Biology and Life Sciences

Abstract: Background/Objectives: Type 1 diabetes mellitus (T1DM) has historically been associated with impaired linear growth and delayed pubertal development due to chronic insulin deficiency. Advances in intensive insulin therapy and glucose monitoring may have substantially reduced these effects. This study evaluated growth and pubertal development in children with T1DM treated with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) compared with healthy controls and investigated whether metabolic control was associated with anthropometric outcomes. Methods: This retrospective observational study included 177 children aged 3–18 years: 102 with T1DM (60 treated with MDI and 42 with CSII) and 75 healthy controls. Height SDS, BMI SDS, Tanner stage, biochemical parameters, and diabetes-related variables were analyzed. Comparisons, correlations and multiple linear regression analyses were performed to evaluate associations between metabolic control and anthropometric parameters. Results: No significant differences were observed between children with T1DM and healthy controls regarding height SDS, BMI SDS, or pubertal development. Likewise, no anthropometric differences were identified between the MDI and CSII groups. Fasting plasma glucose was significantly lower in the CSII group (p<0.001), whereas HbA1c was comparable between treatment modalities. Neither HbA1c nor other routinely assessed metabolic parameters showed significant associations with height SDS or BMI SDS in correlation or multivariable regression analyses. Conclusions: Children and adolescents with T1DM achieved growth and pubertal development comparable to healthy peers, regardless of insulin treatment modality. Routine markers of metabolic control were not independently associated with anthropometric outcomes, suggesting that contemporary intensive diabetes management is sufficient to preserve normal growth in most pediatric patients with T1DM.

Abstract: In type 2 diabetes, adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) to basal insulin can improve glycemic control and reduce insulin requirements while counteracting insulin-associated weight gain. However, the extent to which incretin therapies enable patients to stop or meaningfully reduce insulin, and whether they differ in this respect from other oral antidiabetic agents, remains uncertain. Here we analyzed de-identified electronic health records from a federated U.S. clinical network, comparing patients with type 2 diabetes receiving basal insulin who initiated semaglutide, tirzepatide, or an SGLT2-inhibitor (SGLT2-i). Three comparisons were evaluated using 1:1 propensity-score matching: two incretin-versus-SGLT2-i comparisons, semaglutide versus SGLT2-i (n=1,029) and tirzepatide versus SGLT2-i (n=254), and a head-to-head incretin comparison of tirzepatide versus semaglutide (n=272). Cumulative incidence of basal insulin discontinuation and of ≥20% basal-dose reduction was estimated over 24 months. At 24 months, patients who initiated semaglutide discontinued basal insulin at a significantly higher rate than those who initiated SGLT2-i (27.8% vs 22.2%; subdistribution hazard ratio [sHR] 1.26, 95% CI 1.05–1.52; Gray P=0.013), whereas tirzepatide initiators discontinued more often than SGLT2-i initiators without reaching significance (38.4% vs 31.5%; sHR 1.22, 95% CI 0.86–1.71; P=0.263). In the head-to-head incretin comparison, tirzepatide initiators discontinued basal insulin more often than semaglutide initiators, though this difference did not reach significance (38.0% vs 28.5%; sHR 1.35, 95% CI 0.97–1.89; P=0.080). Reduction of basal insulin dose by ≥20% was significantly higher with each incretin than with SGLT2-i (semaglutide sHR 1.15, P=0.045; tirzepatide sHR 1.40, P=0.015), and, in the head-to-head incretin comparison, significantly higher with tirzepatide than semaglutide (sHR 1.29, P=0.045). These reductions in insulin use were accompanied by improved glycemic control. At 6 months HbA1c dropped 1.16 versus 0.92 percentage points for semaglutide versus SGLT2-i (P=0.013), and tirzepatide lowered HbA1c more than SGLT2-i (1.79 vs 1.44 percentage points), though not significantly (P=0.18); in the head-to-head incretin comparison, tirzepatide lowered HbA1c more than semaglutide (1.85 vs 1.30 percentage points; P=0.008). In summary, in a real-world type 2 diabetes population receiving basal insulin, incretin therapies were associated with higher rates of basal-insulin dose reduction than SGLT2-i—and semaglutide with higher rates of discontinuation—while tirzepatide produced greater dose reduction and glycemic improvement than semaglutide, motivating prospective evaluation of incretin-based insulin de-escalation strategies.

Abstract: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for type 2 diabetes and obesity, but emerging evidence from randomized trials and real-world anecdotes suggest that neurosensory adverse events merit systematic investigation. We analyzed 670,422 initiators of semaglutide or tirzepatide across a large-scale federated EHR network and ascertained 14 new-onset neurosensory phenotypes over 12 months using AI-assisted clinical-note curation harmonized with ICD-10-CM codes. Among 128,377 at-risk GLP-1RA initiators — new users with at least two prescriptions within 12 months and complete 12-month follow-up, free of any studied phenotype at baseline — 29,519 (23.0%) had at least one newly documented phenotype, most commonly hypoesthesia/numbness in 16,143 patients (12.6%) and paresthesia in 15,415 patients (12.0%). Outcome ascertainment was validated by physician-led curation, with the review of 223 AI-identified events yielding a positive predictive value of 88.8% (95% CI, 84.0–92.3). In propensity-score–matched analyses, GLP-1RA initiators were associated with a 23% lower risk than initiators of the antidiabetic medications metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, or sodium-glucose co-transporter-2 (SGLT2) inhibitors (19.7% versus 25.6%; RR, 0.77; 95% CI, 0.75–0.79; q<0.001), with significantly lower risks of hypoesthesia, paresthesia, radiculopathy or sciatica, polyneuropathy, mononeuropathy and painful dysesthesia. GLP-1RA initiators also had a 22% lower associated risk than bariatric-surgery recipients who were additionally matched on achieved weight loss (21.1% versus 27.0%; RR, 0.78; 95% CI, 0.75–0.82; q<0.001). Within GLP-1RA initiators, neurosensory event incidence increased (P for trend<0.001) from 19.3% at a normal HbA1c baseline (<5.7%) to 32.0% for severe hyperglycemics at HbA1c >12%, but showed no ordered association with achieved weight loss (P=0.867), baseline body-mass index (BMI, P=0.784) or BMI reduction (P=0.740). Maximum attained semaglutide/tirzepatide dose was also not enriched among neurosensory event developers in the matched cohort. Taken together, this observational study suggests the hallmark of neurosensory risk after GLP-1RA initiation may be glycemic burden, not the magnitude of achieved weight loss, and emphasizes that population-level neurosensory risk after GLP-1RA initiation was consistently lower than among matched antidiabetic-medication and bariatric-surgery recipients.

Abstract: Polyendocrine metabolic ovarian syndrome (PMOS), previously referred to as polycystic ovary syndrome, is conventionally diagnosed through reproductive manifestations, although its metabolic evolution before diagnosis remains poorly defined. Here we conducted an observational study of de-identified electronic health records from a large federated US network to characterize the prediagnostic evolution of PMOS through four complementary analyses. First, across a reference landscape of 1,929 clinical conditions spanning 15,087,821 people, PMOS combined high body weight at diagnosis of 94.3 kg with marked five-year prediagnostic weight gain of 10.0 kg, corresponding to 15.6%, positioning it alongside insulin resistance, metabolic syndrome and obesity rather than reproductive disorders. This condition-wide pattern placed PMOS within the metabolic disease landscape and raised the question of when the anthropometric divergence begins. Second, among 104,003 women receiving their first recorded PMOS diagnosis at a mean age of 30.9 years (s.d. 9.5) and matched controls, BMI was already higher at the earliest 15-year lookback during adolescence, averaging 23 kg m⁻² versus 20 kg m⁻², respectively (P < 0.001). During the final five years before diagnosis, mean weight increased from 85.9 kg to 94.0 kg, an 8.1 kg gain corresponding to 9.4%, and was 17.9 kg higher than in matched controls at diagnosis (94.0 kg vs 76.1 kg, P < 0.001). This established that the PMOS-associated weight gap was present during adolescence rather than emerging only near reproductive-age diagnosis. Third, among 809,719 women with BMI recorded between 5 and 20 years of age, 19,681 subsequently received a PMOS diagnosis. Ten-year cumulative PMOS incidence increased progressively from 3.3% with healthy BMI to 17.9% with obesity class III, corresponding to an RR of 5.4 (P < 0.001). Black women constituted 11.1% of the healthy-BMI group and 26.5% of the obesity class III group, a 2.4-fold difference across increasing adiposity bands (each band versus healthy BMI, P < 0.001). Thus, early-life adiposity not only preceded PMOS diagnosis but stratified subsequent incidence across a pronounced dose gradient. Fourth, among 1,416 matched case–control pairs with AI-extracted serial body-composition measurements, women with PMOS had 9.8 kg greater fat mass at diagnosis than controls (55.4 kg vs 45.6 kg, P < 0.001). Despite greater absolute lean mass, their lean-mass proportion was 3.8 percentage points lower (52.0% vs 55.8%, P < 0.001). Approximately 72% of the 14.1 kg excess total weight near diagnosis was non-lean mass, revealing that the prediagnostic weight excess was predominantly adipose. Together, these analyses trace an adiposity-linked prediagnostic continuum that begins during pediatric and adolescent years, stratifies more than fivefold variation in subsequent PMOS incidence and culminates in predominantly adipose weight excess before reproductive-age diagnosis.

Abstract: Gonadotropin-releasing hormone agonists are used to treat central precocious puberty and are increasingly prescribed in gender-affirming care. Despite well-established reproductive effects, their broader physiological effects during puberty remain poorly understood. Male and female Wistar rats received a depot triptorelin injection at pubertal onset. Body mass, food intake, and locomotor activity were monitored. After 28 days, reproductive function was assessed, and pituitary and hypothalamic gene expression was analyzed. Changes in gonadal weight, estrous cycle, folliculogenesis, seminiferous tubules’ morphology, and sperm count confirmed the suppression of pubertal maturation. Triptorelin downregulated Gnrhr and Lhb, demonstrating suppression of gonadotrope function. Despite comparable reproductive suppression, metabolic responses to triptorelin were strongly sex-dependent. Females exhibited increased body weight gain accompanied by delayed hyperphagia, whereas males showed reduced body weight gain, unchanged food intake, and increased mean locomotor speed. Female-specific transcriptional remodeling was observed in the hypothalamus, characterized by downregulation of Lepr and Npy and upregulation of Sst and Kiss1 expression. Collectively, these findings demonstrate that pubertal triptorelin treatment induces profound reproductive suppression in both sexes while eliciting sex-specific hypothalamic adaptations in pathways regulating energy homeostasis. This suggests that puberty blockers exert broader neuroendocrine effects beyond the suppression of reproductive maturation.

Abstract: Background/Objectives: This 12-week randomized controlled trial investigated whether progressive resistance training combined with vitamin D supplementation produces synergistic improvements in cardiometabolic profiles and functional capacities compared with monotherapies in elderly Korean women with type 2 diabetes mellitus (T2DM) and vitamin D deficiency. Methods: In a 2×2 factorial design, 52 women (aged 65–80 years) with T2DM and serum 25(OH)D <20 ng/mL were assigned to four groups: Exercise + Vitamin D (Ex+VitD, n=15), Exercise + Placebo (Ex+Placebo, n=13), Vitamin D only (VitD, n=11), or Control (n=13). Exercise groups completed supervised progressive resistance training three times weekly, and vitamin D groups received 2,000 IU/day cholecalciferol. Results: The Ex+VitD group achieved significant improvements in HbA1c (−0.13%, p=0.019), fasting glucose (−0.79 mmol/L, p<0.001), insulin (−1.96 μU/mL, p=0.050), and HOMA-IR (−0.77, p=0.020). Serum 25(OH)D increased substantially (+15.57 ng/mL, p<0.001). Calcitonin rose exclusively in the Ex+VitD group (+2.57 pg/mL, p<0.001, d=3.34), while monotherapies showed no change. Total cholesterol (−23.93 mg/dL), triglycerides (−25.07 mg/dL), and LDL-cholesterol (−10.20 mg/dL) decreased significantly. Both exercise groups showed marked strength gains (chair stand +8.33 to +10.00 repetitions, p<0.001) and balance improvements (functional reach +2.47 to +4.46 cm, p≤0.033). Conclusions: Twelve weeks of progressive resistance training combined with vitamin D supplementation produced synergistic improvements in glycemic control, insulin sensitivity, calcitonin secretion, muscular strength, and lipid metabolism in elderly women with T2DM and vitamin D deficiency, targeting complementary pathways that neither intervention engaged alone.

Abstract: Background: Glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists reduce cardiovascular events, but the underlying cardiac structural remodeling remains unclear. Objectives: This study evaluated longitudinal cardiac remodeling associated with semaglutide and tirzepatide in a real-world cohort and determined its weight-loss dependency. Methods: Using electronic health records from a federated network, we analyzed longitudinal echocardiograms of patients prescribed semaglutide or tirzepatide, stratified by 12-month weight loss into super-responders (>15%), moderate-responders (5%-15%), and minimal-responders (<5%). Additionally, GLP-1/GIP patients with >5% weight loss were propensity-matched with non-GLP-1/GIP weight-loss medication control patients on demographics and baseline body mass index. Results: Among 3,500 GLP-1/GIP patients (422 weight-loss super-responders, 1,426 moderate-responder, 1,652 minimal-responders), left ventricular (LV) mass decreased across all groups proportional to weight loss (super-responders: 198.4 ± 69.6 to 176.6 ± 66.0 g; moderate-responders: 210.7 ± 74.0 to 195.8 ± 68.1 g; minimal-responders: 216.1 ± 68.4 to 204.8 ± 67.4 g; p < 0.001). Left atrial volume and LV systolic and diastolic function did not change. Among weight-loss super-responders, semaglutide (n = 159) showed greater LV mass reduction than tirzepatide (n = 89) (Cohen’s d = -0.389 vs. -0.263), while tirzepatide showed small improvements in right ventricular function. Compared to matched non-GLP-1/GIP controls (n = 118/group), GLP-1/GIP patients exhibited significant LV mass reduction not observed in controls despite similar weight loss. Conclusions: Real-world findings demonstrate that incretin-based therapies are associated with reverse cardiac remodeling characterized by weight-loss-dependent and incretin-specific mechanisms, with potentially distinct structural targets among agents.

Abstract: Alopecia is an emerging concern during tirzepatide or semaglutide therapy for weight management, but whether it is a consequence of weight loss or reflects incretin-specific biology remains unclear. Here we conduct an observational study comparing new users of tirzepatide (Zepbound, Mounjaro) or semaglutide (Wegovy, Ozempic, Rybelsus) with at least two prescriptions, no documented alopecia prior to the first prescription, and complete 12-month follow-up. Incident alopecia was defined using harmonized diagnosis codes and AI-curated clinical notes. Propensity-score matching was performed to balance tirzepatide and semaglutide users on age, race, sex, baseline BMI, and type 2 diabetes. In the matched cohorts (n=12,863 per arm), incident alopecia was more frequent with tirzepatide than with semaglutide (4.20% vs 2.88%; risk ratio [RR]: 1.46; 95% CI [1.28-1.66]; P<0.001). After additional matching on achieved weight loss (n=11,046 per arm), incident alopecia remained significantly higher after tirzepatide than semaglutide (4.24% versus 3.33%; RR: 1.27 [1.11-1.45]; P<0.001). By 6 months, incident alopecia had occurred in 1.55% of tirzepatide users versus 1.24% of semaglutide users, widening by 12 months to 4.20% versus 2.88%, respectively (hazard ratio [HR]: 1.46 [1.28-1.67]; log-rank P<0.001). Incident alopecia remained significantly more frequent with tirzepatide than semaglutide across clinically relevant strata (all P<0.001), including among patients with 20-to-30% weight loss, a range highlighted in pivotal obesity trials (RR: 1.44); in the low and high maximum-dose strata (RR: 1.76 and 1.39, respectively); and among patients with 4-6 prescriptions, a proxy for longer treatment duration (RR: 1.65). Analysis of newly initiated hair-loss therapies showed significantly higher minoxidil (Rogaine) initiation after tirzepatide than after semaglutide (RR, 2.04; P=0.002). Among 8,985 female patients, incident alopecia occurred in 5.44% of tirzepatide users versus 3.63% of semaglutide users (RR: 1.50 [1.31-1.72]; P<0.001), with significant differences in the 10-to-20% weight-loss band (RR: 1.41 [1.11-1.78]; P=0.004) and in the 20-to-30% weight-loss band (RR, 1.47; 95% CI, 1.06 to 2.04; P=0.018). Among tirzepatide users, incident-alopecia developers were more often female than non-developers (90.6% vs 68.9%, SMD: +0.56), and were enriched for underlying endocrine conditions including menstrual irregularity (20.0% vs 13.9%, SMD: +0.17), hypothyroidism (28.1% vs 21.6%, SMD: +0.15), and polycystic ovarian syndrome (6.7% vs 3.6%, SMD: +0.14). Repeated measurements of ferritin, iron, vitamin B12, folate, vitamin D, and zinc showed no significant nutrient decline accompanying incident alopecia. Exploratory single-cell RNA-seq analyses showed no GLP1R or GIPR expression in scalp follicular keratinocytes and identified multiple dermato-immune cell types that expressed GIPR but not GLP1R. Overall, in routine care, incident alopecia was higher after initiation of tirzepatide than semaglutide, motivating prospective comparative studies of incretin-based therapies.

Abstract: Coffee is one of the most widely consumed beverages worldwide. Coffee and its bioactive compounds, including caffeine, chlorogenic acid, and caffeic acid, have received increasing attention due to their potential contribution to coffee-associated health benefits. Evidence from pediatric and adult populations supports a positive association between fructose intake from sugar-sweetened beverages and the increasing prevalence of obesity and other non-communicable diseases. In this context, coffee consumption may represent a potential protective dietary factor against high fructose intake-induced metabolic alterations, including obesity, type 2 diabetes, liver disease, cardiovascular disease, and alterations in gut microbiota composition. However, human evidence on the effects of coffee consumption on fructose-related metabolic alterations remains limited, making it difficult to determine whether the benefits observed in animal models translate to humans. Therefore, this review summarizes current evidence on the potential role of coffee consumption and coffee-derived bioactive compounds in modulating fructose-induced metabolic alterations and discusses the mechanisms involved.

Abstract: Chronic non-communicable conditions – type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), metabolic obesity syndrome (MOS), polycystic ovary syndrome (PCOS), colorectal and extra-intestinal cancers, systemic autoimmune disease, and dermatologic and gynecologic disorders linked to gut dysbiosis – share a prolonged asymptomatic phase during which conventional screening is invasive, insensitive, or resource-intensive. This review synthesizes 2021-2025 literature on fecal microbiome-based artificial intelligence (AI) diagnostics across these conditions. We surveyed machine learning classifiers trained on 16S rRNA and shotgun metagenomic data, extracting reported discriminative performance, validated microbial and short-chain fatty acid (SCFA) biomarkers, and cross-cohort reproducibility. Reported classifiers achieve areas under the curve (AUC) typically between 0.79 and 0.93 across disease domains (e.g., 0.792 for autoimmune disease subtyping, 0.82-0.90 for colorectal cancer, 0.93 for PCOS subtyping), with dietary data integration and SCFA quantification further improving discrimination. We propose a multimodal deep learning architecture – combining a microbiome transformer encoder, dietary embedding module, host feature multilayer perceptron, phylogenetic graph neural network, and cross-attention fusion layer – coupled with explainable AI (SHAP, attention heatmaps, microbial risk scores) for clinical interpretability. We conclude that fecal microbiome-based multimodal AI is a technically mature but clinically unvalidated candidate for population-scale pre-symptomatic screening, pending prospective, harmonized cross-cohort trials.

Abstract: Oral Wegovy (semaglutide weight-loss pill) initiation now spans two clinically distinct real-world entry states: “GLP-starters” without recent GLP-1 receptor agonist (GLP-1RA) prescriptions and “GLP-switchers” with a recent record for a different injectable or oral incretin therapy. Using a large federated U.S. electronic health record network, we studied the five-year history prior to Wegovy pill initiation. Of 891,711 patients with at least one GLP-1RA prescription, 11,215 initiated the Wegovy pill, of whom 6,283 (56.0%) were GLP-starters and 4,932 (44.0%) were GLP-switchers. GLP-starters and -switchers were similar in age (mean 52.4 vs 52.1 years; P=0.21) and sex (75.4% vs 74.4% female; P=0.22). In contrast, GLP-switchers had significantly greater pre-index cardiometabolic and neuropsychiatric burden than GLP-starters (all q<0.001, Benjamini-Hochberg FDR), including type 2 diabetes (Relative Risk [RR] 1.95), obstructive sleep apnea (RR 1.78), heart failure (RR 1.73), atrial fibrillation (RR 1.55), coronary artery disease (RR 1.38), depression (RR 1.32), and migraine (RR 1.25). Of 3,216 disease phenotypes screened, large language model (LLM)-curated clinical notes showed 819 phenotypes significantly higher at baseline in GLP-switchers and none in GLP-starters (all q<0.001), including morbid obesity (RR 1.61), excessive daytime sleepiness (RR 1.56), and fatty liver disease (RR 1.47), with concordantly higher Elixhauser comorbidity index ≥5 (RR 1.47). Among GLP-switchers to Wegovy pill, the most common prior agents in the year before index were injectable Wegovy (40.7%) and Zepbound (36.6%). Among 123 initiators of the recently launched orforglipron pill (Foundayo), only 39.8% had no GLP-1RA exposure in the preceding year, followed by switchers from Zepbound (tirzepatide) injections (31.7%). LLM curation of clinical notes shows the most common reasons for switching to the Wegovy pill include more affordable cost or better insurance coverage (42.7%), oral route or dosing preference (13.1%), and inadequate weight-loss efficacy with prior therapies (10.4%). Studying polypharmacy of Wegovy pill initiators shows significantly larger GLP-switchers (96.9%) than GLP-starters (88.3%) taking other oral medications concomitantly (p<0.001), with GLP-switchers more often taking metformin (RR 1.38), atorvastatin (RR 1.21), losartan (RR 1.28), and insulin glargine (RR 2.60) (all q≤0.001). Consequently, overall polypharmacy was markedly greater in GLP-switchers (mean 13.4 vs 9.7 distinct medications; ≥5 medications 81.6% vs 60.8%; ≥10 medications 48.9% vs 33.1%) (all q<0.001). Medicare-eligible initiators of Wegovy pill (age ≥65 at index, n=2,535) had a substantially greater burden of cardiovascular and renal disease, multimorbidity, and overall polypharmacy than the overall cohort, but less severe obesity (BMI ≥40 in 14.0% vs 23.3%; p<0.001). This study marks the first longitudinal analysis of the incretin care pathway leading up to Wegovy pill initiation and highlights better access and tolerability as leading drivers of patients preferring to switch to Wegovy pill.

Abstract: Despite decades of research, immunonutrition continues to generate heterogeneous and often contradictory clinical outcomes, suggesting that nutrients do not exert fixed immunological effects but rather interact with the biological context in which they operate. Sarcopenic obesity (SO) represents one of the clearest clinical models of this complexity, where chronic low-grade inflammation, mitochondrial dysfunction, anabolic resistance, metabolic inflexibility, and microbiota remodeling converge to impair the adaptive capacity of immune and metabolic integrated systems. We propose that this condition should be interpreted as a state of impaired immunometabolic plasticity, providing a conceptual framework to explain the context-dependent variability of nutritional responses. Within this perspective, micronutrients are reconsidered not simply as cofactors supporting immune competence, but as dynamic regulators of interconnected immunometabolic pathways. Particular attention is devoted to vitamin D and resveratrol, presented as complementary regulators of immunometabolic plasticity. Whereas vitamin D supports biological competence, resveratrol acts as a higher-order signaling modulator through the the SIRT1/AMPK–PGC-1α axis to influence mitochondrial function, inflammatory tone, metabolic flexibility, and epigenetic adaptation. Beyond isolated compounds, bioactive-rich food matrices, exemplified by Opuntia ficus-indica, are discussed as systems-level modulators capable of coordinating inflammatory, metabolic, redox, and microbiota-dependent biological circuitry. Rather than focusing on nutrient supplementation alone, this review introduces immunometabolic plasticity as a unifying concept linking nutritional signals to immune adaptation across different biological contexts. Finally, we discuss how biomarker-guided phenotyping, multi-omics integration, and context-aware nutritional interventions may establish the basis for precision immunonutrition, shifting the field from generalized supplementation strategies toward restoration of adaptive immunometabolic resilience.

Abstract: The U.S. Medicare GLP-1 Bridge program and existing Part D pathways are expanding access to tirzepatide therapy for older adults, including Zepbound through the Bridge for weight management and Mounjaro through Part D coverage for type 2 diabetes. This necessitates identification of clinical vulnerabilities in geriatric patients that may emerge during pharmacologic weight loss. Here we evaluated incident malnutrition, protein-energy malnutrition (PEM), appetite suppression, dehydration, and sarcopenia in the context of tirzepatide-associated weight loss among adults aged 65 years or older, and we quantified associated mortality, intensive care unit (ICU) admission, and hospitalization relative to comparator cohorts of patients who were prescribed other antidiabetic medications (metformin, DPP4 or SGLT2 inhibitors) or underwent bariatric surgery. Incident frailty-related phenotypes rose with larger achieved weight loss. Specifically, anorexia increased from 2.9% (at ≤5% weight loss) to 10.2% (at 30-40%); dehydration from 1.8% to 4.8%; malnutrition from 0.8% to 3.1%; and PEM from 0.5% to 2.9%. Median tirzepatide treatment duration increased from 1.2 months at ≤5% weight loss to 13.2 months at 30-40%, whereas duration was largely invariant by baseline BMI from <30 to >40. The development of frailty phenotypes after tirzepatide initiation was associated with increased rates of mortality (RR 25, 95% CI 18-35), ICU admission (RR 20, 95% CI 16-25), and hospitalization (RR 11, 95% CI 9.8-12) relative to tirzepatide-treated patients who did not develop malnutrition. Baseline features enriched among patients who developed frailty phenotypes after tirzepatide initiation were older age, advanced diabetes, pre-existing MAFLD/MASH, and cardiorenal comorbidities. Physician-reviewed cause-of-death among decedents with incident frailty phenotypes after tirzepatide initiation showed respiratory failure, septic shock, advanced malignancy, and multiorgan failure as leading causes of death. Overall, in this observational study of Medicare-age-eligible adults, incident frailty phenotyping during tirzepatide-associated weight loss identified vulnerable subgroups with baseline cardiometabolic burden, highlighting the need for comprehensive clinical decision support and multimodal patient monitoring with increasing weight-loss.

Abstract: Deuterium is a natural heavy isotope of hydrogen, containing a neutron as well as a proton, making it twice as heavy. Mitochondrial ATP synthase nanomotors are highly sensitive to deuterium, causing them to release reactive oxygen species (ROS) and reducing ATP synthesis. Metabolic processes have evolved to devise ways to reduce the deuterium load in the mitochondria, primarily, we argue, by exploiting several small hydrogen-containing molecular gases. When a gas is produced, deuterium, due to its extra weight, tends to stay behind in the aqueous phase, so the gas becomes deuterium-depleted (deupleted). Furthermore, many of the enzymes that synthesize these small gas molecules are designed to exclude deuterium by exploiting proton tunneling. The gut microbes play a crucial role in producing deupleted gas molecules, such as hydrogen gas (H₂), methane (CH₄), ammonia (NH₃), and hydrogen sulfide (H₂S). During inflammatory bowel disease (IBD), activated immune cells upregulate NADPH oxidase (NOX) to produce superoxide, which is converted to hydrogen peroxide (H₂O₂) by superoxide dismutase. Some microbes can convert H₂O₂ into two molecules of (likely deupleted) water through anaerobic respiration. H₂O₂ readily crosses the mitochondrial membrane, and human mitochondrial glutathione peroxidase can also convert H₂O₂ to water. The glutamate-glutamine exchange that takes place between astrocytes and neurons plausibly capitalizes on NH₃ to safely deliver deupleted protons to neuronal mitochondria. In this paper, we investigate how small molecular hydrogen-containing gases are handled in metabolism, from a perspective that considers the roles that deuterium might play in metabolic policy.

Abstract: Background: Childhood obesity is a growing health concern and added sugar intake has been associated with increased obesity risk. Emerging evidence suggests that miR-143-5p and miR-223-3p are involved in metabolic regulation. Therefore, this study evaluated their plasma expression according to added sugar intake and their association with cardiometabolic risk parameters. Methods: In this cross-sectional study, 91 children aged 6 to 12 years were included (44 normal weight and 47 with overweight/obesity). Anthropometric, and clinical parameters, and dietary added sugar consumption were analyzed. RT-qPCR was performed to assess the expression of miR-143-5p and miR-223-3p in plasma. Results: Compared with low added sugar intake, high added sugar intake was associated with lower plasma miR-143-5p expression and higher miR-223-3p expression. Both miR-143-5p and miR-223-3p expression levels were higher in children with overweight/obesity and insulin resistance than in their respective counterparts. In adjusted analyses, neither miRNA was associated with cardiometabolic risk parameters. However, added sugar intake was positively associated with miR-223-3p expression (β = 0.188, 95% CI: 0.022, 0.354) and glucose levels (β = 1.944, 95% CI: 0.133, 3.755). Conclusions: High added sugar intake was associated with lower miR-143-5p expression, higher miR-223-3p expression, and increased fasting glucose concentrations in school-aged children, suggesting early alterations in metabolic regulation.

Abstract: eranylgeranoic acid (GGA) is an endogenous acyclic diterpenoid metabolite of the mevalonate pathway that has been implicated in programmed cell death in hepatoma cells and may contribute to the elimination of premalignant hepatocytes. Recent metabolomic studies have identified 2,3-dihydrogeranylgeranoic acid (2,3-diGGA), an α-saturated derivative of GGA with reduced cell-death-inducing activity compared with GGA. This concise review examines the hypothesis that diversion of bioactive GGA toward 2,3-diGGA formation represents a metabolic shift that may attenuate hepatic tumor surveillance and influence hepatocellular carcinoma susceptibility. The review summarizes current evidence for endogenous GGA biosynthesis through the mevalonate pathway, MAO-B- and CYP3A4-associated GGA formation, and the tissue- and age-associated distribution of GGA and 2,3-diGGA. It also discusses the proposed 2,3-diGGA-forming activity, whose molecular identity remains unknown, and evaluates the potential utility of the GGA/2,3-diGGA ratio as a candidate biomarker. Finally, future experimental strategies are outlined to identify the responsible enzyme, clarify causality in cellular and animal models, and validate this metabolic framework in human liver tissues, chronic liver disease cohorts, and HCC-associated settings.

Abstract: Hybrid insulin peptides (HIPs) are neoepitopes involved in type 1 diabetes (T1D), but their complete repertoire remains unknown. The vast combinatorial space makes experimental screening unfeasible and requires bioinformatics-based prioritization. We developed a multi-level machine learning pipeline for ranking HIP candidates. First, 36 physicochemical and junction-specific features were computed for a reference library of 240 HIPs with known enzyme-linked immunospot (ELISPOT) reactivity, and a baseline Ridge regression model was trained. Next, all possible HIP candidates with 7–9 amino acid residues per fragment were generated from eight pancreatic β-cell secretory granule source proteins, including insulin chains and C-peptide, islet amyloid polypeptide, chromogranin A, neuropeptide Y, and two secretogranins, yielding 1,057,374 candidates. For each source protein, a local weighted XGBoost (Extreme Gradient Boosting) model was trained using Ridge-score-derived pseudo-labels together with weighted ELISPOT-derived and literature-derived reference HIPs. Finally, anchor-calibrated re-ranking was performed in the global model using cosine similarity to positive anchors (n = 46) and negative anchors (n = 210). The Ridge model achieved 5-fold out-of-fold R² = 0.711 and an area under the receiver operating characteristic curve (AUC) of 0.967. The global model produced a prioritized list of 40 HIP candidates, five per source protein. The highest ranks were observed for candidates with right fragments from neuropeptide Y, secretogranins 1 and 2, islet amyloid polypeptide, and chromogranin A. Candidates carrying the insulin fragment on the right side were systematically down-ranked, suggesting asymmetry in HIP formation. The proposed pipeline reduces the HIPs search space from more than one million sequences to a limited set of candidates for experimental validation and provides a framework adaptable to other chimeric neoepitopes in autoimmunity.

Abstract: Semaglutide and tirzepatide are not approved for type 1 diabetes, and their real-world associations with insulin requirements, metabolic outcomes, and safety remain uncertain. Here we analyzed de-identified federated U.S. EHR data, comparing adults with T1D initiating semaglutide (n=1,424) or tirzepatide (n=578) between Jan 1, 2018, and Dec 31, 2025, with 1:1 propensity-score matched T1D controls without GLP-1RA/tirzepatide exposure (n=2,002). At 12 months mean insulin total daily dose (TDD) percent change was −22.0% (median −9.3%) in the semaglutide subcohort and −19.7% (median −17.2%) in the tirzepatide subcohort versus +10.3% (median +0.4%) in matched controls, widening to −27.4% (median −19.4%) and −25.9% (median −31.5%) versus +10.4% (median −1.1%) in controls at 24 months (all P<0.0001). The rate of patients achieving a ≥10% TDD reduction at 6 months was 51.0% (semaglutide) and 50.3% (tirzepatide) versus 18.4% in controls (both P<0.0001). At 12 months median semaglutide dose was 0.50 mg (Q1, Q3: 0.25, 1.00), with 67.8% of patients above the 0.25 mg starter dose. Median tirzepatide dose was 5.00 mg (Q1, Q3: 2.50, 7.50), with 68.2% of patients above the 2.5 mg starter dose. Stratified analysis of 12-month TDD percent change showed significant heterogeneity by weight-loss category in the semaglutide subcohort with mean TDD reduction of −34.5% in patients losing ≥10% of body weight versus −19.6% in patients with <5% weight loss (P<0.001); semaglutide dose escalation was also associated with mean TDD reduction (1.7–2.4 mg, −31.8%; 0.25 mg, −18.2%; P=0.007) while tirzepatide dose escalation was not significantly associated with TDD reduction (ANOVA P=0.800). At 12 months mean HbA1c percent change from baseline was −4.2% (semaglutide, P<0.0001) and −3.0% (tirzepatide, P=0.007) versus −0.3% in controls and mean body weight percent change was −4.0% and −6.8% versus −0.5% (both P<0.0001). The pre-versus-post 365-day safety profile across 13 prespecified events was gastrointestinal-predominant, with nausea or vomiting increasing by 8.5 percentage points (Benjamini-Hochberg adjusted P [BH P] <0.0001) and smaller increases in hypoglycemia (+3.1 pp, BH P=0.022), constipation (+3.0 pp, BH P=0.003), diarrhea (+2.6 pp, BH P=0.016), decreased appetite (+1.1 pp, BH P=0.016), and acute kidney injury (+1.3 pp, BH P=0.022); diabetic ketoacidosis, severe hypoglycemia, pancreatitis, gallbladder disease, gastroparesis, and retinopathy progression did not change significantly. Among clinical and pharmacologic subgroups, patients with a 6-month TDD reduction of >30% had significantly higher incidence of diabetic ketoacidosis (5.42 events per 100 person-years; BH P=0.034). Across 24 prespecified cardiovascular and renal time-to-event endpoints, exposure to semaglutide or tirzepatide was associated with lower 2-year all-cause mortality (1.4% versus 5.7%; BH P<0.001) and major adverse cardiovascular events (4.2% versus 7.5%; BH P=0.002), with mortality reductions for both drugs individually and a reduction in major adverse cardiovascular events for tirzepatide; no renal endpoint remained significant after multiple-testing correction. In summary, this study demonstrates real-world reductions in daily insulin requirements, HbA1c, and weight in T1D patients after initiation of semaglutide or tirzepatide, motivating prospective evaluation of these therapies as adjunctive therapy in selected T1D adults.

Abstract: Alzheimer’s disease (AD) affects more women than men, and risk rises precipitously during and after the menopausal transition. Estrogen deficiency has been the most prominent hypothesis to explain this sex difference, but increasing evidence also implicates follicle-stimulating hormone (FSH) as an independent contributor to neurodegenerative risk. This narrative review integrates the literature on reproductive aging, AD pathobiology, and sex differences in AD, with an emphasis on endocrine, metabolic, and inflammatory mechanisms relevant to their relationship. PubMed and Google Scholar were searched for peer-reviewed human studies, animal models, and mechanistic investigations published through early 2026, prioritizing primary research and systematic reviews on FSH signaling, ApoE biology, and AD pathophysiology. FSH rises in a graded fashion across the menopausal transition and has been associated with multiple pathways implicated in AD, including C/EBPβ–δ-secretase signaling, mitochondrial function, neuronal glucose metabolism, and autophagic-lysosomal clearance - though the causal directionality of many of these relationships remains to be established in humans. Dysfunction in these interrelated systems has been associated with Aβ accumulation, tau pathology, and chronic neuroinflammation. FSH also appears to influence apolipoprotein biology, particularly ApoE, through actions on lipid metabolism, protein lipidation, and clearance, with downstream effects on Aβ aggregation and inflammatory signaling that differ by ApoE isoform. In addition, reproductive aging is associated with changes in vascular integrity and blood-brain barrier function that may precede classical AD pathology. This review describes the mechanistic pathways through which chronically elevated FSH may contribute to AD risk in women and discusses the potential therapeutic implications of FSH modulation, while acknowledging that much of the current mechanistic evidence derives from preclinical models and requires validation in human populations.

Abstract: Type 2 diabetes mellitus is a highly prevalent, heterogeneous, and progressive chronic disease. In a large proportion of patients, management is based for many years on lifestyle intervention and non-insulin glucose-lowering therapies. This long pre-insulin phase represents a crucial clinical window, in which timely recognition of metabolic deterioration, therapeutic inertia, treatment response, and individual risk trajectories may substantially influence long-term outcomes. However, routine care is still frequently based on intermittent assessments, delayed treatment adaptation, and limited integration of clinical, biochemical, behavioral, and digital data. Artificial intelligence may offer a clinically relevant opportunity to move from reactive management to anticipatory care in non-insulin-treated type 2 diabetes. Rather than replacing clinical judgment or automating treatment decisions, artificial intelligence can support clinicians by identifying hidden patterns, predicting metabolic worsening, stratifying risk, improving the interpretation of glucose data, and personalizing follow-up intensity and therapeutic timing. In this setting, its most meaningful role may be to reduce the silent interval between early deterioration and clinical action. This structured narrative review discusses the rationale, current applications, near-future scenarios, and implementation barriers of artificial intelligence in non-insulin-treated type 2 diabetes. Particular attention is given to advanced interpretation of glycemic data, clinical decision support, prediction of treatment failure, remote monitoring, and the potential integration of multidimensional data into more precise and timely care pathways. The review also emphasizes the need for explainable, clinically validated, equitable, and ethically governed artificial intelligence tools that can be realistically embedded into everyday diabetology practice.