Immunosenescence, characterized by functional decline and altered phenotypes of immune cells with age, can disturb immune tolerance and promote autoreactive responses. Type 1 diabetes (T1D) has traditionally been viewed as a disease of immune dysregulation that leads to the autoimmune destruction of pancreatic β-cells. Emerging evidence suggests that senescence contributes to both the onset and progression of T1D. Autoreactive T cells are associated not only with β-cell death but also with the induction of β-cell senescence. In parallel, senescent β-cells acquire a senescence-associated secretory phenotype that amplifies local inflammation and increases β-cell vulnerability. These interlinked processes position senescence as a mechanistic bridge between aging, immune dysfunction, and autoimmunity. Importantly, a bidirectional loop appears to exist, in which T1D accelerates immune aging while immunosenescence further exacerbates autoimmunity. Recognizing this interplay highlights senescence as a promising and underexplored therapeutic target. Here, we synthesize current knowledge on immunosenescence and cellular senescence, examine their convergence in T1D pathogenesis, and outline future directions where interventions against senescent pathways could open new opportunities for treatment and prevention.

Palmitoylation, the reversible modification of proteins by palmitate, is altered in diabetes. We inactivated acyl protein thioesterase-1 (APT1), a key palmitoylation cycling enzyme, in adipose tissue to study how fat affects systemic metabolism. Given adiposity effects on β-cell failure, we asked if palmitoylation of proteins in fat affects insulin secretion. Adipose APT1-deficient mice had improved glucose metabolism and increased cell-autonomous insulin secretion in two models of insulin resistance, high-fat diet, and aging. Extracellular vesicles from APT1-deficient adipocytes promoted insulin secretion in insulinoma cells. Altering palmitoylation in fat may preserve β-cell function in insulin resistance.

Our goal: limit glycolysis with 2-deoxyglucose (2-DG) in autoreactive CD4 T cells to delay spontaneous type 1 diabetes in NOD mice. Inhibition of glycolysis with 2-DG during autoreactive CD4 T-cell activation and differentiation decreased effector responses (interferon-γ), increased anergic markers (CD73, folate receptor 4), and delayed spontaneous type 1 diabetes in NOD mice. The effects of 2-DG on antigen-presenting cells resulted in a decrease in CD86 expression that may partly explain the induction of anergy. Inhibiting glycolysis is sufficient to diminish autoreactive CD4 T-cell responses and may be therapeutically applicable to other T cell-mediated inflammatory diseases.

The role of the heparanase (HPSE)-heparan sulfate (HS) axis in type 1 diabetes remains incompletely defined. We examined whether myeloid-derived HPSE drives islet inflammation, how HS fragments influence macrophage polarization, and whether pharmacological inhibition is protective. We found that myeloid HPSE disrupts the intraislet HS barrier and that the resulting HS fragments potentiate interferon-γ-STAT1 signaling to promote proinflammatory macrophage polarization. Genetic or pharmacological inhibition of HPSE preserved islet integrity and ameliorated diabetes, identifying this pathway as a potential therapeutic target in type 1 diabetes.

Pan-neddylation inhibitors exhibit potent hypoglycemic effect. The target organs and mechanisms underlying the hypoglycemia effect of pan-neddylation inhibitors are incompletely understood. We found that inhibition of cullin 3 leads to a dual insulin sensitization and insulinotropic effect. Selective inhibition of cullin 3 neddylation is a feasible approach to lower hyperglycemia.

Modulation of prostaglandin E2 (PGE2) signaling improves β-cell health and survival. In this study, we examined whether these β-cell effects could be harnessed alongside known PGE2-mediated immunomodulation to ameliorate β-cell loss in a model of severe islet autoimmunity. Simultaneous pharmacological blockade of the EP3 receptor and activation of the EP4 receptor maintain mature β-cell mass, ameliorate the proinflammatory insulitic microenvironment, and alter β-cell stress responses in female nonobese diabetic mice undergoing aggressive inflammatory assault. EP modulation shows promise to support β-cell resiliency and reduce inflammation in a setting of autoimmune attack, such as type 1 diabetes.

The molecular mechanisms by which primary cilia regulate energy homeostasis remain poorly understood. Here, we evaluated whether the ciliary GTPase ARL13B regulates energy homeostasis and whether its localization to cilia is required to control body weight and feeding. Using genetic tools to isolate cilia-specific functions, we found that systemic exclusion of ARL13B from cilia causes hyperphagia and obesity in mice and that ciliary ARL13B is required in the nervous system for weight control. These findings identify ciliary ARL13B as a key regulator of energy homeostasis, contributing to our understanding of how primary cilia act as metabolic signaling hubs.

SIRT6 downregulation in atherosclerotic vascular endothelial cells (ECs) is exacerbated under diabetic conditions, and EC-specific Sirt6 knockout aggravates diabetic atherosclerosis progression. EC-specific Sirt6 knockout aggravates atherosclerosis progression through vasculature hyperpermeability and monocyte/macrophage accumulation in vessels. SIRT6 directly interacts with transcription factor zinc finger E-box binding homeobox 1 (ZEB1) for deacetylation/degradation, preserving ZEB1 at a low level for normal expression of tight junction protein claudin-1 in ECs to maintain endothelial barrier function for vascular homeostasis. Naringin, a natural flavonoid ZEB1 inhibitor, reverses the diabetes-exacerbated vascular endothelial dysfunction to attenuate atherosclerosis progression, offering a promising, novel therapeutic strategy for diabetic atherosclerotic cardiovascular diseases.

Skeletal muscle microvasculature is essential for nutrient delivery and metabolic regulation, but the vascular actions of glucose-dependent insulinotropic polypeptide (GIP) in muscle are unknown. We investigated whether GIP regulates skeletal muscle microvascular perfusion and interacts with insulin and GLP-1 signaling. GIP receptors are expressed in vascular endothelium, yet GIP alone does not increase muscle perfusion and instead antagonizes insulin- and GLP-1-mediated microvascular recruitment via possibly angiotensin II type 1 receptor-dependent endothelin-1/nitric oxide imbalance. GIP acts as a conditional regulator of skeletal muscle microvascular perfusion, revealing a novel mechanism of tissue-specific incretin regulation of nutrient partitioning.

Diabetic retinopathy (DR) remains a leading cause of blindness, characterized by progressive neurovascular dysfunction. While the enzyme 12/15-lipoxygenase (12/15-LO) and its metabolites are upregulated in DR, their interactions with epigenetic regulators, such as miRNAs, are poorly understood. This study investigates the role of 12/15-LO in miRNA dysregulation and its functional consequences in a type 1 diabetic mouse model. We generated 12/15-LO knockout mice on an (Ins2+/akita) (Akita) background. Retinal miRNA expression was profiled using microarray analysis, and retinal structure and function were assessed using histology and electroretinography. Our results demonstrate that diabetes induces significant dysregulation of a distinct subset of retinal miRNAs (e.g., downregulation of miR-329-3p and miR-431-5p and upregulation of miR-3078-3p and miR-323-5p). Deletion of 12/15-LO normalized a subset of these diabetes-associated miRNA alterations and prevented retinal thinning and the loss of neuronal markers (NeuN and SCGN). Functionally, 12/15-LO deletion rescued diabetes-induced deficits in retinal ganglion cell (positive scotopic threshold response), cone bipolar cell (photopic b-wave), and cone pathway function (response to natural noise). In conclusion, our findings establish 12/15-LO as a critical upstream regulator of miRNA in the diabetic retina and demonstrate that its deletion protects against neuronal damage in DR. Thus, targeting the 12/15-LO pathway may represent a novel therapeutic strategy to mitigate neuronal dysfunction associated with DR progression.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease worldwide, despite therapeutic advances. Podocyte injury constitutes a critical pathogenic process in DKD. This study elucidated the role of the neonatal Fc receptor (FcRn) in DKD-associated podocyte injury. In DKD, glomerular FcRn expression was markedly elevated and inversely correlated with podocin levels. In diabetic mice, podocyte-specific FcRn deficiency significantly ameliorated insulin resistance and mitigated podocyte damage. Mechanistically, FcRn upregulation in diabetic podocytes exacerbated insulin resistance, suppressed AKT/mTOR signaling, and impaired autophagy, thereby promoting podocyte injury. These findings identify FcRn as a pivotal contributor to podocyte injury in DKD and suggest that FcRn targeting represents a promising therapeutic strategy.

Inflammatory stress increases endoplasmic reticulum protein-folding burden in β-cells and amplifies immunogenicity through HLA-I hyperexpression, yet targeted strategies to restore β-cell proteostasis are lacking. We demonstrate that an islet-specific, cell surface-directed antibody is internalized and functions as a zinc transporter 8-selective chaperone, enhancing endoplasmic reticulum folding capacity, attenuating HLA-I hyperexpression, and robustly inducing programmed death-ligand 1. Identification of programmed death-ligand 1 as a direct pharmacodynamic marker of zinc transporter 8-chaperoning links on-target engagement to reinforcement of local immune checkpoint signaling. Humanized Fc-silent Isle43 shows durable pancreatic retention, dose-dependent reversal of new-onset type 1 diabetes in nonobese diabetic mice, sustained remission after treatment cessation, and protection of human islet graft function in vivo. This islet-targeted strategy preserved β-cell function in inflammatory mouse models and human islet grafts, supporting an islet-targeted therapeutic approach for inflammatory β-cell failure.