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The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes

Barghouth, Mohammad LU ; Jiang, Xiaoping LU ; Nagao, Mototsugu LU ; Chen, Ning LU ; Yang, Daowei LU ; Ye, Yingying ; Luan, Cheng LU ; Gomez, Maria F. LU orcid ; Blom, Anna M. LU orcid and Wollheim, Claes B LU , et al. (2022)
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... (More)
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 β-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 β-cells with impaired insulin secretion.Competing Interest StatementThe authors have declared no competing interest. (Less)
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publishing date
type
Working paper/Preprint
publication status
published
subject
publisher
bioRxiv
DOI
10.1101/2022.02.22.481455
language
English
LU publication?
yes
id
d3f28b54-80d1-4465-a020-cc342db0ea41
date added to LUP
2022-10-07 14:29:04
date last changed
2023-05-15 09:29:05
@misc{d3f28b54-80d1-4465-a020-cc342db0ea41,
  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 β-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 β-cells with impaired insulin secretion.Competing Interest StatementThe authors have declared no competing interest.}},
  author       = {{Barghouth, Mohammad and Jiang, Xiaoping and Nagao, Mototsugu and Chen, Ning and Yang, Daowei and Ye, Yingying and Luan, Cheng and Gomez, Maria F. and Blom, Anna M. and Wollheim, Claes B and Eliasson, Lena and Renström, Erik and Zhang, Enming}},
  language     = {{eng}},
  month        = {{02}},
  note         = {{Preprint}},
  publisher    = {{bioRxiv}},
  title        = {{The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes}},
  url          = {{http://dx.doi.org/10.1101/2022.02.22.481455}},
  doi          = {{10.1101/2022.02.22.481455}},
  year         = {{2022}},
}