Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, and depression, are marked by progressive neuronal dysfunction and loss, yet current treatments remain largely symptomatic with limited disease-modifying efficacy. Glucagon-like peptide-1 (GLP-1), an incretin hormone traditionally associated with metabolic regulation, has emerged as a promising neuroprotective agent. Its receptor, GLP-1R, is expressed in key brain regions implicated in cognition, emotion, and motor control, including the hippocampus, frontal cortex, and substantia nigra. GLP-1R agonists (GLP-1RAs) activate multiple intracellular signaling cascades—cAMP/PKA, PI3K/Akt, and MAPK pathways—that collectively promote neuronal survival, enhance synaptic plasticity, reduce oxidative stress, inhibit apoptosis, and modulate neuroinflammation. These agents also regulate autophagy, promote remyelination, and reprogram microglial phenotypes toward anti-inflammatory states. Preclinical models have shown that GLP-1RAs reduce amyloid-β and tau pathology in AD, preserve dopaminergic neurons in PD, protect astrocytes and neural progenitors after ischemic stroke, and alleviate depressive behaviors. Notably, GLP-1RAs such as liraglutide, exenatide, and dulaglutide can cross the blood–brain barrier and have demonstrated safety and potential efficacy in early-phase clinical trials. These studies report attenuation of cortical atrophy, preservation of cerebral glucose metabolism, and improvements in quality of life, though changes in core AD biomarkers remain inconclusive. Ongoing large-scale trials (e.g., EVOKE, ELAD) are further exploring their therapeutic impact. This review consolidates the mechanistic basis and translational potential of GLP-1RAs in age-related neurodegenerative diseases, highlighting both their promise and the challenges that must be addressed in future clinical applications.

Mitochondria are essential for β-cell function, coupling glucose metabolism to ATP production and insulin secretion. In diabetes, β-cell mitochondrial dysfunction arises from oxidative stress, impaired quality control and disrupted dynamics, leading to reduced oxidative phosphorylation, defective insulin release and progressive cell loss. Key transcriptional regulators link genetic susceptibility to mitochondrial dysfunction in both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). These disruptions impair mitophagy, mitochondrial translation and redox homeostasis. Therapeutic strategies that restore mitochondrial function, including mitophagy enhancers, mitochondrial antioxidants, and transcriptional regulators, have shown potential in preserving β-cell integrity. As mitochondrial failure precedes β-cell loss, targeting mitochondrial pathways may represent a critical approach to modifying diabetes progression.

Historically, microglial activation has been associated with diseases of a neurodegenerative and neuroinflammatory nature. Some, like Alzheimer’s disease, Parkinson’s disease, and multiple system atrophy, have been explored extensively, while others pertaining to metabolism not so much. However, emerging evidence points to hypothalamic inflammation mediated by microglia as a driver of metabolic dysregulations, particularly insulin resistance and type 2 diabetes mellitus. Here, we explore this connection further and examine pathways that underlie this relationship, including the IKKβ/NF-κβ, IRS-1/PI3K/Akt, mTOR-S6 Kinase, JAK/STAT, and PPAR-γ signaling pathways. We also investigate the role of non-coding RNAs, namely microRNAs and long non-coding RNAs, in insulin resistance related to neuroinflammation and their diagnostic and therapeutic potential. Finally, we explore therapeutics further, searching for both pharmacological and non-pharmacological interventions that can help mitigate microglial activation.

In the context of cell cycle inhibition, anti-proliferation, and the dysregulation observed in certain cancer pathologies, the protein p21 assumes a pivotal role. p21 links DNA damage responses to cellular processes such as apoptosis, senescence, and cell cycle arrest, primarily functioning as a regulator of the cell cycle. However, accumulating empirical evidence suggests that p21 is both directly and indirectly linked to a number of different metabolic processes. Intriguingly, recent investigations indicate that p21 significantly contributes to the pathogenesis of diabetes. In this review, we present a comprehensive evaluation of the scientific literature regarding the involvement of p21 in metabolic processes, diabetes etiology, pancreatic function, glucose homeostasis, and insulin resistance. Furthermore, we provide an encapsulated overview of therapies that target p21 to alleviate metabolic disorders. A deeper understanding of the complex interrelationship between p21 and diabetes holds promise for informing current and future therapeutic strategies to address this rapidly escalating health crisis.

Introduction: Ischemic heart disease (IHD) remains a major global health burden, highlighting the urgent need for early, non-invasive diagnostic biomarkers. MicroRNAs (miRNAs), small non-coding RNA molecules that regulate gene expression, have emerged as promising candidates due to their stability in circulation and involvement in cardiovascular processes. This systematic review aimed to evaluate the potential of specific miRNAs as early diagnostic biomarkers in IHD.Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were performed in PubMed, Scopus, and Web of Science databases up to June 31, 2024. Eligible studies were selected based on predefined inclusion criteria. We identified recurrently dysregulated miRNAs and used miRTarBase to retrieve experimentally validated gene targets. Subsequently, gene set enrichment analysis (GSEA) was performed using Enrichr, referencing BioPlanet, KEGG, and Panther pathway libraries. Functional annotation was further explored using TAM 2.0.Results: A total of 38 studies met the inclusion criteria. Among the reported miRNAs, miR-126, miR-21, miR-145, miR-92a, and miR-155 were the most frequently and consistently dysregulated across various IHD subtypes. Although expression patterns varied, these miRNAs were recurrently implicated in IHD-related processes. GSEA revealed enrichment of their gene targets in key pathways such as p53, TGF-β, and FoxO signaling, as well as in processes involving apoptosis and angiogenesis critical in vascular injury, remodeling, and immune activation. Several cancer-related pathways were also enriched, underscoring molecular overlaps between tumorigenesis and atherosclerosis. TAM 2.0 functional annotation supported these findings, linking the selected miRNAs to smooth muscle differentiation, cytokine signaling, and regulation by key transcription factors including SMAD4, STAT3, and AP-1.Discussion: Our findings suggest that a panel combining the identified miRNAs may offer greater diagnostic value for IHD than individual markers, given their involvement in multiple IHD-related biological processes and pathways. The recurrent dysregulation of these miRNAs across diverse studies supports their potential as components of a robust, non-invasive diagnostic tool. However, expression variability and pathway overlap with other diseases, such as cancer, indicate the need for further validation. Larger prospective studies are warranted to validate their clinical applicability in IHD screening and risk stratification.Systematic review registration: International Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42024583265.