98.5%; p < 0.001). When using data from only studies with overweight or obese groups with or without dysglycaemia (three studies (four cohorts); pooled n = 332), the difference in circulating ZAG was no longer significant (−0.30 [−3.67, 3.07] mg. L−1; I2 = 28.0%; p = 0.225). These data suggest that ZAG may be implicated in dysglycaemia, although there was significant heterogeneity across different studies and the mediating effect of adiposity cannot be excluded. Therefore, more research is needed before robust conclusions can be drawn

Introduction

info:eu-repo/semantics/publishe

Dysglycaemia and South Asian ethnicity: a proteomic discovery and confirmation analysis highlights differences in ZAG

Aims To (1) explore and verify differences in the plasma proteome of white European (WE) and South Asian (SA) adults with normal glycaemic control (NGC) or non-diabetic hyperglycaemia (NDH) and to (2) validate these findings using a separate WE and SA cohort at a high risk of NDH. Methods Mass spectrometry analysis was performed on fasted samples from 72 WE or SA men with NGC or NDH. These results were verified using specific biochemical assays and validated by repeating the analysis in an additional cohort of 30 WE and 30 SA adults. Proteomic results were analysed using independent samples t test and univariate analysis. The targeted assay results were analysed using generalised linear models with adjustment for appropriate covariates including age, BMI, fasting plasma glucose, high-density lipoprotein-cholesterol, triglycerides and sex. Results Only zinc-alpha-2-glycoprotein (ZAG) significantly differed between both ethnicities and glycaemic control groups. ZAG-specific biochemical assays verified the lower circulating ZAG in SAs (41.09 versus 37.07 (mg L−1); p = 0.014), but not the difference between NGC and NDH groups (p = 0.539). Validation of the ethnicity difference in a separate cohort confirmed that, after adjustment for covariates, ZAG was lower in SAs (p = 0.018). There was no association between ZAG and glycaemic control in the validation cohort. Conclusions Our analyses identified that ZAG is lower in SAs compared to WEs, but its difference between glycaemic control statuses was uncertain. Further research is needed to establish whether lower ZAG in SAs is associated with, or prognostic of, health outcomes, particularly regarding the risk of dysglycaemia

Greater hepatic lipid saturation is associated with impaired glycaemic regulation in men with metabolic dysfunction‐associated steatotic liver disease but is not altered by 6 weeks of exercise training

Aims: To examine the impact of impaired glycaemic regulation (IGR) and exercise training on hepatic lipid composition in men with metabolic dysfunction‐associated steatotic liver disease (MASLD). Materials and Methods: In Part A (cross‐sectional design), 40 men with MASLD (liver proton density fat fraction [PDFF] ≥5.56%) were recruited to one of two groups: (1) normal glycaemic regulation (NGR) group (glycated haemoglobin [HbA1c] < 42 mmol∙mol−1 [<6.0%]; n = 14) or (2) IGR group (HbA1c ≥ 42 mmol∙mol−1 [≥6.0%]; n = 26). In Part B (randomized controlled trial design), participants in the IGR group were randomized to one of two 6‐week interventions: (1) exercise training (EX; 70%–75% maximum heart rate; four sessions/week; n = 13) or (2) non‐exercise control (CON; n = 13). Saturated (SI; primary outcome), unsaturated (UI) and polyunsaturated (PUI) hepatic lipid indices were determined using proton magnetic resonance spectroscopy. Additional secondary outcomes included liver PDFF, HbA1c, fasting plasma glucose (FPG), homeostatic model assessment of insulin resistance (HOMA‐IR), peak oxygen uptake (VO2 peak), and plasma cytokeratin‐18 (CK18) M65, among others. Results: In Part A, hepatic SI was higher and hepatic UI was lower in the IGR versus the NGR group (p = 0.038), and this hepatic lipid profile was associated with higher HbA1c levels, FPG levels, HOMA‐IR and plasma CK18 M65 levels (r s ≥0.320). In Part B, hepatic lipid composition and liver PDFF were unchanged after EX versus CON (p ≥ 0.257), while FPG was reduced and VO2 peak was increased (p ≤ 0.030). ΔVO2 peak was inversely associated with Δhepatic SI (r = −0.433) and positively associated with Δhepatic UI and Δhepatic PUI (r ≥ 0.433). Conclusions: Impaired glycaemic regulation in MASLD is characterized by greater hepatic lipid saturation; however, this composition is not altered by 6 weeks of moderate‐intensity exercise training

Device-assessed sleep and physical activity in individuals recovering from a hospital admission for COVID-19: a multicentre study

Background: The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms. Methods: One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators. Results: Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean ± SD of 14.9 ± 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 ± 1.7 h/day spent inactive and 7.2 ± 1.1 h/day asleep. The values for men were 21.0 ± 22.3 and 12.6 ± 1.7 h /day and 6.9 ± 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes. Conclusions: Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant

The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo

While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes