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Cardiometabolic Effects of Semaglutide in Individuals with Type 2 Diabetes in the United Arab Emirates: Real-World 12-Month Outcomes and Predictors of Response.
Diabetes Ther
Muhammad Hamid Siddique Mian, Kholood Abdulla Hasan Abdulla Janahi, Afnan Tayeb +9 more
There is little real-world evidence on semaglutide effectiveness in the United Arab Emirates (UAE), despite the high local burden of type 2 diabetes (T2DM) and obesity. The aim of this study was to evaluate real-world cardiometabolic outcomes and predictors of response following initiation of semaglutide in a tertiary endocrine clinic.
Effectiveness of tirzepatide in Japanese patients with type 2 diabetes but no obesity: A sub-analysis of Hokkaido-TZP study data.
J Diabetes Investig
Tomoe Abe, Fumika Maruyama, Eisuke Nishikawa +7 more
Although tirzepatide efficaciously reduces glucose concentrations and weight, phase 3 trials evaluated patients with a body mass index (BMI) ≥23 kg/m2. Consequently, clinical evidence in patients with type 2 diabetes but no obesity, common in Asia, is insufficient. In this secondary analysis of the multicentre, real-world Hokkaido-TZP study, we evaluated 107 Japanese patients with T2D and BMI <25.0 kg/m2. Over 6 months, tirzepatide significantly reduced HbA1c in all the BMI tertiles (Low, Middle, High). Seven patients discontinued treatment due to adverse events; notably, all belonged to the Low or Middle BMI groups. The overall BMI also significantly decreased, but the reduction was more pronounced in participants with higher baseline BMIs. Multiple regression analysis identified baseline BMI and dietary consultations as significant independent factors contributing to the BMI reduction. Thus, tirzepatide provides effective glycaemic control in patients without obesity, and its weight-lowering effect might be modulated by baseline BMI and lifestyle interventions.
Sex, Not Age, Predicts Weight Loss Outcomes With Tirzepatide: A Retrospective Analysis.
Obesity (Silver Spring)
Regina Castaneda, Dima Bechenati, Rene de J Rivera Gutierrez +15 more
This study assessed the impact of sex and age on weight loss outcomes in patients receiving tirzepatide in real-world clinical practice.
Liraglutide and Dapagliflozin Synergistically Reshape Gut Microbiota and Metabolic Profiles to Ameliorate Type‑2 Diabetes in Mice.
ACS Omega
An-Jun Tan, Tian-Rong Li, Jing-Jing Yang +3 more
Background: Type-2 diabetes mellitus (T2DM) poses a formidable global health challenge, characterized by persistent hyperglycemia resulting from insulin resistance and progressive β-cell dysfunction. Liraglutide (LIRA), a GLP-1 receptor agonist, and dapagliflozin (DAPA), an SGLT2 inhibitor, are established therapies with complementary mechanisms. However, the potential synergy of their combination, particularly through modulation of the gut microbiota and host metabolism, remains incompletely understood. To elucidate the gut microbiota-metabolite axis underlying the therapeutic effects of combination therapy in T2DM, we explored the interplay between β-cell function, fecal microbiota composition, and microbial metabolites. Methods: A T2DM mouse model was induced by a high-fat diet and streptozotocin. Mice were treated for 4 weeks with LIRA, DAPA, or their combination (COM). We assessed glycemic control, insulin sensitivity, pancreatic islet morphology, serum biochemistry, gut microbiota (shotgun metagenomic sequencing), and plasma metabolome (nontargeted metabolomics). Integrated multiomics analysis was performed to elucidate microbiota-metabolite interactions. Results: Combination treatment demonstrated superior efficacy compared to monotherapies, resulting in significantly greater improvements in body weight, glucose tolerance, insulin sensitivity, lipid profiles, and liver function. Histologically, COM most effectively restored pancreatic islet architecture, increased β-cell mass, and normalized α/β-cell ratio. Metagenomic analysis revealed that COM induced a unique and restorative remodeling of the gut microbiota, distinct from monotherapies. This was characterized by suppression of pathobionts (e.g., Klebsiella and Enterorhabdus) and enrichment of beneficial taxa (e.g., Akkermansia, Lactobacillus, and Faecalibaculum). Metabolomics profiling showed that COM extensively normalized the diabetic plasma metabolome. Key altered pathways included tryptophan metabolism, sphingolipid metabolism, and branched-chain amino acid degradation. Integrated correlation analysis unveiled significant associations between specific microbial genera and host metabolites, suggesting a functional gut microbiota-metabolite axis underpinning the synergistic benefits. Conclusions: The combination of liraglutide and dapagliflozin exerts synergistic antidiabetic effects that extend beyond glycemic control to encompass pancreatic protection and systemic metabolic improvement. This synergy is mechanistically linked to collaborative remodeling of the gut ecosystem and consequent normalization of host metabolic pathways. Our findings provide a novel rationale for this combination therapy and highlight the gut microbiota as a pivotal target for T2DM management.
Pharmacologic Treatments With Lifestyle Modifications in Nonpregnant Adults With Overweight or Obesity in Outpatient Settings: A Living Clinical Guideline From the American College of Physicians (April 2026).
Ann Intern Med
Amir Qaseem, J Thomas Cross, Curtis S Harrod +17 more
The American College of Physicians (ACP) developed this clinical guideline for internal medicine physicians and other clinicians caring in outpatient settings for adults with overweight or obesity.
Effects of insulin and exenatide therapy on glycemic control and β-cell function in patients newly diagnosed with type 2 diabetes and severe hyperglycemia.
J Chin Med Assoc
Tsung-Hui Wu, Chin-Sung Kuo, Harn-Shen Chen
To assess the efficacy of short-term insulin therapy compared with exenatide therapy in glycemic control, remission rate, and β-cell function in patients newly diagnosed with type 2 diabetes and severe hyperglycemia.
Benefits and Harms of Pharmacologic Treatments in Adults With Overweight or Obesity: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.
Ann Intern Med
Johanna A A Damen, Demy L Idema, Robin W M Vernooij +9 more
Overweight and obesity are closely linked to diseases such as type 2 diabetes, coronary heart disease, and stroke and have been shown to increase mortality risk.
Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model.
Circ Heart Fail
Beatrice Vahle, Sven Weidner, André Tomalka +11 more
Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment.
Glymphatic clearance as revealed by diffusion tensor imaging along the perivascular space (DTI-ALPS) is associated with Alzheimer's disease neuropathology and periodic rsEEG alpha rhythms in mild cognitive impairment participants.
Alzheimers Dement (Amst)
Susanna Lopez, Claudio Del Percio, Roberta Lizio +39 more
We evaluated whether the brain glymphatic drainage function estimated by the diffusion tensor imaging along the perivascular space (DTI-ALPS) index relates to white matter (WM) integrity, Alzheimer's disease (AD) neuropathology, resting-state electroencephalogram (rsEEG) alpha rhythms underpinning quiet vigilance, and cognitive decline in mild cognitive impairment (MCI).
Chimeric Antigen Receptor T Cells as Living Therapeutics Targeting Senescence and Age-Related Diseases.
Research (Wash D C)
Qingyi Shao, Danlei Chen, Wenxia Shao +1 more
The aging of the global population exacerbates the burden of age-related diseases; however, therapies that can intervene in fundamental aging processes are lacking. Senescent cells drive chronic inflammation and multitissue dysfunction through the secretion of proinflammatory and profibrotic senescence-associated secretory phenotype cells, making them emerging therapeutic targets. Although first-generation senolytic drugs have entered clinical trials, they face limitations such as insufficient targeting specificity and transient efficacy. The success of chimeric antigen receptor T cell (CAR T cell) therapy in cancer immunotherapy has validated its precision clearance capabilities as a "living drug". This review systematically elaborates on the paradigm shift of extending CAR T cell therapy to aging medicine, from the discovery and validation of surface targets on senescent cells to a CAR engineering design tailored to the senescent microenvironment and from evidence of reversing fibrosis and improving metabolic function in preclinical models to the challenges of specificity, safety, and manufacturing faced in clinical translation. Finally, future directions for integrating technologies such as mRNA delivery and artificial intelligence are envisioned in this article, which proposes that CAR T cell therapy may drive the evolution of medicine from "treating single diseases" to "intervening in shared aging processes", offering transformative strategies to achieve healthy aging.
Optimizing Antibody-Based Therapies for Alzheimer's Disease: From Clinical Limitations to Molecular Engineering Innovations.
Aging Dis
Qian Liu, Rong-Rong Lin
Antibody-based immunotherapy represents one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Recent anti-amyloid-β (Aβ) antibodies have achieved robust plaque clearance and modest cognitive benefits in early AD, establishing clinical proof of concept. However, limited efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIA), continue to restrict their therapeutic potential. This review outlines the current clinical status of antibody therapies targeting Aβ, tau, and neuroinflammatory pathways, and summarizes key antibody optimization strategies, including aggregation-state-selective targeting, Fc engineering, brain shuttle technologies, nanobody platforms, and nanotechnology-enabled delivery. We further discuss emerging concepts from tumor immunotherapy, such as antibody-guided protein degradation and conditionally active biologics, as potential avenues for next-generation AD treatment.
Unlocking the aging brain: mTORC1 as a convergent integrator for neurodegeneration and therapeutic intervention.
Biogerontology
Mokhtar Rejili, Hayder M Al-Kuraishy, Mustafa M Shokr +1 more
Aging is the primary risk factor for neurodegenerative diseases, characterized by a progressive decline in cellular homeostasis. Central to this process is the mammalian target of rapamycin complex 1 (mTORC1), a convergent integrator regulator of metabolism that integrates nutrient sensing with cellular growth. While essential for development, chronic mTORC1 hyperactivity, termed mTORopathy, emerges during aging, driving a deleterious cycle of mitochondrial dysfunction, neuroinflammation, and impaired protein clearance. This pathological state promotes the accumulation of toxic proteins, such as amyloid-beta, tau, and alpha-synuclein, while simultaneously suppressing autophagy and glymphatic function. Furthermore, mTORC1 overactivation in glial cells fuels inflammaging by inducing cellular senescence and the senescence-associated secretory phenotype (SASP), which compromises blood-brain barrier integrity and synaptic plasticity. Conversely, pharmacological inhibition of mTORC1 using rapamycin or its analogs (rapalogs) has demonstrated significant neuroprotective potential. By restoring autophagic flux, rebalancing metabolic axes (AMPK/SIRT1), and suppressing chronic inflammation, these compounds can rescue synaptic function and reactivate neurogenesis. This review synthesizes current evidence regarding mTORC1 as a convergent integrator for brain aging and evaluates the clinical prospects of mTOR-targeted therapies in mitigating neurodegenerative decline.
Sex-related expression of apelin/APJ in the adolescent and adult rat offspring exposed to maternal peripartum depression.
Mol Biol Rep
Jagoda Kruszewska, Katarzyna Czarzasta, Karol Momot +1 more
INTRODUCTION: Maternal Peripartum Depression (MPD) has been linked to health-related complications in offspring. We found that MPD induced in rat dams led to depressive-like behavior and cardiovascular changes in their offspring. Independently, the apelin/APJR system, composed of apelin and its receptor APJ (APJR), is widely expressed and plays a vital role in brain and heart health. Given the potential health impacts, we studied apelin and APJR mRNA expression in offspring of MPD-exposed Sprague-Dawley rat dams compared to controls. METHODS AND RESULTS: The mRNA expression of apelin and the APJR was assessed in the cerebellum, medulla oblongata, and left ventricle collected from adolescents (postnatal day 48) and adults (postnatal day 225) offspring from MPD-exposed (male SOM; female SOF) and control dams (male COM, female COF). Results showed a significant interaction between MDP and sex in mRNA apelin expression in the medulla oblongata of adolescent offspring. Specifically, adolescent COM had higher apelin mRNA expression than adolescent SOM and adolescent COF in the medulla oblongata. Furthermore, MDP decreased apelin and APJR mRNA expression in the cerebellum and left ventricle in adolescent offspring. However, adult males had higher apelin mRNA expression in the medulla oblongata and left ventricle and lower APJR mRNA expression in the left ventricle. CONCLUSIONS: Our results demonstrate a significant effect of MPD on apelin/APJR mRNA expression in the brains and hearts, especially in male adolescent offspring. In adults, sex is the main effect. These data highlight the need to further explore the therapeutic potential of apelin/APJR, especially for sex-dependent effects.
Severe Diabetic Ketoacidosis With Refractory Hypernatremia due to Hypokalemia-Induced Arginine Vasopressin Resistance: A Case Report and Literature Review.
Case Rep Med
Reem Shihab, May Shihab, Hala O Abdallah +2 more
Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes characterized by hyperglycemia, high-anion-gap metabolic acidosis, and ketonemia. Hypernatremia in DKA is uncommon and typically reflects disproportionate free water loss. Arginine vasopressin resistance (AVP-R), previously known as nephrogenic diabetes insipidus, may occur in the setting of hypokalemia, leading to polyuria, hypotonic urine, and worsening hypernatremia. We report the case of a 14-year-old previously healthy female who presented with new-onset severe DKA complicated by profound acidosis, hyperglycemia, hypokalemia, and hypernatremia. Despite standard DKA management, she developed persistent polyuria and rising serum sodium levels. Urine studies demonstrated dilute urine with inappropriately elevated pH, raising suspicion for hypokalemia-induced AVP-R. Management included aggressive potassium repletion, careful adjustment of intravenous fluids, and adjunctive desmopressin therapy. This approach resulted in normalization of electrolyte abnormalities, resolution of polyuria, and full clinical recovery. This case highlights the importance of recognizing hypokalemia-induced AVP-R as a reversible cause of refractory hypernatremia in DKA and underscores the need for individualized fluid and electrolyte management beyond standard treatment protocols.
Erg currents support electrical bursting in murine anterior pituitary corticotrophs.
J Physiol
Sooraj V Nair, Nicola Romanò, Peter J Duncan +3 more
The regulation of electrical excitability of anterior pituitary corticotrophs is critical for an appropriate response of the hypothalamic-pituitary-adrenal (HPA) axis in the face of diverse physiological challenges in health and disease. However ion channels that control corticotroph excitability remain poorly characterised. Members of the mammalian ether-à-go-go (EAG) channel family are voltage-gated potassium channels with diverse functions in the endocrine, cardiovascular and nervous systems. Expression of Kcnh2 mRNA, which encodes for the Eag-related potassium channel Erg1, is enriched in the anterior pituitary although its functional role is poorly understood in native anterior pituitary cells. We reveal that Kcnh2 is the major Eag-channel family member mRNA expressed in male and female murine corticotrophs. Patch clamp electrophysiological analysis revealed corticotrophs exhibit robust Erg-like currents that are inhibited by the selective Erg-inhibitor E4031 but are not regulated by the major hypothalamic secretagogues, corticotrophin releasing hormone (CRH) or arginine vasopressin (AVP), that increase corticotroph excitability. Pharmacological inhibition of Erg currents had no effect on spontaneous electrical excitability in corticotrophs. Rather, paradoxically, Erg currents were important for supporting CRH-induced bursting, similar to the role of large-conductance calcium- and voltage-activated potassium (BK) channels, providing a level of redundancy to control bursting. Indeed mathematical modelling revealed that in the absence of BK channels CRH-induced bursting can be supported in thepresence of Erg current. We thus reveal a novel role for Erg-like channels in controlling CRH-induced bursting in murine anterior pituitary corticotrophs that is likely to be an important determinant of HPA axis regulation in health and disease. KEY POINTS: Voltage-gated ether-à-go-go-related (Erg) potassium channels are key determinants of cellular excitability; however their functional role in native anterior pituitary cells remains poorly understood. Male and female murine corticotrophs predominantly express Kcnh2 (Erg1) mRNA, and electrophysiological recordings reveal functional Erg-like potassium currents sensitive to the Erg inhibitor E4031. Erg currents do not control the basal electrical excitability of corticotrophs. We reveal a novel role for Erg currents in supporting electrical bursting in corticotrophs induced by the hypothalamic secretagogue, corticotrophin releasing hormone (CRH). Bursting in corticotrophs can be supported by both Erg and BK channels revealing a level of redundancy to the CRH response that will be critical for understanding the role of Erg channels in control of the stress axis in health and disease.
Familial glucocorticoid deficiency due to a novel TXNRD2 variant: expanding the spectrum of a rare genetic cause.
Front Endocrinol (Lausanne)
Ibrahim Al Alwan, Kheloud M Alhamoudi, Abdullah Ibrahim Alzaben +9 more
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency and elevated adrenocorticotropic hormone (ACTH) levels. Variants in TXNRD2, which encodes mitochondrial thioredoxin reductase 2, have recently been implicated in FGD; however, the phenotypic and mutational spectrum remain extremely limited.
Blood Urea Nitrogen/Creatinine Ratio in Cushing's Syndrome: Associations With Disease Status and Postoperative Changes.
Int J Endocrinol
C Yarkutay Turkkan, M M Canat, H Erhan Gol +1 more
Although various tests are used for Cushing's syndrome (CS) screening and diagnosis, none exhibit ideal sensitivity or specificity. This study evaluates the association of the blood urea nitrogen (BUN)/creatinine ratio with disease status in CS and subclinical Cushing's syndrome (SCS), and with postoperative changes in patients with CS.
Therapeutic potential of growth hormone-releasing hormone analogues in cardiovascular and cerebrovascular diseases: mechanisms and preclinical evidence.
Front Pharmacol
Hao-Lin Ren, Yuliang Zhang, Kefan Yang +3 more
Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide that stimulates growth hormone (GH) secretion from the pituitary gland, forming the central GHRH-GH-insulin-like growth factor-1 (IGF-1) endocrine axis. Beyond its classical endocrine function, GHRH and its receptors are widely expressed in extrapituitary tissues, where they regulate diverse physiological processes including cardiovascular function and neuroprotection. Preclinical studies demonstrate that synthetic GHRH analogues like MR-409 mitigate vascular calcification in diabetes, enhance cardiac repair post-myocardial infarction, and restore diastolic function in heart failure through calcium-handling modulation. In ischemic stroke models, MR-409 exhibits neuroprotective effects, reducing mortality and promoting neural regeneration. Studies performed in animal models have demonstrated the efficacy and therapeutic benefits of these compounds in diverse cardiomyopathies and ischemic stroke. Notably, these benefits occur independently of GH/IGF-1 signaling, highlighting their therapeutic potential for cardiovascular and cerebrovascular diseases. This narrative review synthesizes evidence from animal models, underscoring GHRH analogues as promising candidates for clinical translation. The articles included were identified through systematic searches in PubMed using keywords such as "GHRH analogues", "cardiovascular disease', and "ischemic stroke", with selection based on relevance to therapeutic applications and preclinical efficacy.
Age-Dependent Effects of Adrenomedullin on Muscle Fiber Composition, Angiogenesis, and Muscle Satellite Cells Maintenance.
Geriatr Gerontol Int
Ryota Iyama, Eriko Kurogi, Takumi Yokokawa +3 more
Sarcopenia has recently become a major public health issue. Adrenomedullin (AM) exerts diverse physiological effects, including angiogenesis, but its role in skeletal muscle is unclear. This study investigates whether AM can attenuate sarcopenic changes in aged mice compared to young adults.
Nacre extract attenuates age-related functional and tissue alterations under post-onset intervention conditions in two murine aging models.
Biogerontology
Momoko Kawaminami, Saki Kimoto, Hana Yamamoto +1 more
Aging is accompanied by the accumulation of senescent cells and chronic low-grade inflammation, which together contribute to functional decline and tissue remodeling across organs. We previously reported that long-term nacre extract supplementation can delay age-related deterioration when initiated early; however, whether it can provide benefit under post-onset intervention conditions remains unclear. Here, we evaluated a water-soluble nacre extract derived from Pinctada fucata using (i) senescence-accelerated mouse prone 8 (SAMP8) mice and (ii) a D-galactose-induced aging paradigm, with treatment administered after the emergence of age-related phenotypes. In SAMP8 mice, nacre extract improved cognitive and neuromuscular performance, including Y-maze spontaneous alternation, novel object recognition, and forelimb grip strength, and showed a partial improvement in composite aging indices. These benefits were accompanied by reduced senescence-associated markers (p16, p21, and phosphorylated histone H2AX (γH2AX)) in skeletal muscle and peripheral organs, suppression of inflammation-associated signaling in skeletal muscle, and improved redox-related marker profiles. Nacre extract also increased satellite cell- and contractile marker-related immunoreactivity in aged skeletal muscle, suggesting improved regeneration- and maturation-related tissue characteristics. In the D-galactose model, nacre extract was introduced after impairments emerged and administered during the final 11 weeks of continued D-galactose exposure; under these post-onset intervention conditions, nacre extract improved grip strength, showed trends toward improved cognitive performance, and reduced senescence-associated markers in skeletal muscle and adipose tissue, supporting reproducibility across paradigms. Collectively, these findings indicate that nacre extract attenuates aging-associated functional and tissue alterations under post-onset intervention conditions by attenuating senescence- and inflammation-associated tissue responses and improving organism-level homeostasis.