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Machine learning-based prediction of mortality and hospitalization in diabetic patients with heart failure with preserved ejection fraction: the GUARDIAN-P risk score.
Eur Heart J Digit Health
Zheng-Wei Chen, Jen-Fang Cheng, Chen-Yu Huang +8 more
Diabetes mellitus (DM) is a major contributor to adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF). We aim to develop and externally validate a machine learning-based model using a random survival forest (RSF) approach for predicting the composite outcome of hospitalization for heart failure (HHF) and cardiovascular (CV) death in patients with DM and HFpEF.
The Role of Vasoactive Intestinal Peptide in Glucagon-like Peptide-2-Mediated Intestinal Lipid Handling.
Int J Mol Sci
Kundanika Mukherjee, Rita Wang, Farnoosh Tabatabaeian +1 more
The gut hormone glucagon-like peptide-2 (GLP-2) plays important roles in regulating lipid handling and promoting anti-inflammatory functions in the intestine. During the postprandial state, it increases lipid absorption. During post-absorptive state, it mobilizes pre-formed chylomicrons. GLP-2 acts through vasoactive intestinal peptide (VIP) in reducing inflammation in rat ileum. However, this pathway has not yet been tested for GLP-2's effects on intestinal lipid handling. Here, in mesenteric lymph duct cannulated rats, we examined whether VIP signaling mediates GLP-2's effects on postprandial lipid absorption and post-absorptive lipid mobilization in the intestine. We administered a VIP receptor antagonist and analyzed lipid output in response to intraperitoneal GLP-2 or PBS during postprandial and post-absorptive states. VIP receptor antagonism reduced GLP-2 mediated lipid output in the post-absorptive state but had no effect during the postprandial state. These results show that GLP-2 functions differently during postprandial and post-absorptive states and VIP aids in GLP-2-mediated lipid output during the post-absorptive state.
Mediterranean Dietary Pattern in Type 2 Diabetes Management: Pathways and Clinical Evidence.
Biomedicines
Dubravka Majić Milotić, Tomislav Bulum, Kristijan Peroš
The Mediterranean diet (MedDiet) has emerged as a promising dietary strategy for the prevention and management of type 2 diabetes mellitus (T2DM). This narrative review provides a comprehensive synthesis linking the biological pathways of the MedDiet with established clinical evidence. Adherence to this traditional dietary pattern-characterized by a high intake of fiber, complex carbohydrates, antioxidants, and healthy fats-has demonstrated significant benefits in terms of glycemic control, enhanced insulin sensitivity, and overall metabolic health. Mechanistically, the review explains how the MedDiet improves health by modulating key physiological processes, including anti-inflammatory and antioxidant pathways, the regulation of branched-chain amino acid metabolism, the enhancement of short-chain fatty acid production via gut microbiota modulation, and upregulated incretin effects. Importantly, this review explains how the MedDiet complements modern medications, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. By integrating molecular mechanisms with human clinical outcomes, this narrative review addresses multiple aspects of the MedDiet in both the prevention and management of T2DM including glycemic control, weight management, and cardiovascular risk reduction, rendering it a valuable dietary strategy for both the prevention and treatment of this chronic condition.
Insulin Resistance as a Systemic Metabolic Risk State for Cancer: Mechanisms, Biomarkers, and Prevention.
Int J Mol Sci
Marijana Matek Sarić, Nataša Lisica Šikić, Tamara Sorić +4 more
Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. Emerging tools such as continuous glucose monitoring and hepatokine profiling may further refine risk detection. Sustained lifestyle modification-diet, physical activity, sleep, and stress regulation-remains central to prevention. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and dual incretin agents, offer additional metabolic benefits, although their long-term impact on cancer risk is still unclear. Therefore, IR is best understood not as an isolated risk factor, but as a systemic metabolic risk state that may influence cancer development, with implications for prevention and early risk stratification.
Cobalt nanoparticles protect against endocrine disruption in response to multiple abiotic stresses in fish.
Front Immunol
Neeraj Kumar, Paritosh Kumar, S A Kochewad +3 more
Climate change, pollution, and deteriorating water quality have emerged as major threats to aquaculture and fish reproduction. Anabas testudineus were exposed to multiple abiotic stressors such as arsenic, ammonia toxicity, low pH, and elevated temperature, which disrupt endocrine regulation, impair reproductive hormones, reduce sperm quality, and ultimately decrease reproductive efficiency. These stressors adversely affect the hypothalamic-pituitary-gonadal axis, resulting in hormonal imbalance and poor gamete quality of fish. The present investigation aims to protect the fish against endocrine disruption and improve reproductive hormones by using cobalt nanoparticles diets (Co-NPs).
Some CYP21A2 Polymorphisms in the Exon 7 Region Might Be Associated with Cortisol Secretion in Polycystic Ovary Syndrome.
J Clin Med
Ralitsa Robeva, Silvia Andonova, Georgi Kirilov +5 more
Background: Polycystic ovarian syndrome (PCOS) and the non-classic form of congenital adrenal hyperplasia (NC-CAH) are hyperandrogenic conditions with overlapping clinical symptoms but different genetic backgrounds. The possible interrelationships between the two conditions remain unclear; thus, the present study aims to investigate the prevalence of CYP21A2 exon 7 genetic variants in patients with PCOS and to explore the possible associations of the polymorphisms with adrenocortical hormonal production. Methods: The CYP21A2 exon 7 region was genotyped in 80 unrelated female patients with PCOS and 12 women with NC-CAH. The associations between genetic variants, clinical characteristics, and adrenocortical hormones were investigated. Results: The pathogenic CYP21A2 NC-CAH variant c.844G>T; p.(Val282Leu) was found in 66.7% (8/12) of patients with NC-CAH but in none of the individuals with PCOS. The benign rs1554305325, rs6465, rs6472, and rs6477 genetic polymorphisms were not related to clinical hyperandrogenism. The rs6472 polymorphic alleles were associated with increased adrenocorticotropic hormone (ACTH) (5.5 vs. 3.4 pmol/L, p = 0.022) and cortisol (460.5 vs. 366.5 nmol/L, p = 0.016) levels. The rs6465 variant alleles were significantly associated with lower pregnenolone (1.43 vs. 3.1 ng/mL, p = 0.031) and ACTH (2.5 vs. 4.5 pmol/L, p = 0.030) levels in the unadjusted model but not after adjustment for potential confounders (p > 0.05). Conclusions: The p.(Val282Leu) variant is very common among Bulgarian patients with NC-CAH but it has not been found in our cohort of women with PCOS. The CYP21A2 exon 7 polymorphisms might be associated with cortisol levels in the patients with PCOS. Further larger studies are needed to confirm or reject the current findings in different ethnic groups.
Immune Checkpoint Inhibitor-Induced Hypophysitis Presenting as Severe Hyponatremia: A Nephrology Perspective on Avoiding the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) Pitfall.
Cureus
Said Al Zein
A 79-year-old woman with malignant melanoma receiving ipilimumab and nivolumab presented with headache, generalized weakness, nausea, vomiting, and severe euvolemic hyponatremia. Her sodium had declined from 136 mmol/L to 111 mmol/L over one week. Initial urine studies showed hypotonic hyponatremia with inappropriately concentrated urine and elevated urine sodium, mimicking the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Nephrology consultation identified central adrenal insufficiency, with morning cortisol at 1.6 mcg/dL and suppressed adrenocorticotropic hormone (ACTH), along with central hypothyroidism in the setting of immune checkpoint inhibitor therapy. Glucocorticoid replacement was initiated prior to levothyroxine, and tolvaptan was used as a temporizing aquaretic therapy for persistent severe hyponatremia while hormone replacement was initiated. Sodium normalized, and the patient was transitioned to outpatient endocrine management. This case highlights the importance of evaluating hypophysitis and pituitary failure in patients receiving immune checkpoint inhibitors who present with severe or refractory hyponatremia. Early recognition can prevent delayed glucocorticoid replacement and adrenal crisis.
Therapeutic Effects of Glucagon-like Peptide-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: A Systematic Review.
Int J Mol Sci
Dina Mahoon, Fares Kellany, Imad Khan +2 more
Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-like peptide-1 (GLP-1) receptor agonists, approved for type 2 diabetes and obesity, possess metabolic effects that may render them suitable for treating NAFLD and metabolic dysfunction-associated steatohepatitis (MASH). To evaluate the therapeutic effects of GLP-1 receptor agonists in adults with NAFLD, non-alcoholic steatohepatitis (NASH), MASLD, or MASH. PubMed, Scopus, Embase, and the Cochrane Library were systematically searched using keywords related to NAFLD and GLP-1 receptor agonists. Given heterogeneity in populations, designs, and outcomes, findings were synthesized narratively. The review is registered with PROSPERO (CRD420261337353). Twelve studies met the inclusion criteria. The most consistent outcome was a reduction in hepatic fat, seen with semaglutide, liraglutide, dulaglutide, and beinaglutide. Improvements in liver enzymes, particularly alanine aminotransferase, were less consistent and best regarded as supportive rather than definitive evidence of histological improvement. Histological benefits were strongest for steatohepatitis resolution in non-cirrhotic MASH. Fibrosis findings were mixed, with the greatest benefit in F2-F3 MASH and limited improvement in established cirrhosis. GLP-1 receptor agonists were generally well tolerated, with gastrointestinal symptoms the most common adverse effects. GLP-1 receptor agonists show promising liver-related benefits in NAFLD and MASH, particularly in obesity, type 2 diabetes, or earlier-stage disease. Their effects on advanced fibrosis and long-term outcomes remain uncertain, warranting larger, longer-term studies.
Altered IGF-1R, p70S6K, and GSK-3β expression in PBMCs of immune thrombocytopenia patients and clinical associations.
Thromb Res
Xin Zhou, Yuqi Shi, Yulu Liu +3 more
To investigate the expression profiles of insulin-like growth factor-1 receptor (IGF-1R), p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK-3β) in peripheral blood mononuclear cells (PBMCs) of adults with newly diagnosed primary immune thrombocytopenia (ITP), and to evaluate their associations with clinical hematologic parameters.
Resident mesenchymal progenitor cells require autocrine IGF-I in homeostatic and regenerating skeletal muscle.
Stem Cell Reports
Yangyi E Luo, Zoe Abe-Teh, Tarek Y Alsaghir +9 more
Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal stromal cells essential for homeostasis and regeneration but can produce fibrosis or intramuscular fat in pathological conditions. Insulin-like growth factor-I (IGF-I) regulates regeneration through actions on muscle fibers, satellite cells, macrophages, and extracellular matrix (ECM) remodeling but has multiple sources. To assess the role of FAP-derived IGF-I, we generated inducible FAP-specific Igf1-deficient (FID) mice. Following BaCl2 injury, FID muscles displayed impaired regeneration, with smaller fibers, fewer Pax7+ and MyoD+ cells, increased CD68+ macrophages, decreased collagen, and suppressed FAP proliferation. After glycerol-induced injury, FID muscles had reduced fat. Primary FID FAPs displayed blunted proliferation, upregulated immune-regulatory genes, and downregulated ECM and growth genes, with delayed fibrogenic and adipogenic differentiation. scRNA-seq of homeostatic muscle revealed reduced protein translation and ECM indices alongside increased senescence markers in FID samples. Taken together, FAP IGF-I is critical for FAP function, with direct and indirect impact on muscle regeneration.
Elevated mitochondrial Ca2+ impairs satellite cell pool expansion in response to skeletal muscle injury.
Stem Cell Reports
Ahmed S Shams, Lalitha S Denduluri, Megan K Sumera +10 more
MICU1 loss-of-function variants in human patients are associated with proximal muscle weakness and myopathy. Mitochondrial Ca2+ levels are basally elevated when MICU1, the gatekeeper of the mitochondrial Ca2+ uniporter, is absent. The importance of regulating mitochondrial Ca2+ in skeletal muscle has generally been studied in mature muscle fibers. How satellite cells are impacted by mitochondrial Ca2+ dysregulation is poorly understood. We investigated Micu1 deletion specifically in Pax7+ satellite cells to address this gap in knowledge. Colony-forming activity in vitro was unaffected in Micu1-deficient satellite cells, but colony sizes were smaller. Although satellite cell homeostasis was not significantly affected 1 month following Micu1 deletion, the regenerative response post-injury was significantly impaired. Satellite cell self-renewal from Micu1-deficient donor cells in transplant recipients was also heavily compromised. Our data suggest that properly gating mitochondrial Ca2+ import via the uniporter is integral to satellite cell activation from quiescence in response to muscle injury.
The risk of retinal vascular events in patients using semaglutide: a scoping review.
Ophthalmologica
Salma Choujaa Goudira, Kurt Højlund, Jakob Grauslund
Background This scoping review aims to explore existing clinical trials on the association between semaglutide use and the occurrence of retinal vascular events to detect any potential safety concern. Summary The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews guidelines. A search was performed across PubMed, Embase via Ovid, ClinicalTrials.gov, and Google Scholar on April 16th, 2025, and Marts 5th, 2026. We aimed to detect clinical trials reporting retinal vascular events while investigating the effect of semaglutide in patients with type 2 diabetes or obesity. Reports on optic ischemic neuropathy were included as a reference outcome, to evaluate whether the method used in the review might be capable of detecting rare ophthalmic vascular adverse events, and thereby a potential safety signal. Key Messages Thirteen randomized clinical trials (predominantly double-blind and placebo-controlled) were included, comparing 17,478 individuals treated with semaglutide and 17,334 placebos. A total of 15 retinal vascular events were reported in the semaglutide groups compared with four events in placebo arms. In large, long-term trials (SELECT, SOUL, FLOW), incidence rates were consistently low but numerically higher in semaglutide-treated patients, ranging from 0 to 0.33 events per 1,000 person-years versus 0 to 0.05 in placebo groups. In trials with active comparators, rates ranged from 0 to 5.99 events per 1,000 person-years in semaglutide groups and 0 to 3.52 in comparator groups. For ischemic optic neuropathies, six events were reported among 11,757 semaglutide-treated patients versus one event among 11,105 placebo-treated individuals; in trials with active comparators, two versus one event were reported. In conclusion, retinal vascular events, especially retinal arterial occlusions, showed a higher pattern of reporting in the semaglutide arm across clinical trials, the majority of which were randomized placebo-controlled-trials. Optic ischemic neuropathies were also found to be higher on the semaglutide-arm. These findings support the need for further investigation through large-scale registry studies.
Hydrophobic ion pairing formed semaglutide designed for oral self-microemulsifying delivery in diabetes treatment.
Eur J Pharm Biopharm
Yuhuan Zhang, Jinghan Cheng, Hanming Wang +4 more
Semaglutide (SET) is a glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes. Although injectable formulations offer high bioavailability, they are associated with poor patient compliance. In contrast, oral tablets are more convenient but suffer from limited absorption due to SET's hydrophilicity and enzymatic instability in the gastrointestinal tract. To address these challenges, we developed a hydrophobic ion pair (HIP) complex of SET and sodium docusate (SET-DOC), which was further incorporated into a self-emulsifying drug delivery system (SD@SEDDS) to facilitate oral delivery. The optimized SD@SEDDS produced a clear emulsion upon dilution, with a uniform particle size of 85.55  nm, high drug loading (2.64  mg/g), and excellent stability. In vitro transport studies using a Caco-2/HT-29 co-culture model demonstrated enhanced permeability and reduced P-glycoprotein-mediated efflux. In vivo studies in a type 2 diabetic rat model showed that SD@SEDDS significantly reduced blood glucose levels, improved lipid profiles, and exhibited good biocompatibility without observable toxicity. These findings suggested that the combination of HIP technology and SEDDS represented a promising strategy for enhancing the oral delivery efficiency of peptide drugs such as SET.
Papillary thyroid carcinoma discovered in a patient on semaglutide therapy for metabolic syndrome: a case presentation and review of current evidence.
Hormones (Athens)
Jawad Haddadin, Aus Haddad, Lina Nahar +2 more
Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is widely used for the management of type 2 diabetes, metabolic syndrome, and obesity. Concerns regarding its potential association with thyroid cancer, particularly medullary thyroid carcinoma, have emerged, although current human evidence remains inconclusive. Reports of papillary thyroid carcinoma (PTC) while using semaglutide therapy are exceedingly rare.
Tirzepatide Efficacy and Tolerability According to Early Weight Response: A Post Hoc Analysis of the SURMOUNT-1 and SURMOUNT-2 Trials.
Diabetes Obes Metab
Alexander Kokkinos, Tina Thethi, Clare J Lee +5 more
Obesity affects over 800 million people globally and is associated with complications including cardiovascular disease and type 2 diabetes (T2D). Early response to weight loss interventions may help optimize achievement of individual treatment goals. Tirzepatide has demonstrated significant weight reduction and improvement in cardiometabolic risk parameters (CRPs) in the SURMOUNT (SM)-1 (NCT04184622) and SM-2 (NCT04657003) trials. We aimed to assess weight reduction, CRPs, tolerability and hypoglycaemia according to early body weight response to tirzepatide in these studies.
Long-Term Mechanical Complications After Lumbar Fusion in Patients Receiving Tirzepatide vs Other GLP-1 Receptor Agonists.
Spine (Phila Pa 1976)
Ryan Wang, Humaira Islam, Arjuna Karikaran +5 more
Retrospective cohort study.
Efficacy and tolerance of GLP-1 analogues in the treatment of adolescent obesity: analysis of a French population.
Arch Pediatr
Sarah Bouhmouch, Béatrice Dubern, Catherine Terraz +1 more
Adolescent obesity is a chronic condition. The pathophysiology of this complex disease involves genetic mechanisms that influence appetite regulation via the hypothalamus, with environmental factors acting as triggers or aggravating factors.
EFFECTS OF GLP-1 RECEPTOR AGONISTS ON PERIODONTAL TISSUE: AN INTERDISCIPLINARY EVIDENCE MAPPING - SCOPING REVIEW.
Ann Pharm Fr
João Pedro Henriques, Artur Villas Boas Weckwerth, Adriana Campos Passanezi Santana +3 more
Diabetes mellitus and periodontal disease are highly prevalent chronic disorders linked by bidirectional inflammatory and oxidative pathways. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are emerging pharmacologic agents with anti-inflammatory properties that may benefit periodontal tissues, although the available evidence remains limited. This scoping review aimed to map the available evidence on the effects of GLP-1 RA on periodontal tissues and their underlying mechanisms of action.
Metabolic state determines the brain and direct islet effects of liraglutide on enhanced insulin secretion.
Diabetologia
Chiara Saponaro, Monica Imbernon, Isaline Louvet +26 more
Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist for type 2 diabetes and obesity management, shows variable patient responses. We investigated the metabolic state-dependent mechanisms underlying this heterogeneity and how liraglutide's mode of action shifts across stages of metabolic dysfunction.
Cellular Senescence Links Muscle Atrophy and Posttraumatic Osteoarthritis after ACL Injury.
Function (Oxf)
Alexander R Keeble, Allison Owen, Sara Gonzalez-Velez +22 more
Traumatic knee injury leads to posttraumatic osteoarthritis (PTOA) and significant skeletal muscle weakness, resulting in chronic disability. The current standard of care frequently fails to prevent musculoskeletal dysfunction, underscoring the need to identify therapeutic mechanisms of PTOA. Using an established preclinical anterior cruciate ligament (ACL) transection model of PTOA and leveraging an innovative SPiDER-senescence associated β-galactosidase stain to discern senescent cells, we investigated cellular senescence at single-cell resolution and identified anti-inflammatory macrophages as a predominant contributor to the senescent cell burden in both muscle and knee joint after injury. Clearance of senescent cells using the senolytic dasatinib and quercetin (D+Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared to cartilage. We also provide clinical evidence of elevated senescent cell burden in muscle of patients following ACL injury and with PTOA, which is obstinate to standard of care, highlighting cellular senescence as a strong therapeutic target to improve functional recovery after traumatic joint injury.