Imbalance of the gut microbiota is an important trigger for insulin resistance in type 2 diabetes mellitus(T2DM). Microbiota-targeted therapies have gradually become an emerging research direction for treating T2DM. However, exogenous strain interventions (supplementing probiotics and fecal microbiota transplantation), endogenous optimization of the gut microbiota (supplementing prebiotics, synbiotics, and postbiotics), and phage therapy focus on "directly introducing microorganisms," "feeding microorganisms," or "directly utilizing microbial components." These approaches cannot cover active substances that target the host as the core and regulate the intestinal microenvironment in a non-nutritional manner, presenting conceptual limitations. In this context, this paper proposes the concept of "Envbiotics, " defined as substances that target the host as the core, optimize the intestinal microenvironment through their own or host metabolites, and directly or indirectly regulate the structure and function of the microbiota in a non-nutritional manner, thereby improving host metabolism and health. Typical evidence, including berberine, urolithin A, plant exosomes, and special targeted delivery technologies, is used to elucidate its mechanism of action. Envbiotics not only fill the gaps in the existing classification system but also provide novel insights for the development of new drugs targeting microbial intervention in T2DM.

Traditional Chinese Medicine constitutes a chemically diverse and pharmacologically rich reservoir of bioactive compounds, often exhibiting multi-target pharmacological properties that are potentially valuable for complex metabolic disorders such as type 2 diabetes mellitus (T2DM). However, systematic prioritization of active and safe constituents remains challenging, as therapeutic efficacy must be optimized concurrently with toxicity risk. Here, we present a safety-aware Multi-Task Graph Attention Network (SM-GAT) framework that jointly models anti-diabetic efficacy and toxicity liabilities of TCM-derived compounds within a unified architecture. Four tasks are simultaneously optimized: inhibition of dipeptidyl peptidase-4 (DPP4), inhibition of α-glucosidase, acute oral toxicity, and clinically relevant toxicity. By enabling shared molecular representation learning across heterogeneous yet biologically related endpoints, SM-GAT facilitates knowledge transfer between efficacy and safety domains. Across all prediction tasks, SM-GAT achieved competitive or superior performance compared with single-task graph neural networks and other baseline models, achieving ROC-AUC values up to 0.892 for α-glucosidase inhibition. Notably, multi-task learning yields pronounced improvements in data-limited settings, highlighting effective cross-task regularization. Large-scale virtual screening of the TCMBank library demonstrates practical applicability, enabling efficient prioritization of structurally diverse candidates with favorable predicted efficacy-safety balance. Several structurally diverse lead compounds, including ellagic acid derivatives, are identified with favorable predicted efficacy-safety balance. Furthermore, atom-level attention analysis highlighted chemically interpretable substructures associated with predicted efficacy and toxicity-related molecular representations. Collectively, this study establishes an interpretable multi-objective framework for safety-aware lead discovery, providing a computational framework for integrating traditional botanical resources into anti-diabetic lead discovery.

To investigate the distribution of PON1 Q192R and L55M polymorphisms and serum PON1 concentration in Saudi patients with T2DM and to evaluate their associations with biochemical parameters and diabetes-related complications.

In this case-control study, 220 patients with T2DM and 120 healthy controls were enrolled from several hospitals in Madinah, KSA, from May 1, 2025 to December 15, 2025. Clinical and biochemical assessments included fasting plasma glucose (FPG), HbA1c, lipid profile, apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB). PON1 Q192R and L55M genotypes were determined using PCR-RFLP, and serum PON1 concentration was measured by ELISA. Associations between genotypes, PON1 levels, metabolic indices, and diabetic complications were analyzed.

Serum PON1 levels were significantly lower in patients with T2DM compared with controls (p < 0.001). The genotype and allele frequencies of PON1 Q192R and L55M polymorphisms did not differ significantly between groups (p=0.18); Q192R allele: (p=0.21); L55M genotype: (p=0.58); L55M allele: (p=0.43). While neither polymorphism was associated with T2DM susceptibility, the Q192R variant was significantly associated with cardiovascular disease among patients with T2DM (p = 0.04). Both polymorphisms were significantly associated with serum PON1 concentration and glycemic indices (FPG and HbA1c; p < 0.05), whereas no significant associations were observed with BMI or lipid parameters.

In Saudi patients with T2DM, PON1 levels are notably lower, indicating reduced antioxidant defense. Although certain genetic polymorphisms of PON1 do not affect diabetes susceptibility, the Q192R variant may increase cardiovascular risks in T2DM, suggesting its role as a biomarker for cardiometabolic risk rather than disease development.

Polycystic ovarian syndrome (PCOS) is by far the most prevalent metabolic disease affecting women during their reproductive life. Obesity is a frequently associated manifestation of polycystic ovary syndrome. Central body fat accumulation has been associated with the production of a variety of cytokines associated with low-grade inflammation in polycystic ovary syndrome. This study aimed to evaluate the effect of metformin and cabergoline, each alone and in combination, on several immune markers in women with hyperprolactinemia. The three-arm interventional study included 75 women with PCOS according to the Rotterdam criteria. They were categorized into three groups: those given metformin alone, those given cabergoline alone, and those given combined agents. Baseline and follow-up characteristics included immune markers such as anti-glutamic acid decarboxylase (anti-GAD) antibodies, gonadotropin-releasing hormone (GnRH) antibodies, and interleukin-18 (IL-18). It was observed that the use of either drug alone resulted in no significant change in the level of anti-GAD; however, combined use of the two drugs resulted in a significant reduction in the level, indicating that these two drugs acted synergistically. It was observed that the combined use of either drug resulted in a more significant reduction of GnRH antibody level. It was observed that the combined use of either drug resulted in a more significant reduction of IL-18 level (P <0.001). Metformin and cabergoline are efficient, act synergistically, and are safe when used in combination, reducing IL-8 levels and autoantibodies to GAD and GnRH in women with PCOS.

To analyze the relationship between CTLA-4 (+49A/G) polymorphism and pediatric type 1 diabetes mellitus (T1DM).

The observational case-control study was done for 18 months in 44 children (1-16 years of age), 22 of whom had T1DM and 22 controls, were included. CTLA-4 (+49A/G) gene polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism and validated by Sanger sequencing. Various clinical, anthropometric, and biochemistry variables were documented.

The cases and controls were similar in terms of age, gender distribution, family history of diabetes, and consanguinity. The average hemoglobin A1c values were higher in case groups compared to controls (12.41% ±3.09% vs. 4.21 ± 0.5%; P < 0.001). The CTLA4 (+49A/G) gene showed higher frequencies of the G/G genotype in cases compared to controls (54.55% vs. 22.73%; P = 0.030), whereas A/A was found to be higher in controls (P = 0.014). The frequency of the G allele in cases (0.66) was higher than in controls (0.32). The G/G genotype showed higher prevalence in the case group at a younger age, and siblings of offspring showed clustering of the G/G genotype.

In particular, the G/G genotype of the CTLA-4 + 49A/G polymorphism was found to be significantly associated with T1DM in children and to influence the age of onset.

We report a 20-year-old female who presented with acute abdominal pain and vomiting, with a background of diabetes mellitus and severe hypertriglyceridemia since the age of 16 years. Clinical examination revealed a marked paucity of subcutaneous adipose tissue throughout the body. Laboratory investigations confirmed severe insulin resistance with HbA1c (glycated hemoglobin) of 8.5%, massive hypertriglyceridemia (1257 mg/dL), and preserved C-peptide levels (3.75 ng/mL). The clinical phenotype and biochemical profile suggested a diagnosis of congenital lipodystrophy, though genetic confirmation was not feasible due to financial constraints. Congenital lipodystrophy is characterized by ectopic fat accumulation in the liver, muscles, and pancreas, with resultant severe insulin resistance and metabolic complications. Management with dual PPAR agonist therapy (saroglitazar), omega-3 fatty acids (icosapent ethyl), thiazolidinediones (pioglitazone-metformin combination), and basal insulin resulted in significant improvement in lipid and glycemic parameters on subsequent follow-ups.

In this review, we cover the discovery of hybrid insulin peptides (HIPs) as antigens for CD4 T cells involved in pathogenesis and regulation of autoimmune diabetes. HIPs represent a unique posttranslational modification in autoimmunity and consist of peptide sequences from two beta-cell proteins, one being proinsulin, covalently joined to form new nongenomic peptides. Using the nonobese diabetic (NOD) mouse model, we showed that HIPs are target antigens for a panel of diabetogenic CD4 T-cell clones. The prototype clone of this panel is BDC-2.5, and the first HIP identified was the peptide ligand for BDC-2.5, the 2.5HIP, consisting of an insulin C-peptide fragment combined with a natural cleavage product of chromogranin A. T cells with different TCRs, all specific for the 2.5HIP, were shown to be a dominant population among the T cells infiltrating the islets of NOD mice. T cells reactive to HIPs are significantly elevated in the PBMC of newly diagnosed patients with type 1 diabetes (T1D) and in at-risk subjects, an important finding from a clinical standpoint. When coupled to biodegradable nanoparticles (NPs), HIPs can serve as epitopes to induce antigen-specific tolerance. 2.5HIP NPs not only prevent transfer of disease by BDC-2.5 T cells but also prolong islet graft survival in diabetic NOD mice. Investigation of the mechanisms underlying 2.5HIP NP-induced tolerance revealed that protection occurs through an IL-10-dependent process in which regulatory T cells in the graft tissue are increased, limiting dendritic cell licensing and the subsequent terminal differentiation of both CD4 and CD8 islet-specific T cells.

Type 1 diabetes is characterized by autoimmune destruction of pancreatic β-cells, resulting in insulin deficiency and impaired blood glucose regulation. Cell encapsulation using alginate-based hydrogels offers immunoprotection but faces challenges due to low oxygen solubility, compromising cell survival to restore vascularization after implantation. To address this, we developed an alginate hydrogel reinforced with graphene oxide (ALGO) and integrated calcium peroxide (CPO) as an oxygen-releasing system, stabilized with poly-L-lysine (PLL). Physicochemical and mechanical characterization confirmed incorporation of all components and improved elasticity with increasing CPO concentration. Hydrogels maintained structural stability for eight days and released oxygen throughout this period. Biocompatibility assays revealed that ALGO containing 0.25% CPO (0.25CPO) preserved cell viability and proliferation for 96 h, while 1% CPO negatively affected survival. Oxygen consumption analysis showed that 0.25CPO sustained mitochondrial respiration and enhanced maximal respiratory capacity. Glucose-stimulated insulin secretion demonstrated that 0.25CPO maintained functional responsiveness under low and high glucose conditions. These findings indicate that 0.25CPO hydrogels provide controlled oxygen delivery, mechanical stability, and improved biocompatibility, making them a promising platform for pancreatic β-cell encapsulation and future preclinical applications in type 1 diabetes therapy.

Despite the goal of utilization management (UM) to facilitate high-value cancer care, concerns about care denials persist. Evaluating justifications for denied claims can clarify the quality of UM decisions.

To examine second-level appeals for denied anticancer medications in Medicare Part D to assess the quality of UM decisions.

This cross-sectional study used a large language model (ChatGPT 5 Mini, OpenAI) to analyze texts of second-level appeals decisions on denied Part D medications, rendered by a Medicare-contracted reviewer. Data were analyzed from March 13, 2025, to May 12, 2026.

From decision summaries, the reasons for first-level denials (as cited by Part D plans) and the outcomes of second-level appeals (favorable vs unfavorable) were examined. The reasons for unfavorable reviews (clerical vs nonclerical) were also examined.

We included 4952 second-level appeals from 2020 to 2024 by beneficiaries with hematological (n = 1155 [23.3%]), prostate (n = 876 [17.7%]), digestive (n = 650 [13.1%]), breast (n = 613 [12.%]), and lung, bronchus, and respiratory (n = 430 [8.7%]) cancers. Most appeals were for targeted therapy (n = 2889 [58.9%]) or hormonal therapy (n = 959 [19.4%]). The most common reasons for initial denial or appeals were "non-medically acceptable" indications (ie, off-label use; 3410 [68.9%]), formulary exceptions (545 [11.0%]), and failure to meet preapproval coverage criteria (mostly on-label prescribing; 463 [9.3%]). Overall, 19.5% (95% CI, 18.4%-20.6%) received favorable reviews, and 55.2% (95% CI, 53.8%-56.6%) and 25.3% (95% CI, 24.1%-26.5%) received unfavorable reviews due to clerical and nonclerical issues, respectively. Favorable reviews were more prevalent among appeals for drugs initially failing to meet preapproval coverage criteria (61.1% [95% CI, 56.7%-65.6%]), but less so among appeals for off-label therapies (16.5% [95% CI, 15.2%-17.8%]). More than 87.9% (95% CI, 86.1%-89.6%) of successfully appealed off-label therapies were for medically acceptable indications supported by Medicare-approved clinical compendia and/or peer-reviewed literature.

In this cross-sectional study of second-level appeals for denied anticancer medications in Medicare Part D, a considerable number of successfully appealed claims (especially for therapies prescribed on label) were found, which suggests potentially inappropriate UM decisions by Part D plans. However, the appeal outcomes varied substantially by the nature of the denials. Streamlining the preapproval process for on-label therapies and establishing accessible, transparent criteria for off-label prescribing may optimize UM processes for anticancer medications.

Limited granular data exist on breast cancer in transgender, nonbinary, and/or gender-diverse (TGD) individuals.

To describe patient demographic and tumor clinicopathological variables, clinically relevant risk factors, method of breast cancer detection, treatment characteristics, and locoregional outcomes and to estimate a 5-year breast cancer-specific survival (BCSS).

This cohort study obtained data on patients treated from 1990 to 2023 from 22 US academic medical centers using institutional databases, electronic medical records, and tumor registries. Included participants were TGD individuals 18 years or older with stage 0 to IV breast cancer. A comparative breast cancer cohort was selected from the 2016 to 2021 Surveillance, Epidemiology, and End Results Program (SEER) breast cancer dataset. Data were analyzed from January to October 2025.

Breast cancer.

Estimated 5-year BCSS and locoregional recurrence rates. Wilcoxon rank sum and χ2 tests were used to compare continuous and categorical variables. Kaplan-Meier analysis was used to estimate 5-year BCSS.

A total of 112 TGD persons (median [IQR] age at diagnosis, 42.5 [36.5-51.0] years; 104 individuals [92.9%] were assigned female at birth) with breast cancer and 1 with bilateral disease were included in the analysis. Forty-three patients (38.4%) used gender-affirming hormone therapy before diagnosis. Among the entire cohort, 58 patients (51.8%) detected their own breast cancer, 68 (60.7%) had a familial breast cancer history, and 16 (14.3%) had a pathogenic germline variant. Tumors were predominantly hormone receptor positive (96 [85.7%]) and early stage (29 [25.7%] ductal carcinoma in situ [DCIS]; 51 [45.1%] stage I). The TGD cohort, compared with patients with breast cancer in the SEER dataset (N = 480 915), was younger (median [IQR] age, 42.5 [36.5-51.0] years vs 62.0 [52.0-72.0] years), had a higher proportion of persons assigned male at birth (8 [7.1%] vs 3522 [0.7%]), more often had progesterone receptor-positive disease (89 [79.5%] vs 335 491 [69.8%]), and presented with earlier-stage disease (eg, DCIS: 29 [25.9%] vs 79 604 [16.6%]). With a median (IQR) follow-up time for the TGD cohort of 38 (24-74) months, 5-year BCSS was favorable at 96.2% (95% CI, 85.3%-99.0%).

This cohort study of TGD patients with breast cancer found that this population was young and often detected their own tumors via self-examination, suggesting opportunities to improve early detection through screening for individuals at elevated risk. Although short-term BCSS appeared favorable, prospective research is essential to define evidence-based guidelines and elucidate long-term outcomes.