PURPOSE: This study aimed to investigate the relationship between metabolic indices and Polyendocrine Metabolic Ovarian Syndrome (PMOS) in normal-weight women and to evaluate their individual and combined discriminatory performance. PATIENTS AND METHODS: This retrospective case-control study included 86 normal-weight women (BMI <25 kg/m) with PMOS and 88 healthy controls. Electronic medical records were used to calculate the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Triglyceride-Glucose (TyG) index, Atherogenic Index of Plasma (AIP), and Metabolic Score for Insulin Resistance (METS-IR). Receiver operating characteristic (ROC) curve analysis was used to assess discriminatory performance, and optimal cut-off values were determined using the Youden index. Combined analyses were performed according to concordant classification of the component indices relative to their respective cut-off values. RESULTS: Fasting glucose, fasting insulin, triglyceride levels, HOMA-IR, TyG, AIP, and METS-IR were significantly higher in women with PMOS (p<0.05). Among individual indices, TyG showed the highest discriminatory performance (AUC=0.775; 95% CI: 0.706-0.843). HOMA-IR and AIP demonstrated moderate discriminatory performance, whereas METS-IR showed lower performance. Among the combined assessments, HOMA-IR and TyG yielded an AUC of 0.830 (95% CI: 0.747-0.913), with 80.8% sensitivity and 85.2% specificity. CONCLUSION: Metabolic indices, particularly TyG, may be useful for identifying metabolic abnormalities in normal-weight women with PMOS. Combined assessment of complementary metabolic indices may provide additional information for metabolic risk evaluation. These findings support further investigation of such indices as practical tools for metabolic assessment and risk stratification, rather than as independent diagnostic criteria for PMOS.

BACKGROUND: Suboptimal glycemic control remains a major challenge among adults with type 2 diabetes (T2D). Illness perceptions may influence diabetes self-management behaviors and glycemic control. PURPOSE: To evaluate the effects of a nurse-led diabetes perception intervention delivered via a mobile messaging platform (LINE) on glycemic control, illness perceptions, and patient satisfaction among adults with T2D and poorly controlled glucose. METHODS: A randomized controlled trial was conducted among 102 adults aged 30-59 years with T2D and poorly controlled glucose [HbA1c 7.5-9.0% or FPG ≥130 mg/dL]. Participants were randomly assigned to either a nurse-led diabetes perception intervention delivered via LINE plus standard care (n = 51) or standard care alone (n = 51). HbA1c, FPG, and patient satisfaction were assessed at baseline and week 13, and illness perceptions at baseline, week 6, and week 13. Data were analyzed using analysis of covariance and repeated-measures analysis of variance. RESULTS: Baseline characteristics were comparable between groups. At week 13, after adjustment for baseline values, the intervention group demonstrated significantly lower HbA1c (7.26% vs 7.91%; mean difference = -0.65%, 95% CI: -1.14 to -0.17; p = 0.008), FPG (123.12 vs 164.36 mg/dL; mean difference = -41.24 mg/dL, 95% CI: -57.37 to -25.11; p <0.001), and illness perception scores (31.90 vs 38.39; mean difference = -6.49, 95% CI: -9.58 to -3.40; p <0.001), together with higher patient satisfaction scores (63.90 vs 58.63; mean difference = 5.27, 95% CI: 2.38 to 8.17; p <0.001), compared with the control group. CONCLUSION: The nurse-led diabetes perception intervention delivered via LINE significantly improved glycemic control, illness perceptions, and patient satisfaction among adults with T2D and poorly controlled glucose. These findings support the potential integration of this accessible and feasible nursing intervention into diabetes self-management support in clinical practice.

Charcot-Marie-Tooth (CMT) disease is the collective term for the most common inherited peripheral neuropathies, affecting both motor and sensory nerves. A typical CMT patient presents with slowly progressive distal muscle weakness and atrophy that primarily involves the small foot muscles, peroneal muscles, and, often later, the muscles of the hands and forearms. Foot deformities, most commonly pes cavus and claw toes, are common and can lead to gait impairments. In this paper, we report a patient with an intermediate CMT (CMT-Int) type carrying a novel pathogenic variant in the gene combined with type 2 diabetes. The patient's initial symptoms included a gradual onset of muscle wasting, weakness, and sensory impairment in the lower limbs. Electrophysiological findings suggested widespread peripheral nerve damage affecting both sensory and motor fibers, with a predominant demyelinating pattern accompanied by axonal damage. Genetic testing identified a previously unreported heterozygous mutation in the gene, specifically c.548G > A, p.Trp183∗. This alteration results in the replacement of the 183rd amino acid (tryptophan) by a stop codon. This premature stop codon is predicted to escape nonsense-mediated mRNA decay, resulting in a C-terminally truncated protein that may exert a dominant-negative effect. Although a different variant affecting the same codon (c.549G > A, p.Trp183∗, VCV000917145.1) has been documented, this particular pathogenic mutation has not been previously recorded. After being diagnosed with CMT, the patient developed type 2 diabetes following pancreatic cyst surgery in September 2022. The presence of both conditions exposed her peripheral nerves to congenital structural abnormalities combined with the metabolic consequences of chronic hyperglycemia and local ischemia, thereby exacerbating nerve injury.

PURPOSE: To evaluate the effects of long-term use of symptomatic slow-acting drugs for osteoarthritis (SYSADOA), including glucosamine and diacerein, on glycemic control in patients with knee osteoarthritis (KOA) and type 2 diabetes mellitus (T2DM). METHODS: We conducted a retrospective cohort study of patients aged ≥ 40 years with KOA and T2DM. Participants were categorized into glucosamine, diacerein, and non-SYSADOA groups. Glycemic outcomes, including glycated hemoglobin (HbA1c) and fasting blood glucose (FBG), were assessed every three months over 24 months. Baseline covariables were collected to control for potential confounding factors, including sex, age, body mass index, baseline glycemic control (poor glycemic control defined as HbA1c > 7% or FBG > 130 mg/dL), number of antidiabetic drug classes, and the use of NSAIDs, opioid analgesics, lipid-lowering agents, and antihypertensive medications. Longitudinal changes were analyzed using multivariable multilevel Gaussian regression time-by-group interaction. RESULTS: A total of 409 patients were included in the FBG analysis and 304 in the HbA1c analysis. Baseline characteristics were generally comparable across treatment groups. Over the 24-month follow-up period, neither glucosamine nor diacerein was associated with significant changes in glycemic outcomes compared with non-SYSADOA use. Adjusted baseline differences in HbA1c were 0.06% (95% CI -0.15 to 0.28) for glucosamine and - 0.05% (95% CI -0.32 to 0.21) for diacerein. Corresponding adjusted differences in FBG were - 2.35 mg/dL (95% CI -8.35 to 3.66) and - 3.32 mg/dL (95% CI -11.20 to 4.55). CONCLUSION: SYSADOA use was not associated with clinically meaningful changes in glycemic control over 24 months in patients with KOA and T2DM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s40200-026-02069-1.

To report a rare case of endogenous endophthalmitis complicated by iris abscess formation secondary to a septic urinary tract infection and liver abscess. A single case was reviewed. A 57-year-old man with diabetes mellitus developed acute vision loss shortly after hospitalization for sepsis secondary to a urinary tract infection and liver abscess sensitive to cephalosporins. Ocular examination revealed hypopyon and severe intraocular inflammation. Initial treatment included intravitreal (IVT) vancomycin and ceftazidime with anterior chamber paracentesis. Intraocular cultures demonstrated newly acquired resistance to cephalosporins, prompting a switch to IVT moxifloxacin. Progressive inflammation necessitated pars plana vitrectomy and surgical debridement of an iris abscess. Postoperatively, weekly IVT moxifloxacin injections were administered for 3 weeks, resulting in resolution of infection. This case demonstrates rare iris abscess formation in endogenous endophthalmitis and underscores the importance of intraocular cultures in guiding targeted antimicrobial therapy.

BACKGROUND: The steadily increasing aging population highlights the importance of maintaining health at an advanced age. Metabolic diseases are among the most prevalent age-related disorders, and the Langerhans islets, critical regulators of glucose homeostasis, are particularly susceptible to disturbed insulin secretion and functional decline. Multiple stimuli contribute to islet dysfunction during aging, including bacterial products that increase with age and can activate Toll-like receptor (TLR) signaling. TLR2, which recognizes a broad spectrum of microbial ligands including components from Gram-positive bacteria, has been implicated in type 2 diabetes; however, its role in β-cell function during aging remains unclear. Accordingly, we hypothesize that TLR2 signaling contributes to inflammation and remodeling during aging in Langerhans islets. RESULTS: To determine the role of TLR2 in islet aging, we compared young and old male TLR2-deficient mice with age-matched C57BL/6J controls. Old TLR2 mice showed an altered ex vivo glucose-stimulated insulin secretory response, together with attenuated age-related islet hypertrophy and β-cell mass expansion. Immunohistochemical analysis further revealed that this was accompanied by decreased intra-islet immune cell accumulation, in particular macrophages, but also reduced fibrosis. In a complementary approach, 17-month-old C57BL/6J mice with elevated levels of TLR2 ligands were pharmacologically treated with the TLR2 inhibitor ortho-vanillin (60 mg/kg bodyweight) for four months. This intervention attenuated insulitis by reducing intra-islet leukocyte accumulation, particularly macrophage infiltration, and significantly reduced islet fibrosis, as indicated by decreased collagen and αSMA staining. Since mice at the investigated age-time points do not show metabolic impairments of glucose handling, these histological improvements were not yet reflected by improved glucose tolerance. CONCLUSIONS: Overall, our results suggest that TLR2 signaling contributes to immune cell accumulation and fibrotic remodeling during aging, linking inflammation to pancreatic islet aging in mice. These findings identify TLR2 as a potential mediator of age-related islet dysfunction and a candidate target for further investigation.

BACKGROUND: Metabolic bariatric surgery is the most effective treatment for obesity and related type 2 diabetes mellitus (T2DM), but T2DM remission post-surgery is heterogeneous. Existing prediction models were developed largely in Western populations, often for gastric bypass and short-term outcomes, limiting applicability to Chinese patients undergoing laparoscopic sleeve gastrectomy (LSG). We aimed to develop a preoperative model for predicting mid-term T2DM remission after LSG. METHODS: We performed a retrospective cohort study of Chinese patients with obesity and T2DM who underwent primary LSG between 2017 and 2023. Mid-term remission was assessed over 2-7 years of follow-up. Candidate preoperative variables were screened by univariate analysis and LASSO regression, followed by multivariable logistic regression and 2,000-bootstrap internal validation. The final model was simplified into a scoring system. RESULTS: Among 221 patients included (median baseline HbA1c 7.20%), 81.4% achieved T2DM remission at a mean follow-up of 3.60 ± 1.49 years, with median HbA1c decreasing to 5.60%. The final model retained three predictors: number of hypoglycemic agents, insulin use, and 2-hour plasma C-peptide, and showed strong discrimination (AUC 0.876). Bootstrap validation confirmed robust performance (mean AUC 0.878, 95% CI 0.809-0.935). The simplified score (2-hour plasma C-peptide-5 × number of hypoglycemic agents - insulin use score [11/0]) showed the same AUC, and higher scores indicated greater remission probability. CONCLUSIONS: We developed and internally validated a preoperative model for predicting mid-term T2DM remission after LSG in Chinese patients with obesity and T2DM. The model was translated into a simple scoring system that may support individualized management and decision-making.

BACKGROUND: Adolescent myopia has risen sharply, yet the role of metabolic dysregulation remains unclear. This cross-sectional study investigated the association between the Metabolic Score for Insulin Resistance (METS-IR) and myopia in adolescents, and tested whether the interaction with obesity reflects biological synergy. METHODS: Cross-sectional analysis of 3946 adolescents aged 12-19 years from NHANES with complementary analysis in an independent clinical cohort of 561 East Chinese adolescents. Myopia was defined as spherical equivalent ≤ -0.5 diopters. Multivariable logistic regression, subgroup analyses, restricted cubic spline analyses, and sensitivity analyses were performed to assess the association, identify effect modifiers, characterize dose-response relationships, and evaluate the interaction. RESULTS: In NHANES, myopic adolescents had significantly higher METS-IR levels than non-myopes (32.1 vs. 31.3, P = 0.024). After full adjustment, high METS-IR (>31.84) was associated with 17% greater odds of myopia (OR = 1.17, 95% CI: 1.03-1.34), with a linear dose-response relationship and a myopia-specific exploratory reference point of 31.67. The association was significantly stronger in adolescents with obesity (P for interaction = 0.039). Sensitivity analyses using individual METS-IR components and the BMI-independent triglyceride-glucose index confirmed that the amplification of risk by obesity represents a statistical interaction consistent with biological synergy. In the independent cohort, the association remained significant after adjusting for parental myopia (OR = 1.13, 95% CI: 1.02-1.26). CONCLUSION: Higher METS-IR is independently associated with increased myopia risk in adolescents, particularly in those with obesity, and highlights METS-IR as a practical metabolic marker for risk stratification that may help guide nutritional and lifestyle interventions.

BACKGROUND: Simultaneous pancreas-kidney transplantation (SPK) with enteric drainage is the preferred treatment for selected patients with type 1 diabetes mellitus and end-stage renal disease. Despite its benefits, pancreas transplantation remains associated with the highest rate of surgical complications among solid organ transplants. Gastrointestinal bleeding originating from the donor-recipient enteric anastomosis is an uncommon but potentially life-threatening complication. Conventional management options include endoscopic therapy, interventional radiology embolization, and surgical revision; however, altered postoperative anatomy may limit endoscopic access, embolization carries a risk of bowel ischemia, and surgical revision may increase morbidity and jeopardize graft integrity. CASE PRESENTATION: We describe 2 patients who developed severe gastrointestinal bleeding from the donor-recipient enteric anastomosis following SPK. Both patients underwent exploratory laparotomy with creation of a targeted enterotomy, allowing direct intraoperative endoscopic access to the bleeding site. Hemostasis was successfully achieved using endoscopic clips while preserving the existing duodenojejunostomy. No recurrent bleeding, anastomotic complications, or graft-related adverse events occurred. At 8 and 4 years of follow-up, respectively, both pancreatic and renal grafts remained functional without transplant-related rehospitalizations. CONCLUSION: A hybrid surgical-endoscopic approach may represent a feasible rescue strategy for selected patients with persistent enteric anastomotic bleeding after SPK. This technique allows precise hemostatic control while preserving the enteric reconstruction and avoiding the potential morbidity associated with embolization or formal surgical revision. Further experience is needed to define its role relative to alternative treatment strategies.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) affects hundreds of millions of people worldwide. Self-management education is a cornerstone of diabetes care. Digital technology-based interventions have demonstrated short-term benefits; however, their medium-term to long-term effects remain unclear. METHODS AND ANALYSES: We will systematically search seven databases (PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure [CNKI], the China Biomedical Literature Database [CBM], Wanfang and the China Science Journal Database [VIP]) and three clinical trial registries (ClinicalTrials.gov, Chinese Clinical Trial Registry [ChiCTR] and WHO International Clinical Trials Registry Platform [ICTRP]) from inception to March 2026. We will include randomised controlled trials that provide diabetes self-management education via digital technologies, such as mobile applications, websites, text messaging, remote monitoring or computer programmes. Interventions may be fully digital or hybrid, provided that digital technology is the core delivery method. Eligible studies will involve adults with T2DM or studies in which at least 80% of the participants have T2DM, with a minimum follow-up of 12 months. Primary outcomes will be mortality, diabetes-related complications, hospitalisations, severe hypoglycaemia, quality of life and glycated haemoglobin. Secondary outcomes include fasting plasma glucose, lipids, blood pressure, anthropometric measures and patient-reported outcomes such as self-management behaviours and diabetes distress. Two reviewers will independently screen studies, extract data and assess the risk of bias using the Cochrane Risk of Bias 2 (RoB 2) tool. Where data are sufficient and studies are adequately comparable in terms of participants, interventions, comparators, outcomes and study design, we will perform meta-analyses using Cochrane Review Manager (RevMan) V.5.3 and Stata V.19.0. Heterogeneity will be explored through subgroup analyses and meta-regression. The certainty of evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: As this study will synthesise the published data, ethical approval is not required. PROSPERO REGISTRATION NUMBER: CRD420251135023.

BACKGROUND: Type 2 diabetes (T2DM) and cognitive impairment are common long-term chronic conditions affecting older people in hospital. Cognitive impairment can complicate glucose monitoring and lead to diabetes-related emergencies in T2DM. Traditionally, point of care test measurements of capillary blood glucose are conducted in-hospital for T2DM while continuous glucose monitoring (CGM) is not widely used. AIM: To understand the feasibility, acceptability and tolerability of using CGM in older inpatients with T2DM and cognitive impairment. METHODS: 32 older people (mean age=78.7±6.7 years) with comorbid T2DM and cognitive impairment (Abbreviated Mini-Mental Test ≤8/10 and Mini-Addenbrooke's Cognitive Examination ≤22/30) were recruited within a tertiary care hospital in the UK. All participants were naive to CGM and were asked to wear blinded Dexcom G7 sensors for up to 10 days. Participants were asked about feasibility, acceptability and tolerability questions at the point of sensor removal. RESULTS: 29 participants (96%) reported no pain during CGM fitting. All participants (100%) agreed that they did not notice wearing the sensor, and it did not affect their day-to-day hospital activities. All participants (100%) found it 'very easy' or 'easy' to have the sensor fitted and wearing it for 10 days, with 27 participants (90%) finding CGM convenient. 17 participants (57%) reported favourable perceptions of the subcutaneous sensor sensation. CONCLUSION: CGM use in older inpatients with T2DM and cognitive impairment is highly feasible and acceptable for patients. Future studies and trials are now needed to evaluate the clinical use of CGM for glucose monitoring in hospitalised or community-dwelling older individuals with T2DM and cognitive impairment.

INTRODUCTION: Life expectancy for people with type 1 diabetes has increased due to improved treatment of diabetes and its comorbidities, allowing many to reach old age. Still, we lack knowledge of how individuals with type 1 diabetes age. On one hand, those who reach older age can be considered survivors, but on the other hand their long-standing diabetes might still exhibit negative impacts on their health and functional ability. Healthy ageing is the WHO's priority for this decade. The focus has shifted from chronological age to functional ability, which reflects the ability of individuals to perform meaningful activities. Functional ability is shaped by intrinsic capacity, the environment and their interaction. Intrinsic capacity encompasses five main domains: cognition, vitality, sensory function, locomotion and psychological domain. This observational study aims to assess how this vulnerable group of individuals with type 1 diabetes age and to identify factors that contribute to their healthy ageing, intrinsic capacity and its domains. METHODS AND ANALYSIS: The FinnDiane LifeOne Study is a prospective observational cohort study. We aim to recruit a minimum of 300 individuals with type 1 diabetes from the FinnDiane Study, aged >65 and a minimum of 100 matched controls without insulin-dependent diabetes. The cohort will be comprehensively characterised, including clinical assessment, laboratory tests, questionnaires and a geriatric assessment of different aspects of functioning ability, with 5 years intervals. We will compare the individuals with type 1 diabetes to their matched controls. For those with type 1 diabetes, we will further assess which factors from the FinnDiane baseline and trajectories during follow-up predict healthy ageing in above 65-year-olds. ETHICS AND DISSEMINATION: The LifeOne Study protocol is approved by the Ethics Committee of HUS Helsinki University Hospital (HUS/4387/2023) and the study adheres to the Declaration of Helsinki. Written informed consent is obtained from each participant. Findings will be published in international peer-reviewed journals with an open access choice. TRIAL REGISTRATION NUMBER: NCT07289204.

BACKGROUND: Little is known about venous thromboembolism (VTE) and arterial thromboembolism (ATE) risk in melanoma patients receiving immune checkpoint inhibitors (ICI), compared to other therapies. OBJECTIVES: We assessed incidence, risk factors, and impact on survival of thromboembolism (TE) in patients receiving ICI, chemotherapy, or targeted therapy. METHODS: We conducted a cohort study using SEER-Medicare to evaluate TE rates in patients treated 2008-2019 with ICI, chemotherapy, or BRAF/MEK inhibitors within two years after treatment initiation. Associations between TE, treatment, and clinical risk factors were evaluated using weighted competing risk regression (CRR). Overall survival was estimated by Kaplan-Meier and Cox regression models. RESULTS: Among 6,218 patients, 62.1% (3,860) received first line ICI, 30.4% (1,890) chemotherapy, and 7.5% (468) targeted therapy. Cumulative incidence of VTE was similar among all treatment types: 7.7% for ICI, 8.4% for chemo, and 7.4% for targeted therapy at 12 months (p=0.80). Similarly, ATE rates were 5.3% for ICI, 5.0% for chemo, and 6.5% for targeted therapy at 12 months (p=0.30). History of VTE (SHR: 2.81; [95%CI: 2.19-3.61]) and brain metastases (SHR: 1.33 [1.06-1.66]) were associated with increased risk of VTE. When compared to chemotherapy, ICI and targeted therapy had similar VTE risk (p>0.05). For ATE, cardiovascular disease (SHR: 1.49 [1.14-1.93]), diabetes mellitus (SHR: 1.27 [1.04-1.57]), history of ATE (SHR: 1.61 [1.13-2.29]), and antiplatelet therapy (SHR: 1.37 [1.03-1.83]) were associated with increased risk. Patients with VTE or ATE experienced two-fold worse survival (HR: 2.17 [1.64-2.87] and HR: 2.58 [1.92-3.47], respectively). In ICI sub-analysis, combination ipilimumab/nivolumab had higher cumulative incidence of VTE: 11.9% at 12 months, 9.3% for ipilimumab, 7.5% for pembrolizumab, and 5.8% for nivolumab (p<0.05). When compared to nivolumab, combination ipilimumab/nivolumab (SHR: 1.66 [1.09-2.54]) and ipilimumab (SHR: 1.43 [1.03-2.00]) had greater VTE risk. VTE and ATE were associated with worse survival (HR: 3.24 [2.30-4.58] and HR: 1.89 [1.20-2.99], respectively). CONCLUSIONS: ICI, chemotherapy, and targeted therapy are associated with a high incidence of TE; TE is associated with substantial worsening of survival.

Cardiovascular-kidney-metabolic (CKM) stage 4 is an advanced systemic disorder with disproportionately high risks for adverse clinical outcomes, underscoring the need for accessible screening tools like estimated pulse wave velocity (ePWV) to predict its onset. To investigate the longitudinal association between baseline ePWV and incident CKM stage 4, this study analyzed harmonized data from 22,530 participants across three large-scale prospective aging cohorts-the US Health and Retirement Study (HRS), the English Longitudinal Study of Ageing (ELSA), and the China Health and Retirement Longitudinal Study (CHARLS)-using Kaplan-Meier survival curves, Cox proportional hazards regression models, and restricted cubic splines. The survival analysis revealed that higher baseline ePWV quartiles were significantly associated with a progressively lower probability of remaining CKM4-free across all three cohorts (p < 0.001). Furthermore, fully adjusted multivariable models confirmed that continuous ePWV is an independent, significant predictor of incident CKM4 (HRS: HR 1.373; ELSA: HR 1.397; CHARLS: HR 1.288; all p < 0.001), demonstrating a continuous, positive dose-response relationship, although this predictive association lost statistical significance among participants with pre-existing diabetes mellitus. Ultimately, elevated baseline ePWV independently and consistently predicts the risk of progressing to CKM stage 4 across diverse global populations, supporting its utility as a cost-effective, non-invasive screening tool to identify high-risk individuals for early clinical intervention.

Chronic inflammation is a hallmark of obesity and its associated metabolic disorders. Adipose tissue macrophages (ATMs) play a crucial role in maintaining tissue homeostasis and orchestrating metabolic inflammation. Importantly, the regulation of proinflammatory gene translation is critical for macrophage activation, a process that has been closely linked to the onset of insulin resistance and type 2 diabetes. Histone deacetylase 3 (HDAC3) is a contributing factor of inflammatory gene expression; however, its precise role in modulating adipose tissue inflammation and type 2 diabetes remains poorly understood. This study demonstrates that metabolically stressed-induced HDAC3 mediates ATMs inflammation. HDAC3 deficiency in macrophages reduces adipose tissue macrophage infiltration and fibrosis, improves hyperglycemia, and reduced weight gain, adiposity in diet-induced obesity mice. HDAC3 deficiency mitigated the chronic inflammation and fibrosis in adipose tissue by suppressing inflammatory cytokine production via H3K4Me3/H3K27Ac-mediated chromatin remodeling. Mechanistically, growth differentiation factor 3 (GDF3) functions as a sensor of metabolic stress, interacts with HDAC3 through histone modification-mediated chromatin remodeling of inflammation genes. Critically, HDAC3 and GDF3 co-expression increased in adipose tissue/ATMs of obese humans, correlating positively with BMI, blood glucose, and proinflammatory gene levels. Our finding identifies HDAC3 as a molecular nexus connecting ATMs activation to systemic insulin resistance and type 2 diabetes. The GDF3-HDAC3 axis drives transcriptional reprogramming through H3K4Me3/H3K27Ac modifications, revealing a novel therapeutic target for obesity-associated metabolic disease.

BACKGROUND: Treatment with dipeptidyl peptidase-4 inhibitors (DPP-4i) is a strong risk factor for developing bullous pemphigoid, a dermatological disorder that is itself strongly associated with multiple sclerosis (MS). We therefore hypothesized that DPP-4i would also increase the risk of MS. OBJECTIVE: To investigate whether prior use of DPP-4i is associated with incident MS. METHODS: This nationwide register-based matched case-control study included individuals with incident MS identified by date of diagnosis (index date) in the Danish Multiple Sclerosis Registry between 2008 and 2023 matched 1:10 with population controls based on year of birth, gender, place of residence, and index date. Exposure was classified as a three-level mutually exclusive variable based on redeemed prescriptions at any time before the index date: any DPP-4i use, other type 2 diabetes medication use, or non-use. Conditional logistic regression was used to estimate odds ratios with 95% confidence intervals. RESULTS: A total of 9063 incident cases of MS and 90,630 controls were identified. The mean age at the index date was 41.36 years for patients with MS and 41.48 years for controls. Prior DPP-4i exposure was observed in 27 MS cases (0.30%) and 405 controls (0.45%), corresponding to an odds ratio of 0.67 (95% CI, 0.45-0.99) versus non-use. Other type 2 diabetes medication use was observed in 274 MS cases (3.02%) and 2474 controls (2.73%), corresponding to an odds ratio of 1.11 (95% CI, 0.98-1.26) versus non-use. CONCLUSION: DPP-4i use was not associated with an increased risk of MS and may be protective.

OBJECTIVES: This case series describes the clinical presentation and longitudinal course of four adolescents with genetically confirmed -associated congenital generalized lipodystrophy (CGL) followed at a pediatric lipodystrophy center. CASE PRESENTATION: Despite shared phenotypic features - including generalized lipoatrophy, muscular hypertrophy, acromegaloid features, and hyperphagia - metabolic severity varied markedly, even between siblings carrying the same homozygous variant. All three female patients experienced rapid metabolic deterioration during puberty, developing insulin resistance, diabetes, and severe hypertriglyceridemia, while the male patient remained relatively metabolically stable. Three patients developed progressive albuminuria during adolescence, and two required ACE inhibitor therapy for hypertension, highlighting early renal involvement independent of diabetes. Metreleptin therapy led to substantial metabolic improvement in all treated patients, with normalization of glycemic control, triglyceride levels, and liver enzymes, as well as reduced hyperphagia and, in one case, spontaneous menarche. However, metabolic decompensation occurred during acute illness in one patient, necessitating treatment escalation, indicating that metreleptin does not fully protect against metabolic stress. Notably, pronounced daytime fatigue persisted in three patients despite metabolic stabilization, suggesting an underrecognized, potentially central component of the disease. CONCLUSIONS: These findings underscore the phenotypic variability of -associated CGL, the critical impact of puberty - especially in females - the frequent early onset of nephropathy, and the partial but incomplete response to leptin replacement. Close monitoring during adolescence and individualized management are essential.

INTRODUCTION: Explore association between a weighted social determinants of health (SDOH) score and incident dementia in adults with and without type 2 diabetes (T2D). METHODS: Among 10,071 UK Biobank adults with T2D and 11,780 euglycemic individuals, SDOH indicators were weighted using elastic net and categorized as favorable, medium, or unfavorable. Sex- and T2D-stratified associations with incident dementia were estimated using multivariable Cox models and validated in All of Us. RESULTS: Over 14 years of follow-up in UKB, 247 T2D and 149 euglycemic participants developed dementia. In T2D, higher SDOH score was significantly associated with increased risk of all-cause dementia. Comparing unfavorable vs. favorable SDOH, hazard ratios (HRs) were 2.4 (95% CI: 1.7-3.6) overall, 1.7 (1.1-2.6) in men, and 5.4 (2.0-13.9) in women (interaction p 0.009). In euglycemic, corresponding HRs were 2.4 (1.4-3.8) overall, 2.4 (1.3-4.3) in men, 2.9 (0.9-8.9) in women. Stratified by SDOH category, T2D (vs. euglycemia) was significantly associated with higher dementia risk in the unfavorable/medium SDOH group: 2.9 (1.8-4.6) in all,1.7 (0.8-3.6) in men, and 3.1 (1.1-8.7) in women. CONCLUSIONS: Adverse SDOH was associated with higher dementia risk, with stronger T2D-related risk among medium/unfavorable SDOH groups, especially in women with T2D.

The Diabetes Prevention Program (DPP) is a Center for Disease Control and Prevention (CDC) endorsed lifestyle intervention aimed at preventing Type-2 Diabetes Mellitus. Despite demonstrated effectiveness, DPP implementation remains limited outside clinical settings, often due to funding challenges, difficulties obtaining CDC recognition and limited reimbursement, especially for programs serving minority populations. This analysis estimated start-up and protocol costs of a culturally-tailored DPP and a standard CDC protocol, using Activity-Based Costing methodology. Both the standard CDC DPP and a culturally-tailored DPP protocol were developed by defining all program components, activities, personnel involved and time associated with all activities. Start-up costs were estimated utilizing data on standard start-up activities from two sites prior to launching the tailored DPP. Protocol and start-up costs were calculated by multiplying the wage for varying personnel by the time allocated to each defined start-up and protocol activity, costs are presented in 2025 USD. National average wage data were extracted from the Bureau of Labor Statistics O*Net database. Start-up costs totaled $87,886, with a cost per planned participant of $1,465. Implementing the standard CDC DPP protocol cost $10,573 in total, or $705 per participant. The culturally tailored protocol cost $23,849, or $1,590 per participant. This analysis is one of the first to estimate of start-up costs of a tailored DPP, and compare implementation costs for the culturally-tailored DPP with a standard CDC protocol. Understanding these costs is essential for organizations planning to implement DPP, especially in community settings. The findings offer insight into the necessary investments for a sustainable and culturally-tailored DPP.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a prevalent condition affecting 25-30% of the global population and is closely linked to obesity, type 2 diabetes, and other cardiometabolic risk factors. Although liver biopsy remains the gold standard for diagnosis, its invasive nature has prompted a shift toward non-invasive biomarkers for disease assessment, staging, and monitoring. Multiple non-invasive biomarkers have been studied or are currently under investigation to assess both fibrosis and steatosis among patients with MASLD. This review aims to summarize the current literature on emerging and established biomarkers for MASLD, focusing on their roles in detecting inflammation, fibrosis, metabolic dysfunction, and steatosis, including imaging-based surrogate endpoints and composite biomarker panels.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes and obesity, but their effects on musculoskeletal health remain completely misunderstood. OBJECTIVE: This systematic review/meta-analysis aims to synthesise clinical data on the effects of GLP-1 RAs on key relevant bone, muscle, and joint outcomes. METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) (both via Ovid platform) and Embase were searched from inception to March 2025 to identify relevant randomised controlled trials (RCTs) or real-world evidence (RWE) studies to be included. This bibliographic search was completed manually. A random-effect model meta-analysis was performed for any outcome reported in at least 2 studies. Subgroup analyses were performed on the type of GLP-1 RAs, type of comparator used and study design. Sensitivity analyses (i.e., leave-out sensitivity analyses and analyses restricted to the most adjusted effect estimate) were performed to test the robustness of the data. The strength of evidence was assessed using GRADE. This work has been performed in adherence with PRISMA statement. (PROSPERO Record ID: CRD420251024082). RESULTS: From 1148 potentially relevant references, 60 articles (46 RCTs, 13 RWE studies and 1 pharmacovigilance study, comprising 1,250,717 individuals) met our inclusion criteria. Different GLP-1 RAs were represented across the panel of studies, i.e., semaglutide, liraglutide, exenatide, dulaglutide, tirzepatide (dual agonist gastric inhibitory polypeptide [GIP]/GLP-1) and others. No effect on bone outcomes (i.e., bone mineral density [all sites] and fractures [all sites]) were observed when the meta-analytical models included the most adjusted effect size. Regarding muscle outcomes, a significant decrease of lean body mass/fat-free mass was consistently observed with GLP-1 RAs in the global model (k = 28, standardised mean difference [SMD] 0.52, 95% confidence interval [CI] -0.8; -0.23, I 88%, p-value for heterogeneity <0.0001), which remained robust in all sensitivity analyses. Subgroup analyses showed that the effect was mainly driven by liraglutide and semaglutide, with a decrease in lean body mass/fat-free mass observed when GLP-1 RAs were compared with placebo. No publication bias was found. Regarding joint outcome, models revealed no significant change in The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function and stiffness. CONCLUSIONS: This meta-analysis is the first to investigate the effects of GLP-1 RAs on a large panel of musculoskeletal health outcomes. While no significant effects were observed on bone- or joint-related outcomes, GLP-1 RAs were associated with reductions in lean body mass/fat-free mass, although the certainty of evidence was low and these changes appeared largely related to weight loss. Whether these changes translate into clinically meaningful impairments in muscle function or physical performance remains uncertain. Further studies in this field, including those looking at muscle function, strength or performance and using multivariate models considering confounding are needed to better reinforce the models and final findings.

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious chronic microvascular complications of diabetes. Animal and clinical studies on the renoprotective effects of metformin have reported inconsistent results. OBJECTIVE: This study investigated the relationship between long-term metformin use and DN risk in patients with type 2 diabetes mellitus (T2DM), to determine whether this relationship exhibits a dose-dependent pattern. METHODS: This was a retrospective cohort study using data from a nationally representative database in Taiwan. Patients given a diagnosis of new-onset T2DM between 2002 and 2013 were divided into 2 groups: metformin and sulfonylurea treatment. We evaluated DN risk after a 5-year follow-up period. Using the Cox proportional hazard model, we estimated DN risk in correlation with the cumulative defined daily dose (cDDDs) of metformin, with adjustment for sex, age, income, urbanization level, diabetes severity, and various comorbidities. RESULTS: In the metformin-treated group, the DN incidence rates were 7.02%, 8.09%, 9.24%, and 10.75% for metformin administered at cDDDs of < 3 0, 30 to 120, 120 to 240, and > 240, respectively. After adjustments for relevant variables, relative to sulfonylurea-treated patients, patients who received metformin at cDDDs of < 30, 30 to 120, 120 to 240, and > 240 exhibited adjusted hazard ratios (95% CIs) for DN of 1.06 (1.03-1.09), 1.24 (1.21-1.27), 1.45 (1.41-1.49), and 1.72 (1.65-1.80), respectively. CONCLUSIONS: In patients with T2DM, metformin treatment exhibited a dose-dependent relationship with an increased DN risk after 5 years of follow-up. Further large-scale prospective studies are warranted to confirm these findings and elucidate the biological mechanisms underlying this observed association.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as foundational therapies across the cardio-kidney-metabolic (CKM) syndrome. Initially developed as glucose-lowering agents for type 2 diabetes mellitus (T2DM), these medications demonstrated substantial cardiovascular and renal benefits in large cardiovascular outcomes trials, fundamentally changing the management of heart failure (HF), chronic kidney disease (CKD), and T2DM. Early landmark trials, including EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and VERTIS CV, established reductions in hospitalization for heart failure (HHF) and favorable renal outcomes in patients with T2DM, with more selective effects on atherosclerotic cardiovascular disease outcomes. Subsequent dedicated HF trials demonstrated that SGLT2 inhibitors provide clinically meaningful benefit across the left ventricular ejection fraction spectrum. In patients with heart failure with reduced ejection fraction (HFrEF), DAPA-HF and EMPEROR-Reduced showed significant reductions in worsening HF and cardiovascular death regardless of diabetes status. Similar benefits were later demonstrated in heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) in EMPEROR-Preserved and DELIVER, establishing SGLT2 inhibitors as among the first therapy classes to consistently reduce HF events across the HF spectrum. Dedicated CKD trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, further showed substantial slowing of kidney disease progression and reduction in cardiorenal outcomes, both in patients with and without T2DM. Despite robust evidence and incorporation into major international guidelines, uptake of these therapies in clinical practice remains suboptimal. Increased implementation of these therapies in routine clinical practice is essential to improve outcomes across the CKM spectrum.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed as glucose-lowering agents but have emerged as cardiorenal therapies in people with and without diabetes. Their primary pharmacological action is restricted to the proximal renal tubule, where inhibition of SGLT2 reduces glucose and sodium reabsorption and induces sustained glycosuria. This chapter examines the physiological cascade linking this renal effect to systemic metabolic, hemodynamic, and cardiorenal consequences. In both diabetic and non-diabetic individuals, SGLT2 inhibition lowers the renal threshold for glucose excretion, increases distal sodium delivery, and transiently promotes osmotic diuresis and natriuresis. Downstream SGLT1 partially compensates for reduced proximal glucose reabsorption, limiting urinary glucose losses despite SGLT2 blockade.The resulting fall in plasma glucose and insulin shifts substrate utilization from carbohydrate toward fatty acids and ketone bodies, while uricosuria lowers serum uric acid. Over longer periods, changes include modest reductions in plasma volume and blood pressure, mobilization of tissue sodium, increased hematocrit and hemoglobin, altered renal oxygenation, and an initial decline followed by slower long-term loss of glomerular filtration rate. These effects interact across renal, metabolic, and hemodynamic pathways. Glycosuria also creates a chronic negative energy balance, although compensatory hyperphagia limits the degree of weight loss. Secondary consequences include modulation of intrarenal hemodynamics, endogenous glucose production, circulating substrates, vascular function, oxygen delivery, and established cardiorenal risk factors. Evidence from physiological studies and large clinical trials supports glycosuria as the initiating event from which multiple downstream effects arise. No single mechanism fully explains the long-term cardiovascular and renal benefits of SGLT2 inhibition. Rather, repeated, substantial glycosuria appears to induce a coordinated transition to a distinct physiological state in which several individually modest renal, metabolic, and hemodynamic adaptations converge to produce cardiorenal protection. This integrated model may better explain why clinical benefits extend beyond glucose lowering and are observed across populations, including individuals without diabetes.