RT Journal Article
SR Electronic
T1 The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.22.481455
DO 10.1101/2022.02.22.481455
A1 Barghouth, Mohammad
A1 Jiang, Xiaoping
A1 Nagao, Mototsugu
A1 Chen, Ning
A1 Yang, Daowei
A1 Ye, Yingying
A1 Luan, Cheng
A1 Gomez, Maria F.
A1 Blom, Anna M.
A1 Wollheim, Claes B
A1 Eliasson, Lena
A1 Renström, Erik
A1 Zhang, Enming
YR 2022
UL http://biorxiv.org/content/early/2022/02/23/2022.02.22.481455.abstract
AB 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.