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JAMA Network Open Jun 2024A major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
A major concern with weight loss is concomitant bone loss. Exercise and glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent weight loss strategies that may protect bone mass despite weight loss.
OBJECTIVE
To investigate bone health at clinically relevant sites (hip, spine, and forearm) after diet-induced weight loss followed by a 1-year intervention with exercise, liraglutide, or both combined.
DESIGN, SETTING, AND PARTICIPANTS
This study was a predefined secondary analysis of a randomized clinical trial conducted between August 2016 and November 2019 at the University of Copenhagen and Hvidovre Hospital in Denmark. Eligible participants included adults aged 18 to 65 years with obesity (body mass index of 32-43) and without diabetes. Data analysis was conducted from March to April 2023, with additional analysis in February 2024 during revision.
INTERVENTIONS
After an 8-week low-calorie diet (800 kcal/day), participants were randomized to 1 of 4 groups for 52 weeks: a moderate- to vigorous-intensity exercise program (exercise alone), 3.0 mg daily of the GLP-1 RA liraglutide (liraglutide alone), the combination, or placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in site-specific bone mineral density (BMD) at the hip, lumbar spine, and distal forearm from before the low-calorie diet to the end of treatment, measured by dual-energy x-ray absorptiometry in the intention-to-treat population.
RESULTS
In total, 195 participants (mean [SD] age, 42.84 [11.87] years; 124 female [64%] and 71 male [36%]; mean [SD] BMI, 37.00 [2.92]) were randomized, with 48 participants in the exercise group, 49 participants in the liraglutide group, 49 participants in the combination group, and 49 participants in the placebo group. The total estimated mean change in weight losses during the study was 7.03 kg (95% CI, 4.25-9.80 kg) in the placebo group, 11.19 kg (95% CI, 8.40-13.99 kg) in the exercise group, 13.74 kg (95% CI, 11.04-16.44 kg) in the liraglutide group, and 16.88 kg (95% CI, 14.23-19.54 kg) in the combination group. In the combination group, BMD was unchanged compared with the placebo group at the hip (mean change, -0.006 g/cm2; 95% CI, -0.017 to 0.004 g/cm2; P = .24) and lumbar spine (-0.010 g/cm2; 95% CI, -0.025 to 0.005 g/cm2; P = .20). Compared with the exercise group, BMD decreased for the liraglutide group at the hip (mean change, -0.013 g/cm2; 95% CI, -0.024 to -0.001 g/cm2; P = .03) and spine (mean change, -0.016 g/cm2; 95% CI, -0.032 to -0.001 g/cm2; P = .04).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, the combination of exercise and GLP-1RA (liraglutide) was the most effective weight loss strategy while preserving bone health. Liraglutide treatment alone reduced BMD at clinically relevant sites more than exercise alone despite similar weight loss.
TRIAL REGISTRATION
EudraCT: 2015-005585-32.
Topics: Humans; Female; Male; Middle Aged; Liraglutide; Glucagon-Like Peptide-1 Receptor; Bone Density; Adult; Exercise; Obesity; Weight Loss; Hypoglycemic Agents; Aged; Combined Modality Therapy; Denmark
PubMed: 38916894
DOI: 10.1001/jamanetworkopen.2024.16775 -
Reumatismo Jun 2024Fragility fractures (FF) resulting from osteoporosis pose a significant public health challenge in Italy, with considerable socio-health and economic implications....
OBJECTIVE
Fragility fractures (FF) resulting from osteoporosis pose a significant public health challenge in Italy, with considerable socio-health and economic implications. Despite the availability of safe and effective drugs, osteoporosis remains underdiagnosed and undertreated, leaving over 2 million high-risk Italian women without treatment. This paper aims to identify and propose key improvements in the management of osteoporosis, focusing particularly on the critical issues related to the use of anabolic drugs in secondary prevention, according to the current Italian Medicines Agency (AIFA) Note 79.
METHODS
The Expert Panel, composed of nine recognized Italian experts in rheumatology, analyzed current practices, prescribing criteria, and the most recent literature. Three main reasons for revising the indications on pharmacological treatment of osteoporosis were identified: inadequate treatment of osteoporosis, new evidence regarding frontline placement of anabolics in high-risk conditions, and emerging sequential or combined strategies.
RESULTS
The proposed improvements include the adoption of the Derived Fracture Risk Assessment algorithm for accurate fracture risk assessment, revision of AIFA Note 79 to reflect current evidence, improved prescribing appropriateness, broader access to anabolic agents, and the provision of sequential therapies with antiresorptives for teriparatide. These changes aim to enhance patient outcomes, streamline healthcare processes, and address the high percentage of undertreated individuals.
CONCLUSIONS
This expert opinion emphasizes the importance of the appropriate use of anabolic drugs to reduce FF and associated costs while ensuring the sustainability of the National Health Service. The proposed recommendations are in line with the latest scientific evidence, providing a comprehensive strategy to optimize the management of osteoporosis in Italy. On behalf of the Study Group on Osteoporosis and Skeletal Metabolic Diseases of the Italian Society of Rheumatology.
Topics: Humans; Italy; Anabolic Agents; Osteoporosis; Bone Density Conservation Agents; Osteoporotic Fractures; Female; Teriparatide; Risk Assessment; Secondary Prevention; Expert Testimony
PubMed: 38916162
DOI: 10.4081/reumatismo.2024.1696 -
Frontiers in Endocrinology 2024Spexin (SPX, NPQ) is a 14-amino acid neuroactive peptide identified using bioinformatics. This amino acid sequence of the mature spexin peptide has been highly conserved... (Review)
Review
Spexin (SPX, NPQ) is a 14-amino acid neuroactive peptide identified using bioinformatics. This amino acid sequence of the mature spexin peptide has been highly conserved during species evolution and is widely distributed in the central nervous system and peripheral tissues and organs. Therefore, spexin may play a role in various biological functions. Spexin, the cognate ligand for GALR2/3, acting as a neuromodulator or endocrine signaling factor, can inhibit reproductive performance. However, controversies and gaps in knowledge persist regarding spexin-mediated regulation of animal reproductive functions. This review focuses on the hypothalamic-pituitary-gonadal axis and provides a comprehensive overview of the impact of spexin on reproduction. Through this review, we aim to enhance understanding and obtain in-depth insights into the regulation of reproduction by spexin peptides, thereby providing a scientific basis for future investigations into the molecular mechanisms underlying the influence of spexin on reproductive function. Such investigations hold potential benefits for optimizing farming practices in livestock, poultry, and fish industries.
Topics: Animals; Reproduction; Peptide Hormones; Vertebrates; Humans; Hypothalamo-Hypophyseal System
PubMed: 38915898
DOI: 10.3389/fendo.2024.1422711 -
Drug Design, Development and Therapy 2024Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether...
Short-Term Preconditioning with Insulin and Glucose Efficiently Protected the Kidney Against Ischemia-Reperfusion Injury via the P-AKT-Bax-Caspase-3 Signaling Pathway in Mice.
OBJECTIVE
Insulin attaches insulin receptor to activate the PI3-kinase/Akt signaling to maintain glucose homeostasis and inhibit apoptosis. This study determined whether preconditioning with insulin and glucose protects the kidney against ischemia-reperfusion injury (IRI).
METHODS
Kidney IRI was performed in C57BL/6 mice by clamping the renal vessels for 30 min, followed by reperfusion for 24 h. A total subcutaneous 0.1 unit of insulin along with 10% glucose in drinking water was treated on the mice for 24 h before kidney IRI. The kidney function and injuries were investigated through the determination of BUN and Cr in blood plasma, as well as the apoptosis and the expression of P-AKT, BAX, and caspase-3 in the kidneys. The role of P-AKT in insulin-treated IRI kidneys was tested using an AKT inhibitor. The effects of the preconditional duration of insulin and glucose on IRI kidneys were investigated by expanding the treatment duration to 1, 3, and 6 days.
RESULTS
Preconditioning with insulin and glucose protected the kidney against IRI as manifested by a decrease in creatinine and BUN and a reduction of kidney tubular injury. The protection effect was mediated by P-AKT-BAX-caspase-3 signaling pathway resulting in suppression of apoptotic cell death. An AKT inhibitor partially reversed the protective effects of preconditional insulin. The preconditional duration for 1, 3, and 6 days had no differences in improving kidney functions and pathology.
CONCLUSION
A short-term preconditioning with insulin and glucose protected the kidney from IRI through the activation of p-AKT and subsequent reduction of BAX-caspase-3-induced apoptosis. The short-term precondition provides a practicable strategy for protecting the kidney against predictable IRI, such as kidney transplant and major surgical operations with high risk of hypotension.
Topics: Animals; Reperfusion Injury; Proto-Oncogene Proteins c-akt; Mice; Mice, Inbred C57BL; Signal Transduction; Insulin; Male; Caspase 3; Glucose; bcl-2-Associated X Protein; Kidney; Apoptosis
PubMed: 38915866
DOI: 10.2147/DDDT.S465836 -
BioRxiv : the Preprint Server For... Jun 2024Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1 ) neurons are responsible for the pulsatile...
Hypothalamic kisspeptin (Kiss1) neurons are vital for pubertal development and reproduction. Arcuate nucleus Kiss1 (Kiss1 ) neurons are responsible for the pulsatile release of Gonadotropin-releasing Hormone (GnRH). In females, the behavior of Kiss1 neurons, expressing Kiss1, Neurokinin B (NKB), and Dynorphin (Dyn), varies throughout the ovarian cycle. Studies indicate that 17β-estradiol (E2) reduces peptide expression but increases mRNA and glutamate neurotransmission in these neurons, suggesting a shift from peptidergic to glutamatergic signaling. To investigate this shift, we combined transcriptomics, electrophysiology, and mathematical modeling. Our results demonstrate that E2 treatment upregulates the mRNA expression of voltage-activated calcium channels, elevating the whole-cell calcium current and that contribute to high-frequency burst firing. Additionally, E2 treatment decreased the mRNA levels of Canonical Transient Receptor Potential (TPRC) 5 and G protein-coupled K (GIRK) channels. When TRPC5 channels in Kiss1 neurons were deleted using CRISPR, the slow excitatory postsynaptic potential (sEPSP) was eliminated. Our data enabled us to formulate a biophysically realistic mathematical model of the Kiss1 neuron, suggesting that E2 modifies ionic conductances in Kiss1 neurons, enabling the transition from high frequency synchronous firing through NKB-driven activation of TRPC5 channels to a short bursting mode facilitating glutamate release. In a low E2 milieu, synchronous firing of Kiss1 neurons drives pulsatile release of GnRH, while the transition to burst firing with high, preovulatory levels of E2 would facilitate the GnRH surge through its glutamatergic synaptic connection to preoptic Kiss1 neurons.
PubMed: 38915596
DOI: 10.1101/2024.02.20.581121 -
Scientific Reports Jun 2024High sugar consumption is associated with cardiovascular diseases and diabetes. Current sugar substitutes may cause taste sensations and gastrointestinal symptoms. ENSO... (Randomized Controlled Trial)
Randomized Controlled Trial
High sugar consumption is associated with cardiovascular diseases and diabetes. Current sugar substitutes may cause taste sensations and gastrointestinal symptoms. ENSO 16 is a combination of 16 different sugar substitutes and plant fibers and has been designed as a sugar alternative. The impact on plasma glucose metabolism as well as on gastrointestinal tolerance has not been investigated yet. 17 healthy participants were enrolled in this randomized, double-blind trial. Participants received a single oral dose of 30 g glucose or 30 g ENSO 16 and crossed over to the alternate treatment after a 7 day wash out period. The study endpoint was the effect on plasma glucose, insulin, C-peptide concentrations and gastrointestinal disorders. A questionnaire regarding gastrointestinal symptoms was used for individual subjective scoring. The mean baseline adjusted plasma glucose AUC was significantly greater after glucose administration compared to ENSO 16 (n = 15, p = 0.0128, paired t-test). Maximum plasma glucose elevation over baseline was 117 mg*dl and 20 mg*dl after oral glucose or ENSO 16, respectively. Insulin and C-peptide AUC were significantly greater after glucose compared to ENSO 16 intake (p < 0.01, Wilcoxon rank sum test). The mean maximal concentrations of plasma glucose, insulin and C-peptide after glucose intake were 1.5, 4.6 and 2.7-fold greater after glucose intake compared to ENSO 16 intake, respectively. Adverse reactions were mostly mild and not different between treatments. Conclusion. ENSO 16 has only a small impact on plasma glucose metabolism. This may be of interest in a dietary context and may help to reduce calory intake.Trail registration NCT05457400. First registration: 14/07/2022. https://clinicaltrials.gov/study/NCT05457400 .
Topics: Humans; Male; Female; Adult; Blood Glucose; Cross-Over Studies; Double-Blind Method; C-Peptide; Insulin; Glucose; Healthy Volunteers; Young Adult; Middle Aged
PubMed: 38914694
DOI: 10.1038/s41598-024-65560-w -
JAMA Network Open Jun 2024Congenital heart disease (CHD) is the most common human organ malformation, affecting approximately 1 of 125 newborns globally.
IMPORTANCE
Congenital heart disease (CHD) is the most common human organ malformation, affecting approximately 1 of 125 newborns globally.
OBJECTIVES
Assessing the performance of 2 diagnostic tests using minimal amounts of dried blood spots (DBS) to identify high-risk CHD compared with controls in a Swedish cohort of neonates.
DESIGN, SETTING, AND PARTICIPANTS
This diagnostic study took place in Sweden between 2019 and 2023 and enrolled full-term babies born between 2005 and 2023. All cases were identified through centralized pediatric cardiothoracic surgical services in Lund and Gothenburg, Sweden. Controls were followed up for 1 year to ensure no late presentations of high-risk CHD occurred. Cases were verified through surgical records and echocardiography.
EXPOSURE
High-risk CHD, defined as cases requiring cardiac surgical management during infancy due to evolving signs of heart failure or types in which the postnatal circulation depends on patency of the arterial duct. Using 3-μL DBS samples, automated quantitative tests for NT-proBNP and interleukin 1 receptor-like 1 (IL-1 RL1; formerly known as soluble ST2) were compared against established CHD screening methods.
MAIN OUTCOMES AND MEASURES
Performance of DBS tests to detect high-risk CHD using receiver operating characteristic curves; Bland-Altman and Pearson correlation analyses to compare IL-1 RL1 DBS with plasma blood levels.
RESULTS
A total of 313 newborns were included (mean [SD] gestational age, 39.4 [1.3] weeks; 181 [57.8%] male). Mean (SD) birthweight was 3495 (483) grams. Analyzed DBS samples included 217 CHD cases and 96 controls. Among the CHD cases, 188 participants (89.3%) were high-risk types, of which 73 (38.8%) were suspected prenatally. Of the 188 high-risk cases, 94 (50.0%) passed pulse oximetry screening and 36 (19.1%) were initially discharged after birth without diagnoses. Combining NT-proBNP and IL-1 RL1 tests performed well in comparison with existing screening methods and enabled additional identification of asymptomatic babies with receiver operating characteristic area under the curve 0.95 (95% CI, 0.93-0.98).
CONCLUSIONS AND RELEVANCE
In this diagnostic study, NT-proBNP and IL-1 RL1 DBS assays identified high-risk CHD in a timely manner, including in asymptomatic newborns, and improved overall screening performance in this cohort from Sweden. Prospective evaluation of this novel approach is warranted.
Topics: Humans; Infant, Newborn; Heart Defects, Congenital; Neonatal Screening; Dried Blood Spot Testing; Biomarkers; Female; Male; Sweden; Natriuretic Peptide, Brain; Peptide Fragments; Case-Control Studies; Interleukin-1 Receptor-Like 1 Protein
PubMed: 38913376
DOI: 10.1001/jamanetworkopen.2024.18097 -
Journal of Applied Biomedicine Jun 2024Myo-inositol (MI), present in a variety of foods, is essential in several important processes of cell physiology. In this study, we explored the protective effects of MI...
Myo-inositol (MI), present in a variety of foods, is essential in several important processes of cell physiology. In this study, we explored the protective effects of MI against hyperglycemia and dyslipidemia in db/db mice, a typical animal model of type 2 diabetes mellitus (T2DM). MI supplement effectively suppressed the high plasma glucose and insulin levels and markedly relieved the insulin resistance (IR) in the db/db mice, comparable to metformin's effects. In MIN6 pancreatic β cells, MI also restrained the upsurge of insulin secretion stimulated by high-concentration glucose but had no impact on the promoted cell proliferation. Moreover, MI abated the enhanced plasma triglyceride and total cholesterol levels in the db/db mice. Notably, the lipid droplet formation of mesenchymal stem cells (MSCs) from db/db mice was significantly diminished after the treatment of MI, indicating that MI could effectively inhibit the differentiation of db/db mouse MSCs into adipocytes. However, MI regretfully failed to control obesity in db/db mice. This work proved that MI significantly helped db/db mice's metabolic disorders, indicating that MI has potential as an effective adjunctive treatment for hyperglycemia and dyslipidemia in T2DM patients.
Topics: Animals; Insulin Resistance; Dyslipidemias; Inositol; Mice; Diabetes Mellitus, Type 2; Male; Insulin; Mesenchymal Stem Cells; Blood Glucose; Insulin-Secreting Cells; Adipocytes; Hyperglycemia
PubMed: 38912862
DOI: 10.32725/jab.2024.009 -
Heliyon Jun 2024Alzheimer's disease (AD) is a brain illness that causes cognitive impairment in the elderly, especially females, as a result of genetics, hormones, and life experiences....
Alzheimer's disease (AD) is a brain illness that causes cognitive impairment in the elderly, especially females, as a result of genetics, hormones, and life experiences. It becomes more severe with age and is associated with cardiovascular disease, hypertension, and diabetes. Beta-amyloid plaques and hyper phosphorylated Tau protein buildup are common clinical findings. Misfiling of amyloid precursor protein (APP) and Amyloid beta peptide (Aβ) proteins contributes to Alzheimer's disease. Enzyme Acetylcholinesterase enzyme interacts with amyloid-beta, enhancing its accumulation in insoluble plaques, leading to successful treatment for Alzheimer's disease primarily based on lowering this enzyme. Treatments include using the Rivastigmine for mild, moderate, or severe Alzheimer's disease, which inhibits acetylcholinesterase, but may cause side effects; Solanine derivatives, nightshade toxin, it is cholinesterase inhibitory, may mitigate Alzheimer's illness is progressing. In this research utilized a molecular docking program, which is a computer's computational ability to determine the optimal position for a specific compound to bind to a protein or target, forming a target-ligand complex and displaying biological activity and aiding in the development of effective anti-AD treatments and understanding AD pathological mechanisms. The study examined complexes of 3LII (Acetylcholinesterase receptor) in the A and B chain with Solanine and Rivastigmine derivatives, using an in-silico approach. PyRx default sorter was used to improve docking accuracy. Four compounds were selected based on their higher binding affinities in chain A and B. The results showed that Solanine derivatives (alpha-Solanine, Beta1-Solanine and Beta2-Solanine) have higher binding strength (-9.0,-9.3 and -8.6) than Rivastigmine (-7.2) in chain A, and also the binding strength was high for the Solanine derivatives (alpha-Solanine, Beta1-Solanine, and Beta2-Solanine) (-9.0,-8.8 and -8.9) is higher than Rivastigmine (-6.0) in the chain B. Solanine derivatives showed higher binding strength with acetylcholinesterase, potentially for to reduce the progression of the disease.
PubMed: 38912489
DOI: 10.1016/j.heliyon.2024.e32209 -
The Journal of Maternal-fetal &... Dec 2024The current study aims to evaluate the correlation between oxytocin augmentation and postpartum hemorrhage. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The current study aims to evaluate the correlation between oxytocin augmentation and postpartum hemorrhage.
METHOD
PubMed, Web of Science, and Scopus has been searched for studies assessing the correlation between oxytocin augmentation and postpartum hemorrhage up to January 24, 2024. The search strategy included relevant keywords related to PPH and oxytocin augmentation. The risk of bias assessment was conducted by two reviewers using the Newcastle-Ottawa Scale (NOS). To pool the effects sized of included studies odds ratios (OR) of interest outcome with their 95% confidence interval (CI) were used.
RESULTS
Eight studies were included in this meta-analysis. The pooled analysis of the included studies showed a statistically significant association between oxytocin augmentation and increased odds of PPH (pooled odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.05-1.53; I2 = 84.94%; = 0.01). Publication bias was assessed using funnel plots, which appeared relatively asymmetrical, indicating significant publication bias. Galbraith plot and trim and fill plot were used for publication bias. Sensitivity analyses were performed by leave one out method.
CONCLUSION
This meta-analysis suggests that using oxytocin for labor augmentation is linked to a significant increase in the risk of PPH. It highlights the need for careful monitoring and consideration when using oxytocin, especially in low and middle-income countries where guidelines and supervision are crucial.
Topics: Humans; Oxytocin; Female; Postpartum Hemorrhage; Pregnancy; Oxytocics
PubMed: 38910114
DOI: 10.1080/14767058.2024.2369210