This article begins by providing historical insight into the discovery, development, and use of glucagon-like peptide-1 receptor (GLP-1R) agonist medications in the treatment of type 2 diabetes and obesity. Next, the mechanism of action and impacts of GLP-1R agonists are discussed, along with an overview of the Food and Drug Administration-approved GLP-1R agonists currently on the market. Comparison in effects on weight loss of the available GLP-1R agonists is briefly discussed, along with its use in the context of bariatric surgery. Finally, perioperative considerations for surgical patients using GLP-1R agonists are reviewed along with suggested recommendations.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. ELAVL1, an RNA-binding protein, is involved in the regulation of genes closely associated with DN pathogenesis, whereas suPAR acts as a circulating mediator that promotes podocyte damage and contributes to proteinuric kidney disorders. However, whether ELAVL1 regulates suPAR release in DN remains unexplored.

Clinical samples from patients with DN were collected and analyzed. In vitro, podocytes were treated with high glucose, and ELAVL1 or PLAUR (encoding uPAR) was knocked down or overexpressed using lentiviral transduction. In db/db mice, podocyte-specific manipulation of Elavl1 or Plaur was performed via adeno-associated virus-mediated delivery. Renal function was assessed by measuring the urinary albumin-to-creatinine ratio (UACR) and serum creatinine. Glomerular pathology and inflammatory markers were evaluated histologically and biochemically.

ELAVL1 was upregulated in DN and positively correlated with podocyte injury. Knockdown of ELAVL1 mitigated hyperglycemia-induced podocyte damage and inflammatory responses. Mechanistically, ELAVL1 directly bound to and stabilized PLAUR mRNA, leading to increased uPAR protein expression and elevated suPAR secretion. The protective effects of ELAVL1 knockdown were reversed by PLAUR overexpression in podocytes. In diabetic mice, podocyte-specific knockdown of Elavl1 or Plaur markedly lowered circulating suPAR levels and alleviated renal dysfunction and histopathological injury. Moreover, restoration of the PLAUR-suPAR axis abolished the renoprotective benefits conferred by Elavl1 knockdown.

Hyperglycemia-induced ELAVL1 upregulates PLAUR and suPAR release from podocytes, promoting renal inflammation and injury. Targeting the ELAVL1-PLAUR-suPAR axis may offer a therapeutic strategy for DN.

Sodium-glucose cotransporter 2 inhibitors (SGLT2) were initially developed as antihyperglycemic agents for the management of type 2 diabetes mellitus (T2DM). This study sought to evaluate the impact of sodium-glucose cotransporter 2 inhibitors on blood glucose levels in patients with HFrEF without diabetes.

This randomized controlled trial included 130 patients without diabetes diagnosed with HF classified as NYHA class II to IV, with an ejection fraction (EF) below 40% as determined by echocardiography within the preceding three months. Baseline assessments included serum creatinine, random and fasting blood glucose, 2-hour postprandial glucose, HbA1c, urine acetone, BMI, blood pressure, and serum electrolytes (sodium, potassium, magnesium, ionized calcium, and phosphorus). After three months of treatment, all these clinical and laboratory parameters were reassessed in both groups.

Treatment led to significant improvements in cardiac function, including reductions in left ventricular diameters and volumes, and increases in ejection fraction, tricuspid annular plane systolic excursion, and right ventricular fractional area change (P<0.05). Glycemic control also improved, with significant decreases in fasting, postprandial, HbA1c, and random blood glucose (P<0.001). Serum creatinine, magnesium, and phosphorus levels increased significantly (P<0.001). Adverse events were minimal, with only one patient showing urine acetone positivity (1.5%, P=0.99), and no symptomatic hypoglycemia, ketoacidosis, or significant hypotension occurred.

SGLT2 inhibitors safely reduce blood glucose in patients with HFrEF without diabetes without causing hypoglycemia, highlighting their potential cardiovascular and metabolic benefits and supporting their use in this population.

Pluripotent stem cell (PSC)-based therapies hold the potential to unlock cures for numerous diseases, including, but not limited to, Parkinson's disease, macular degeneration, heart failure, type 1 diabetes, and cancer. Yet as protocols to differentiate PSCs into therapeutically useful cell types have progressed rapidly, immunological rejection remains a major barrier that may limit the widespread use of such PSC-based therapies. In recent years, strategies to genetically modify PSCs to prevent immunological rejection of the downstream cell product have become a point of emphasis. Here, we provide an immunological perspective on these strategies, discussing the breadth of rejection mechanisms that have been uncovered through decades of research and the relative simplicity of designing PSC immune evasion strategies to circumvent these mechanisms. We focus in particular on how these strategies apply to the treatment of type 1 diabetes.

Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular risk, enhanced platelet activation, and substantial interindividual variability in response to aspirin. However, the term 'aspirin resistance' has been used inconsistently and is strongly influenced by the assay applied. In many cases, apparent non-response may reflect exposure-related pseudoresistance rather than true pharmacodynamic failure, particularly in the setting of enteric-coated formulations, impaired absorption, poor adherence or pharmacological interactions. This systematic review with narrative synthesis, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISRMA) 2020, evaluated the prevalence, determinants, and clinical relevance of aspirin hyporesponsiveness in T2DM. Searches of PubMed, Embase, the Cochrane Library, and Latin American and Caribbean Health Sciences Literature identified 21 eligible studies. The reported prevalence varied widely (0-57%), mainly owing to differences in study populations, aspirin formulations, platelet function assays, and cut-off definitions. Small pharmacodynamic studies suggested that twice-daily aspirin regimens may provide greater suppression of platelet reactivity than once-daily dosing, whereas pharmacokinetic/pharmacodynamic evidence consistently indicated reduced thromboxane B2 suppression with enteric-coated aspirin. However, evidence linking laboratory-defined hyporesponsiveness with clinical outcomes was limited and inconsistent, and the largest available randomised outcome trial did not show a reduction in major cardiovascular events with twice-daily aspirin. Overall, aspirin hyporesponsiveness in T2DM appears to be multifactorial and insufficiently standardised. Current evidence does not support routine platelet function testing or empirical dose escalation. Clinical management should prioritise confirming the indication for aspirin, assessing adherence, selecting the appropriate formulation, avoiding clinically relevant drug interactions, and optimising overall cardiometabolic risk.

Current research on pathological retinal neovascularization primarily focuses on growth factors, inflammation, and endothelial signaling pathways. However, increasing attention is being directed toward disruptions in the retinal immune microenvironment. Therefore, deciphering the immune-angiogenic interplay could uncover therapeutic avenues for neovascular disorders. Through integrative analyses of single-cell RNA sequencing from human fibrovascular membranes and multicohort clinical datasets, we identified neutrophil infiltration as an independent risk factor for diabetic retinopathy progression. Mechanistically, activated microglia preceded and potentiated neutrophil infiltration by secreting galectin-3 (GAL3), establishing a self-amplifying feedback loop that sustained microglial activation and drove pathological angiogenesis in mice with oxygen-induced retinopathy (OIR). To therapeutically disrupt this loop, we engineered a photocurable hydrogel for the sustained intravitreal delivery of GAL3 and vascular endothelial growth factor (VEGF)-neutralizing antibodies, which effectively suppressed aberrant angiogenesis in mice with OIR. Together, these findings reinforce the concept of retinal neovascularization as an immunovascular disorder and underscore the therapeutic potential of microenvironment-modulating strategies using biomaterials.

The efficacy of cell-based therapeutics is often compromised by host immune recognition of implanted cells and biomaterials, resulting in fibrotic encapsulation and loss of function. Here, we address this challenge with an immunomodulatory cell-based therapy, in which alginate-encapsulated retinal pigment epithelial cells continuously secrete cytokines to locally modulate the implant microenvironment. In a healthy rodent model, the localized production of interleukin-10 (IL-10) or IL-12 from encapsulated cytokine-producing cells prevented foreign body response to alginate capsules. Mechanistically, treatment was associated with reduced expression of profibrotic genes and immune shifts consistent with macrophage and T cell regulation, supporting a cytokine-mediated mitigation of foreign body response. In a diabetic murine model (streptozotocin-induced C57BL/6J), coimplantation of human islets with IL-10-producing cells attenuated pericapsular fibrosis, preserved islet viability, and restored normoglycemia for up to 100 days (4.76 times longer than islets alone). Notably, IL-10-producing cells were also effective in enabling the durability and function of encapsulated cells in a healthy nonhuman primate, showing translational feasibility. Collectively, these findings suggest that localized cytokine delivery can reduce fibrotic encapsulation and support durable graft function, offering a path to lessen reliance on systemic immunosuppression in islets transplantation and other implantable biomaterial therapies.

Recent clinical trials have shown that dual GLP-1R/GCGR agonists, including mazdutide and cotadutide, provide kidney benefits in patients with type 2 diabetes and CKD, suggesting a potential contribution of GCGR activation to these renal effects. However, whether GCGR directly confers renoprotection and the underlying mechanisms remain unclear. Here, using tubule-specific GCGR loss- and gain-of-function mouse models and human kidney samples, we show that tubular GCGR signaling exerts an important renoprotective role in DKD. Tubular GCGR expression is reduced in humans and mice with DKD and correlates with worse kidney function and increased renal injury. Genetic ablation of tubular GCGR markedly exacerbates DKD and induces pronounced phospholipid accumulation within enlarged lysosomes. Mechanistically, GCGR loss disrupts its association with the V-ATPase V1A subunit ATP6V1A, compromises V1-V0 assembly, and thereby impairs lysosomal acidification. This defect leads to impaired phospholipid hydrolysis and protease maturation, blockade of autophagic flux, and ultimately tubular cell injury. In vivo, ATP6V1A overexpression markedly reverses GCGR deficiency-induced lysosomal dysfunction and DKD progression. Consistently, re-expression of tubular GCGR via AAV9 restores lysosomal function, reduces phospholipid accumulation, and mitigates renal injury in DKD. Together, these findings provide genetic evidence for the renoprotective role of tubular GCGR in DKD, delineate a kidney-intrinsic GCGR-ATP6V1A-lysosome axis that protects tubular integrity, and extend prior GCGR-in-kidney observations into a more concrete GCGR-lysosome mechanism.

BACKGROUND Septic shock is highly prevalent in clinical practice. Some cases present insidiously and have poor prognoses. We report a case of a patient with a dislodged catheter who developed septic shock during a cystostomy procedure. CASE REPORT Our patient was a 76-year-old man with a history of hypertension, type 2 diabetes mellitus, and cerebral infarction. He had been confined to bed for a long time following a cerebral infarction and had impaired consciousness. One year prior, he developed urinary retention due to benign prostatic hyperplasia. As he did not undergo surgical treatment, a long-term indwelling urinary catheter was subsequently placed. He initially presented to the emergency department of our hospital at 8: 30 PM on November 1, 2025, 8 hours after accidental urethral catheter dislodgement. A cystostomy was recommended, but he refused and left against medical advice. At approximately 8: 00 AM on November 2, 2025, he returned to the hospital and consented to cystostomy. During the procedure, he developed septic shock. Postoperatively, he was transferred to the intensive care unit for further treatment. Three days later, the family decided to discontinue active treatment and took the patient home. Follow-up revealed that the patient died 2 days after discharge. CONCLUSIONS This case highlights the critical importance of early infection screening and prompt sepsis recognition prior to surgical procedures in elderly, frail, and catheter-dependent patients. It also highlights the importance of keeping the catheter unobstructed and ensuring proper home care.

Specific heterozygous pathogenic variants in LMNA have been reported in patients with Dunnigan-type familial partial lipodystrophy (FPLD2), while other variants cause autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). FPLD2 is characterized by variable loss of subcutaneous fat from the extremities and trunk, and AD-EDMD is characterized by early joint contractures, proximal muscle weakness, and cardiac conduction defects. Previously, only 2 families have been reported with combined features of FPLD2 and AD-EDMD.

To report the overlapping phenotype of both FPLD2 and AD-EDMD in 5 families with heterozygous LMNA variants.

Clinical, anthropometric, laboratory, and genotyping data of affected subjects from 5 families with female probands presenting with FPLD2 and AD-EDMD phenotypes were collected.

Affected individuals (8 females, ages 18-57 years; 3 males, ages 25-41 years) harbored heterozygous p.T528R, p.R527P, p.R541P, or p.R453W LMNA variants. Five females and 2 males had joint contractures and proximal muscle weakness, and 4 females and 1 male had pacemaker-defibrillator implantation for cardiac arrhythmias, confirming AD-EDMD. Subcutaneous fat loss from the extremities confirming FPLD2 was observed in all females but only in 2 males. Four females had diabetes mellitus and hypertriglyceridemia, and 1 male had hypertriglyceridemia. Two females, 50 and 58 years old, died due to aspiration pneumonia and cerebrovascular accident, respectively, and one 40-year-old male died of alcoholic liver disease.

Our report brings attention to the frequent co-occurrence of FPLD2 and AD-EDMD. In the future, all patients with AD-EDMD should be carefully evaluated for clinical signs of lipodystrophy and metabolic complications.