Altered BAG3-insulin colocalization is associated with impaired first phase insulin secretion in humans

Aims: Alterations in first-phase insulin secretion are pivotal in the early development of T2DM. BAG3 has been implicated in regulating insulin secretion in murine models, but its role in humans remains unexplored. This study investigates BAG3 expression in human pancreatic islets and its relationship with β-cell functionality. Methods: Pancreatic tissue samples were obtained from 12 patients with no previous T2DM diagnosis enrolled for partial pancreatectomy. Patients underwent deep metabolic evaluation, including OGTT, hyperglycemic clamp and euglycemic hyperinsulinemic clamp. Immunofluorescence and confocal microscopy were used to assess BAG3-insulin colocalization and further correlated with metabolic findings, categorizing subjects into LOW and HIGH BAG3 groups. Results: Patients with HIGH BAG3 expression exhibited significantly impaired first-phase insulin secretion, evidenced by reduced rate sensitivity during OGTT and higher plasma glucose levels at 30 and 60 min post-glucose challenge. Islets from HIGH BAG3 patients showed increased size but no differences in insulin/glucagon ratios or insulin sensitivity, suggesting a specific disruption in the insulin secretory machinery rather than β-cell mass or insulin resistance. Conclusions: BAG3 appears associated to first-phase insulin secretion in humans by influencing insulin granule exocytosis. Targeting BAG3 could represent a novel therapeutic approach to prevent or delay β-cell dysfunction and the onset of T2DM.