The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
Barghouth, M.; Jiang, X.; Nagao, M.; Chen, N.; Yang, D.; Ye, Y.; Luan, C.; Gomez, M.; Blom, A. M.; Wollheim, C.; Eliasson, L.; Renstrom, E.; Zhang, E.
Show abstract
Exocytosis in excitable cells is essential for their physiological functions. Although the exocytotic machinery controlling cellular secretion has been well investigated, the function of the vesicular cargo, i.e. secretory granular content remains obscure. Here we combine dSTORM imaging and single-domain insulin antibody, to dissect the in situ structure of insulin granule cores (IGCs) at nano level. We demonstrate that the size and shape of the IGCs can be regulated by the juxta-granular molecules Nucleobindin-2 and Enolase-1, that further contribute to the stimulated insulin secretion. IGCs located at the plasma membrane are larger than those in the cytosol. The IGCs size is decreased by [~]20% after glucose stimulation due to the release of the peripheral part of IGCs through incomplete granule fusion. Importantly, the reduction of the IGCs size is also observed in non-stimulatory pancreatic {beta}-cells from diabetic db/db mice, Akita (Ins2+/-) mice and human Type-2 diabetic donors, in accordance with impaired secretion. These findings overall highlight the structure of exocytotic insulin cores as a novel modality amenable to targeting in the stimulated exocytosis in {beta}-cells with impaired insulin secretion.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Pancreatic beta-cell specific deletion of VPS41 causes diabetes due to defects in insulin secretion 96%
- Dynamic Ins2 gene activity defines β-cell maturity states 96%
- Pancreatic β-cell specific loss of E2f1 impairs insulin secretion and β-cell identity through the epigenetic repression of non β-cell programs 95%
Similar papers in this journal
- Purification of age-distinct insulin secretory granules through antigen restriction 94%
- Target deconvolution of an insulin hypersecretion-inducer acting through VDAC1 with a distinct transcriptomic signature in beta-cells 94%
- Single-cell analysis of the human pancreas in type 2 diabetes using multi-spectral imaging mass cytometry 93%
Similar papers in this journal
- Microtubules regulate pancreatic beta cell heterogeneity via spatiotemporal control of insulin secretion hot spots 96%
- Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ channel function to control glucose dependent insulin secretion. 94%
- BLOS1 mediates kinesin switch during endosomal recycling of LDL receptor 94%
Similar papers in this journal
- SLAPSHOT reveals rapid dynamics of extracellularly exposed proteome in response to calcium-activated plasma membrane phospholipid scrambling 94%
- Chromogranin A and catestatin regulate pancreatic islet homeostasis, endocrine function, and neurotransmitter signaling 94%
- Role of the G-Protein Coupled Receptor 3-Salt Inducible Kinase 2 Pathway in Human β CellProliferation 92%
Similar papers in this journal
- Signal transduction pathways controlling Ins2 gene activity and β cell state transitions 94%
- The HDAC inhibitor trichostatin A impairs pancreatic β-cell function through an epigenome-wide reprogramming 93%
- Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet IGF-1 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.