insulin (Univia / rh Insulin / Insulin R)

From Disposal to Display: Crinophagy as a β-Cell Source of Neoantigens in Type 1 Diabetes.

Zou Angela J AJ, Wan Xiaoxiao X

Type 1 diabetes (T1D) arises when autoreactive lymphocytes target pancreatic β-cells, yet the mechanisms that convert β-cell self-proteins into disease-relevant antigens remain incompletely defined. β-cells are uniquely positioned to generate neoantigens because they devote extraordinary protein synthesis capacity to insulin production and maintain thousands of dense-core insulin granules. While a small fraction of granules undergoes glucose-stimulated exocytosis, excess, aged, or immature granules can be degraded through crinophagy, a lysosomal pathway in which secretory granules fuse with lysosomes to form crinosomes. Recent immunopeptidomic studies suggest that crinosomes are not merely disposal compartments but antigen-editing organelles that remodel insulin granule cargo into pathogenic epitopes. These include free insulin B-chain peptides, hybrid insulin peptides, post-translationally modified insulin and C-peptide epitopes, and stress-induced insulin sequence variants such as insulin B-peptide C19S. Because several crinosome-associated epitopes are poorly represented in the thymus, crinophagy may create a peripheral antigen repertoire that permits escape from central tolerance and activation of autoreactive T cells in islets and draining lymphoid tissues. This review discusses the physiology of β-cell granule turnover, the mechanisms of crinosome-associated neoantigen generation, and their implications for T1D pathogenesis, biomarkers, and therapeutic targeting.

Prognostic stratification in a diabetic kidney disease trial using plasma concentrations of soluble tumor necrosis factor receptor 1.

Petrovic Vladimir V, Malkov Vladislav A VA, Billin Andrew N AN, Patel Uptal D UD et al.

Concentration of circulating soluble tumor necrosis factor receptor 1 is associated with faster progression in patients with diabetic kidney disease based on data obtained from large longitudinal cohort studies. A cutpoint of 4.3 ng/mL baseline plasma concentration was identified to stratify patients and predict clinical outcome. We set out to test the prognostic utility of this cutpoint in a randomized clinical trial. Soluble tumor necrosis factor receptor 1 concentration was measured across plasma samples from Joslin cohort and selonsertib trial cohort. Estimated glomerular filtration rate slope was calculated using a patient-specific linear regression model based on serum creatinine concentration and compared between the cohorts. Kidney-related events were plotted using Kaplan-Meier estimates for both cohorts. Participants from both the clinical study cohort and the observational cohort showed an inverse relationship between baseline plasma concentrations of tumor necrosis factor receptor 1 and estimated glomerular filtration rate. When stratified based on baseline soluble tumor necrosis factor receptor 1 cutpoint, higher probability of experiencing a clinical event was found in patients with levels of soluble tumor necrosis factor receptor 1 exceeding 4.3 ng/mL in either of the cohorts. We demonstrated the prognostic utility of plasma concentrations of circulating soluble tumor necrosis factor receptor 1 in identifying individuals with diabetic kidney disease at an elevated risk of progressive kidney function decline in a randomized clinical study setting. This data supports previous findings from large observational cohorts and supports the use of this marker as a reliable predictor of disease outcome.

Retraction: Mammalian Target of Rapamycin Inhibitors Activate the AKT Kinase in Multiple Myeloma Cells by Up-regulating the Insulin-like Growth Factor Receptor/Insulin Receptor Substrate-1/Phosphatidylinositol 3-Kinase Cascade.

Shi Yijiang Y, Yan Huajun H, Frost Patrick P, Gera Joseph J et al.

Physical activity and human IAPP islet amyloidosis: mechanistic plausibility, missing evidence, and future directions.

Servitja Joan-Marc JM, Novials Anna A, Montane Joel J

Islet amyloid deposition derived from human islet amyloid polypeptide (hIAPP, amylin) is a hallmark of type 2 diabetes (T2D) and is tightly linked to progressive β-cell dysfunction and loss. It is now well established that the "toxic oligomer" hypothesis, in which soluble or intracellular hIAPP assemblies contribute to β-cell proteotoxicity and to the amplification of inflammatory stress, coexists with fibril associated and inflammation-driven mechanisms of toxicity. Regular physical activity (PA) is a cornerstone of T2D management and improves insulin sensitivity, glycemic control, ectopic lipid handling, and systemic inflammation, all of which could reduce β-cell secretory burden and the cellular milieu that favors hIAPP misfolding. However, direct demonstrations that PA delays or reduces islet amyloid formation remain scarce. This gap largely reflects methodological constrains in quantifying amyloid dynamics in humans and the absence of exercise studies with amyloid-specific endpoints. Herein, we synthesize mechanistic links by which exercise could influence hIAPP aggregation propensity (β-cell workload, glucolipotoxicity, endoplasmic reticulum stress, mitochondrial function, and inflammatory signaling) and highlight proteostasis pathways, particularly autophagy/lysosomal clearance, that are experimentally shown to defend β-cells against hIAPP oligomer toxicity. Overall, while direct evidence remains sparse, substantial mechanistic plausibility supports a link between PA and hIAPP amyloid biology. Future studies incorporating amyloid-specific outcomes are needed to determine whether exercise directly modifies amyloid formation, reduces oligomer burden, or primarily enhances β-cell resilience to proteotoxic stress.