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Rare types of congenital adrenal hyperplasia: report of five children with 11β-hydroxylase deficiency including pathogenic and novel CYP11B1 variants.
Arch Endocrinol Metab
Anju Bala, Sayan Banerjee, Arun George +6 more
11β-hydroxylasedeficiency (11β-OHD) is a rare form of congenital adrenal hyperplasia caused by biallelic pathogenic variants in the CYP11B1 gene. It leads to impaired cortisol synthesis, resulting in increased adrenocorticotropic hormone stimulation and consequent accumulation of steroid precursors, which are diverted to androgen synthesis. In addition, the accumulation of 11-deoxycorticosterone, which is a potent mineralocorticoid, causes hyporeninemic hypokalemic hypertension. We report the clinical, hormonal, and genetic profiles of five children with 11β-OHD, emphasising phenotypic variability, a median 2-year diagnostic delay, the crucial role of hormonal profile in diagnosis, and management challenges, including post-treatment central precocious puberty. Two novel CYP11B1 variants were identified in two unrelated patients. Hydrocortisone replacement resolved hypertension in only one of the three hypertensive patients; others required spironolactone. Early differentiation of 11β-OHD from 21-hydroxylase deficiency is critical to prevent hypertension-related morbidity.
Nutrient-dependent hippocampus dopamine signaling enhances meal-related episodic memory and reduces food intake.
bioRxiv
Alexander G Bashaw, Léa Décarie-Spain, Jessica J Rea +6 more
Dopamine (DA) is a neurotransmitter critically involved in food-related reinforcement learning. While mesolimbic DA reward-associated signaling in the nucleus accumbens has been widely investigated, far less is known about DA function in the hippocampus (HPC), a brain region traditionally known for its role in episodic and spatial memory processes that has recently been associated with appetite and food intake control.
Efficacy and Safety of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Ventricular Arrhythmias and Cardiovascular Events: A Disease-Stratified Network Meta-Analysis.
Diabetes Obes Metab
Wen-Ting Sun, Rui-Xing Liu, Yao-Hao Jiang +5 more
The effects of individual sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) on ventricular arrhythmias (VAs) remain uncertain. This study aimed to comprehensively compare their effects on VAs and cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) and/or heart failure (HF).
Identification of glicentin as a low-potency glucose-dependent insulinotropic polypeptide receptor agonist.
Peptides
Paula-Peace James-Okoro, Joss Field, Graeme Davies +7 more
The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a class B1 G protein-coupled receptor (GPCR) that promotes glucose-dependent insulin secretion upon activation by GIP. Dual agonism of GIPR and glucagon-like peptide-1 receptor (GLP-1R) has emerged as a breakthrough therapeutic strategy for type 2 diabetes and obesity, improving glycaemic control and promoting weight loss. Although GIPR is widely expressed in the central nervous system, endogenous GIP expression in the brain is controversial, and peripherally-administered fluorescent GIPR/GLP-1R agonists predominantly localise to circumventricular organs, suggesting a lack of GIP-ligand for receptors shielded by the blood-brain barrier. Here, we considered the existence of alternative endogenous ligands for GIPR, potentially modulated by receptor activity-modifying proteins (RAMPs). Ligand activity was profiled at heterologously expressed human GIPR using cAMP accumulation, calcium mobilisation, and cAMP inhibition assays. Among the 42 ligands tested, glicentin was the only non-proGIP-derived peptide to elicit a cAMP response at GIPR (EC₅₀ = 877nM). No ligand-induced calcium mobilisation or cAMP inhibition was observed. Glicentin also activated human GLP-1R and glucagon receptor (GCGR), with receptor-specific antibody blockade reducing potency by 10-20-fold at all three receptors. Glicentin's activity was conserved at rodent GIPRs, albeit with reduced potency. Co-expression with RAMP2 or RAMP3 attenuated cAMP responses to GIPR-active ligands, including glicentin, but did not affect other ligands tested. These findings show that the GIPR is highly selective and identifies glicentin as a low-potency, cross-reactive agonist at GIPR, GLP-1R and GCGR, although its high EC₅₀ makes it unlikely to act as a physiological ligand under basal conditions.
Stimulating Thyrotropin Receptor Antibodies Enhance the Expression of Both Thyrotropin Receptors and Insulin-Like Growth Factor 1 Receptors in Fibroblasts.
Thyroid
Pingping Xiang, Mihaly Mezei, Rauf Latif +1 more
Thyrotropin (TSH) and insulin-like growth factor 1 (IGF-1) signals have been shown to be additive in their action on thyroid cells and fibroblasts, and this coordination emphasizes the role of TSH receptor (TSHR) and IGF-1 receptor (IGF-1R) signaling exerted by stimulating TSHR antibodies in patients with thyroid eye disease (TED). Here, we have reanalyzed the influence of TSHR autoantibodies on TSHR and IGF-1R expression in a fibroblast model.
Pharmacological Therapy for Metabolic Dysfunction-Associated Steatotic Liver Disease in a New Era for Obesity and Metabolic Medicine: A State-of-the-Art Review.
J Obes Metab Syndr
Wah-Kheong Chan, Hak-Keith Leung, Guo-Jeng Tan +4 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and a major cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Weight loss via positive health behavioral change is the cornerstone of management of MASLD. However, this is a huge challenge for many patients, highlighting the need for effective pharmacological therapies. Two pharmacological agents have received conditional approval for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), the progressive inflammatory form of MASLD, namely resmetirom, an oral, liver-directed, selective thyroid hormone receptor-β agonist, and semaglutide, a glucagon-like peptide-1 receptor agonist. Despite recent advances, effective pharmacological therapy for MASH-related cirrhosis remains an unmet need, underscoring the importance of early identification and intervention. This narrative review summarizes the current pharmacological therapy landscape of MASLD, including emerging incretin-based therapies and fibroblast growth factor-21 analogues, as well as current guidance on the use of non-invasive tests for treatment selection and monitoring for treatment response. It also provides a background on recent advances in obesity and metabolic medicine, highlighting the evolving paradigm of complication-centric obesity management and the potential role of incretin-based therapies as the backbone of the management of obesity and obesity-related conditions, including MASLD.
Special Considerations When Using GLP-1 Receptor Agonists in the Treatment of Obesity and Diabetes Mellitus Type 2 in Older Adults.
Adv Ther
Anna Geraldina Pendrey, Jennyfer Alejandra Rivera Sierra, Fernando Alberto Alvarez Lobo +3 more
The prevalence of obesity and type 2 diabetes mellitus (T2DM) in the older adult population is rising continuously worldwide, with approximately 40% and 29% of individuals affected in this group, respectively. These conditions have a substantial impact on older adults and are associated with reduced quality of life, increased morbidity, functional decline, and cardiovascular disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as an important option for the management of T2DM and obesity. However, special considerations are needed for specific age groups due to risks of adverse effects and increased comorbidity burden. GLP-1 RAs, including tirzepatide, liraglutide, and semaglutide, promote weight loss by suppressing appetite, improving insulin secretion, and delaying gastric emptying. Large clinical trials have supported GLP-1 RAs as an excellent option for reducing glycated hemoglobin and body weight, as well as for reducing major renal and cardiovascular adverse effects; however, evidence in older adults remains limited. Given the health considerations for older adults, weight loss efforts with GLP-1 RAs require cautious approaches, as sarcopenia is a relevant topic in this specific age group. Polypharmacy and side effects also need to be considered when treating an older adult with GLP-1 RA. Overall, GLP-1 RAs represent a valuable and promising treatment option for older adults with T2DM and obesity.
Patterns of Use for GLP-1 Receptor Agonists in a Weight Management Cohort: A Military Health System Database Analysis of Active Duty Service Members From 2021 to 2025.
Mil Med
Luke B Miller, Matthew J Dellen, Ester J Gilbert +3 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for weight management, but real-world data on long-term persistence are crucial for understanding their effectiveness. This study aimed to compare persistence, adherence, and predictors of discontinuation among new users of different GLP-1RAs in the Military Health System (MHS).
Association of Glucagon-Like Peptide-1 Receptor Agonists With Menstrual Events in Reproductive-Aged Patients.
Obstet Gynecol
Connor Frey, Mahyar Etminan
Glucagon-like peptide-1 receptor agonists are increasingly prescribed to reproductive-aged patients, yet pharmacovigilance data on menstrual outcomes remain sparse. Using the FDA Adverse Event Reporting System data through March 2026, we performed disproportionality and Bayesian analyses restricted to female patients aged 12-55 years in a retrospective cohort study. Semaglutide demonstrated the broadest signal profile, with disproportionate reporting of heavy menstrual bleeding, intermenstrual bleeding, menstrual clots, oligomenorrhea, and anovulatory cycles. Tirzepatide generated signals for intermenstrual bleeding and menstrual clots. Liraglutide produced no significant signals. These findings suggest pleiotropic effects on menstrual physiology and may support inclusion of menstrual health in counseling for reproductive-aged patients.
Effect of glucagon-like peptide-1 receptor agonists on body weight and urinary albumin-to-creatinine ratio in patients with and without type 2 diabetes: A systematic review and meta-analysis.
J Int Med Res
Rong Huang, Bin Wang
ObjectiveGlucagon-like peptide-1 receptor agonists are established for weight management and cardiovascular risk reduction, with emerging evidence for kidney protection. Whether albuminuria-lowering effects extend to nondiabetic chronic kidney disease remains uncertain.MethodsWe performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guided meta-analysis of randomized controlled trials comparing glucagon-like peptide-1 receptor agonists with placebo or standard care. Primary outcomes were change in body weight (kg) and percentage change in urinary albumin-to-creatinine ratio; change in estimated glomerular filtration rate was the secondary outcome. We conducted prespecified subgroup analyses (including glycemic status) and random-effects meta-regression to explore heterogeneity. Risk of bias assessment (2.0), small-study effects (funnel plot and trim-and-fill analyses), sensitivity analyses (leave-one-out and low-risk-only), and Grading of Recommendations Assessment, Development and Evaluation certainty ratings were applied.ResultsTen trials (n = 26,088) were included. Glucagon-like peptide-1 receptor agonists reduced body weight (mean difference, -5.85 kg; 95% confidence interval: -7.78 to -3.92) with a consistent direction of effect across studies despite heterogeneity. Glucagon-like peptide-1 receptor agonists lowered urinary albumin-to-creatinine ratio overall (mean difference, -27.94%; 95% confidence interval: -37.72 to -18.15). Stratified analyses showed a precise reduction in type 2 diabetes mellitus (mean difference, -25.70%; I2 = 0%) and a directionally concordant but less precise reduction in populations without type 2 diabetes mellitus (mean difference, -30.93%; I2 = 96%). A modest between-group difference in estimated glomerular filtration rate was also observed (mean difference, -0.82 mL/min/1.73 m2; I2 = 0%). Meta-regression indicated attenuation with longer treatment duration and greater benefit with higher baseline albuminuria; drug class and glycemic status were not consistent moderators of urinary albumin-to-creatinine ratio in prespecified subgroups. Findings were robust to multiple sensitivity analyses. Certainty of evidence was high for weight and moderate for urinary albumin-to-creatinine ratio.ConclusionsGlucagon-like peptide-1 receptor agonists were associated with clinically meaningful weight loss and lower urinary albumin-to-creatinine ratio across included trials. A directionally similar signal was observed in populations without type 2 diabetes mellitus, although interpretation of this subgroup remains limited by heterogeneity, imprecision, and the inability to evaluate intermediate glycemic phenotypes. Variability in urinary albumin-to-creatinine ratio estimates appears to reflect duration and baseline risk more than a lack of effect.
Macrophage-mediated nutrient recycling: evolutionary insights into the metabolic role of professional phagocytes.
Front Immunol
Gabriela Krejčová, Adam Bajgar
Removal of senescent and damaged cells is fundamental for tissue homeostasis. While macrophage recognition and clearance of apoptotic cells are well characterized, the ultimate fate of the digested material remains poorly understood. Here, we explore current knowledge on the fate of engulfed material and examine how the metabolic nature of engulfed cargo shapes downstream signaling and phagocyte polarization. We also discuss emerging evidence that macrophages act as metabolic hubs, recycling and supplying nutrients to surrounding tissues. Drawing on studies in invertebrate phagocytes, we explore the evolutionary origins of this "nurturing" function and highlight its conservation in mammals, emphasizing its physiological relevance and potential contributions to metabolic disease.
Rethinking PINK1/Parkin-mediated mitophagy in Parkinson's disease: functional continuity and activation-clearance uncoupling.
Front Aging Neurosci
Lingzhe Wang, Bin Xu
Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of nigral dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited. Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network. This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.
Reduced inflammatory and Th1 transcriptional profiles in geriatric versus adult cotton rats infected with respiratory syncytial virus.
PLoS Pathog
Jonathan Miller, Cameron Leedale, Ayse Selen Yilmaz +6 more
Human respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease in elderly populations. RSV clearance is delayed in individuals over 65 years of age, a finding that is recapitulated in the geriatric cotton rat model. Altered inflammatory responses in elderly populations have been implicated with impaired clearance of several pathogens but remain poorly described for RSV. We performed RNA sequencing (RNA-seq) and pathway analysis on lung tissue of RSV-infected adult and geriatric cotton rats to characterize differential host immune responses between these age groups. No differences in inflammatory gene expression were observed between uninfected adult and geriatric cotton rats. At day 1 post-infection, adult cotton rats expressed higher levels of genes encoding several cytokines and transcription factors associated with acute inflammation and initiation of a Th1 response, including IFN- β, IL12, and Tbet, compared to geriatric cotton rats. By day 4 post-infection, adult cotton rats additionally expressed higher levels of genes encoding effector molecules associated with Th1 responses, including IFN-γ. Pathway analysis showed significantly increased activation of several pro-inflammatory pathways in adults, including the Th1 pathway, macrophage classical (M1) activation, and pathogen-induced cytokine signaling. To evaluate lymphocyte Th1/Th2 polarization resulting from RSV infection in both age groups, we stimulated splenocytes with RSV antigen at day 28 post-infection and measured IFN-γ and IL-4 production by ELISA. Splenocytes of all adult cotton rats produced detectable IFN-γ and no IL-4, indicating Th1 polarization. Splenocytes of all geriatric cotton rats produced detectable IL-4, indicating Th2 polarization. Collectively, these results indicate that geriatric cotton rats exhibit impaired generation of a Th1 response and a decreased inflammatory response overall to RSV.
The Association Between Bending Photoplethysmography Waveform Area Index and Congestive Heart Failure.
Clin Cardiol
Xianghui Zeng, Qingfeng Zeng, Chunqing Xiao +2 more
Congestive heart failure (CHF) is closely associated with a decrease in cardiac output, and photoplethysmography (PPG) parameters can experimentally assess cardiac output. It is unclear whether there is an association between the change of bending photoplethysmography waveform area index (BPWAI) due to postural changes and CHF.
Obesity in Adults with Type 1 Diabetes Mellitus.
J Obes Metab Syndr
Adnan Batman, Cem Sulu, Dilek Yazıcı +3 more
The prevalence of overweight and obesity in individuals with type 1 diabetes mellitus (T1DM) has increased significantly due to multifactorial causes, paralleling global trends. Beyond known causes of obesity, pathophysiological and biopsychosocial causes specific to T1DM also have a role in the development of obesity. Obesity in T1DM may arise from treatment-related factors (intensive insulin therapy and defensive carbohydrate intake), behavioral aspects (reduced physical activity due to fear of hypoglycemia), and pathophysiological mechanisms such as adipose tissue dysfunction. Clinically, obesity in T1DM is associated with increased risk of cardiovascular disease, nephropathy, retinopathy, and psychosocial burden. Weight gain and increased insulin dependence have created a vicious cycle in the management of obesity in T1DM. Recent clinical studies have shown that incretin-based therapies, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual GIP/GLP-1 agonists, can reduce body weight and insulin requirements without significant safety concerns. Similarly, sodium-glucose cotransporter 2 inhibitors offer metabolic benefits but carry a risk of diabetic ketoacidosis. The lack of regulatory approval for obesity treatment agents in these patients highlights the importance of further research. In this review, we address the pathophysiology of obesity in T1DM, its clinical implications, and therapeutic approaches using an evidence-based approach.
Case Report: Dramatic metabolic improvement with tirzepatide in a patient with acquired partial lipodystrophy following hematopoietic stem cell transplantation.
Front Endocrinol (Lausanne)
Yuri Tanaka, Hiroaki Ueno, Hirotake Sawada +8 more
Acquired lipodystrophy is a rare disorder characterized by adipose tissue loss or dysfunction and is frequently associated with severe insulin resistance and metabolic complications. Metabolic complications of lipodystrophy have occasionally been reported after hematopoietic stem cell transplantation (HSCT), but their clinical features and optimal treatment strategies remain poorly defined. Tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has recently emerged as a novel therapy for type 2 diabetes.
Tesamorelin as an Adjunct to Exercise for Improving Physical Function in HIV (TRIUMPH): a clinical trial protocol.
BMJ Open
Kristine M Erlandson, Laurel Gustafson, Julia E Johnson +13 more
The Tesamorelin as an Adjunct to Exercise for Improving Physical Function in HIV (TRIUMPH) study is a randomised controlled trial with the overall goal of examining the combined effect of exercise and the growth hormone-releasing hormone analogue tesamorelin on physical function.
Neuropsychiatric Outcomes With Tirzepatide, Semaglutide, and Other GLP-1 Receptor Agonists.
Diabetes Obes Metab
Solomon Chih-Cheng Chen, Tso-Jen Wang, Chu-Kuang Chou +1 more
Neuropsychiatric safety concerns, including depression and suicidal ideation, have emerged during the expanding clinical use of incretin-based therapies for type 2 diabetes mellitus (T2DM) and obesity. However, whether risks differ across successive generations of incretin-based therapies remains uncertain.
GLP-1R and GIPR crosstalk modulates insulinotropic signaling pathways.
Cell Chem Biol
Peter Lindquist, Luuk R H Dijkhof, Anna K Drzazga +15 more
Drugs targeting glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors (GLP-1R and GIPR) show strong clinical effects in type 2 diabetes and obesity. Both GIPR agonism and antagonism enhance GLP-1R agonist efficacy, indicating important incretin receptor crosstalk. We show that GLP-1 and semaglutide, but not exendin-4, promote heterodimerization between GLP-1R and GIPR through interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics and molecular dynamics reveal that dimerizing and non-dimerizing agonists differentially influence GLP-1R, activating divergent signaling pathways in human pancreatic islets. Moreover, semaglutide and exenatide display distinct patterns in their FDA-reported safety profiles. When co-expressed, GLP-1R enhances GIPR signaling in a β-arrestin-dependent manner, while increasing GIPR levels decreases GLP-1R signaling. Additionally, we show that changes in GIPR expression are clinically associated with adiposity and diabetic phenotypes. These findings highlight heterodimerization and receptor expression as key modulators of GLP-1R/GIPR signaling, offering mechanistic insights, and guiding drug design strategies that incorporate receptor crosstalk.
Peptide delivery in the management of diabetes: exploring bioinspired nanoarchitectures using stimuli-responsive materials and supramolecular depots.
Int J Pharm
Aliyu Dantani Abdullahi, Mohammed Auwal Ibrahim, June C Serem
Peptide therapeutics such as insulin and glucagon-like peptide-1 (GLP-1) analogues are central to diabetes management but remain constrained by rapid enzymatic degradation, poor epithelial permeability and short systemic half-life. Bioinspired nanoarchitectures have emerged as promising strategies to address these challenges by mimicking biological membranes, extracellular matrices and supramolecular peptide assemblies to enhance peptide stability, absorption and pharmacokinetic control. This review synthesised advances in membrane-mimetic lipid nanocarriers, polymer-based systems, peptide-driven self-assembling depots and stimuli-responsive nanoarchitectures. Lipid-inspired systems including hydrophobic ion-paired exenatide lipid nanocarriers achieved oral bioavailability of 16.3-27.9%. Comparably, polymer-based systems incorporating adaptive electrostatic or stimuli-responsive designs such as charge-switchable PCB122/INS nanoparticles coated capsules, enabled oral insulin bioavailability approaching ∼27%, translating into sustained glucose lowering effects in vivo. In addition, a polymeric D-PLA-PEG stereocomplex nanoassembly enabled ultra-long insulin release for up to 16 weeks following a single subcutaneous administration, maintaining controlled blood glucose levels in type 1 diabetic models. Peptide-driven supramolecular systems such as GLP-1 nanofibre hydrogels and cassette-assembled peptides demonstrated sustained glycaemic control lasting weeks to over 40 days in preclinical models. Interestingly, emerging glucose-responsive platforms including glucose oxidase-integrated hydrogels and ROS-responsive polymersomes, further enabled closed-loop insulin release with polymersomes releasing > 90% insulin under hyperglycaemic conditions. Importantly, several nanoarchitectures also supported cell-based therapies such as biomimetic pancreatic constructs combining stem-cell-derived islet cells with peptide-loaded nanomatrices to restore glycaemic regulation in type 1 diabetes models. Overall, these bioinspired platforms illustrate how nanomedicine can integrate barrier penetration, pharmacokinetic control and stimuli-responsive release to advance next-generation peptide delivery strategies for diabetes therapy.