Insulin secretion is a tightly regulated process that is vital for maintaining blood glucose homeostasis. Although the molecular components of insulin granule trafficking and secretion are well established, how they are regulated to rapidly fine-tune secretion in response to changing environmental conditions is not well characterized. Recent studies have determined that dysregulation of RNA-binding proteins (RBPs) and aberrant mRNA splicing occurs at the onset of diabetes. We demonstrate that the RBP, RBFOX2, is a critical regulator of insulin secretion through the alternative splicing of genes required for insulin granule docking and exocytosis. Conditional mutation of Rbfox2 in the mouse pancreas results in decreased insulin secretion and impaired blood glucose homeostasis. Consistent with defects in secretion, we observe reduced insulin granule docking and corresponding splicing defects in the SNARE complex components. These findings identify an additional mechanism for modulating insulin secretion in both healthy and dysfunctional pancreatic β cells.

Post-translational modifications (PTMs) provide an integrated regulatory layer that couples nutrient and hormonal signals to whole-body energy homeostasis across metabolic organs. PTMs modulate protein activity, localization, stability, and metabolic networks in a tissue- and state-specific manner. Through network remodeling, PTMs integrate receptor signaling with chromatin and organelle function and align transcriptional control with mitochondrial function, proteostasis, and membrane trafficking. PTM crosstalk connects kinase cascades, nutrient-sensing pathways, and ubiquitin-family modifiers to orchestrate gluconeogenesis, lipolysis, glucose uptake, thermogenesis, and insulin secretion in response to nutrient cues. The metabolic state regulates PTM enzymes through changes in cofactors, redox tone, and compartmentalization, and PTM-dependent changes in transcription and signaling feedback to metabolic tone. In obesity and diabetes, dysregulated post translational modification networks disrupt insulin receptor signaling, disturb organelle quality control, and impair beta cell function, which promotes insulin resistance and beta cell failure. Consequently, PTMs organize metabolic information flow and modulate tissue responses to overnutrition and metabolic stress. A systems-level understanding of PTMs clarifies mechanisms of whole-body energy homeostasis and supports the discovery of new therapeutic targets in metabolic disease.

The global surge in type 2 diabetes mellitus (T2DM) requires a thorough understanding of pancreatic β-cell dysfunction, which remains a central determinant of the disease. However, the evaluation of β-cell insulin secretory capacity is often challenging in clinical practice due to its inherent complexity. This review presents a comprehensive technical overview of diverse assessment methodologies, ranging from conventional fasting-based indices and glucose tolerance tests to advanced mathematical modeling and artificial intelligence-driven approaches. A detailed examination of the methodological strengths and limitations of these various tools is provided to guide their appropriate clinical application. Furthermore, we explore the clinical implications of these assessments in enhancing diagnostic accuracy and tailoring therapeutic strategies. Particular emphasis is placed on the pivotal role of β-cell function evaluation in predicting and achieving diabetes remission—an emerging clinical priority. By integrating the technical landscape of β-cell assessment with practical applications, this review provide a structured framework for optimizing T2DM management and improving long-term patient outcomes.

The progressive decline in functional β-cell mass in Type 2 Diabetes (T2D) is increasingly recognized not as a simple apoptotic loss, but as a complex erosion of cellular identity termed “dedifferentiation.” Central to this phenotypic shift is the metabolo-epigenetic axis, where mitochondria act as the primary sensing hub, transducing nutrient flux into biochemical signals that govern the chromatin landscape. This review synthesizes current evidence on how mitochondrial metabolites—including Acetyl-CoA, α-ketoglutarate, and NAD+—serve as obligatory co-factors for the epigenetic machinery. We explore how chronic metabolic stress triggers a “Systemic epigenetic destabilization,” leading to the loss of lineage-specific markers and the formation of persistent “metabolic scars.” Furthermore, we discuss the clinical implications of these changes, specifically regarding the phenomenon of metabolic memory and the molecular limits of β-cell reversibility. By integrating foundational transcriptional studies with emerging epigenomic data, we propose that targeting the mitochondrial–epigenetic axis offers a strategic window for re-differentiating failing β-cells and restoring glycemic homeostasis.

Background: Estrogen deficiency following human menopause or rodent ovariectomy (OVX) induces adverse alterations in body composition and metabolic function. This study investigated the combined effects of acetic acid supplementation and voluntary exercise on metabolic health and skeletal muscle mitochondrial function using an OVX mouse model. Methods: Forty female C57BL/6J mice (8 weeks old) were randomly assigned to 5 groups: sham (SHM), ovariectomized control (OVX), OVX with exercise (OVX-E), OVX with acetic acid (OVX-A), and OVX with both interventions (OVX-AE). Following a 1-week recovery from OVX, a 13-week intervention was initiated: 5% sodium acetate-supplemented chow and/or voluntary wheel running. Body composition, glucose tolerance, total energy expenditure, skeletal muscle mitochondrial function, and the contents of AMPKα, PGC-1α, and carbonyl protein were assessed. Results: OVX impaired whole-body metabolism and skeletal muscle mitochondrial function, specifically in the gastrocnemius muscle. While the exercise alone failed to mitigate the OVX-induced mitochondrial dysfunction, the combined treatment of exercise and acetic acid supplementation significantly rescued from the OVX-induced mitochondrial dysfunction. Conclusions: OVX resulted in detrimental changes in whole-body metabolism, but voluntary exercise and/or acetic acid supplementation had no rescuing effects on those parameters. In gastrocnemius muscle, acetic acid supplementation during exercise enhanced mitochondrial function in OVX mice.