Diabetes mellitus is a chronic metabolic disease characterized by elevated blood glucose that results from defects in insulin secretion and/or action. Until now, the cellular mechanisms and molecular components responsible for the biogenesis of insulin granules are still not fully understood. PICK1 (Protein Interacting with C Kinase 1) is a peripheral membrane protein which forms a tight heteromeric complex with ICA69 (Islet Cell Autoantigen 69kD). This complex is able to tether membrane proteins to vesicles and hence regulate their trafficking. Previously, our lab found that PICK1-ICA69 was associated with insulin granules and deficiency of PICK1-ICA69 in mice led to glucose intolerance and decreased insulin level. However, the detailed molecular mechanism underlying the defect...[ Read more ]

Diabetes mellitus is a chronic metabolic disease characterized by elevated blood glucose that results from defects in insulin secretion and/or action. Until now, the cellular mechanisms and molecular components responsible for the biogenesis of insulin granules are still not fully understood. PICK1 (Protein Interacting with C Kinase 1) is a peripheral membrane protein which forms a tight heteromeric complex with ICA69 (Islet Cell Autoantigen 69kD). This complex is able to tether membrane proteins to vesicles and hence regulate their trafficking. Previously, our lab found that PICK1-ICA69 was associated with insulin granules and deficiency of PICK1-ICA69 in mice led to glucose intolerance and decreased insulin level. However, the detailed molecular mechanism underlying the defects is unclear.

In my study, I further investigated the PICK1-ICA69’s role in insulin granule biogenesis. I first examined the glucose metabolism in Ica69-/- mice and found that they mimicked the phenotype of Pick1-/- mice, which was manifested by impaired glucose tolerance and insufficient insulin secretion. Molecular studies showed that PICK1 and ICA69 specifically affected the dense-core insulin granules in the regulated secretory pathway but not other types of granules in β cells. In the absence of PICK1-ICA69, ~50% of the insulin granule contents were lost due to the missorting for lysosomal degradation. Upon glucose stimulation, the budding and maturation of insulin granules were also compromised. Moreover, the important insulin granule metal ion Zn²⁺ was significantly reduced in Pick1-/- and Ica69-/- islets. PICK1 interacted with β cell specific zinc transporter, ZnT8, regulated its expression and subcellular localization, hence Zn²⁺ homeostasis in β cells. Taken together, these results provide evidence that PICK1-ICA69 complex plays important roles in cargo sorting, vesicle budding and Zn²⁺ homeostasis in pancreatic β cells.