PT  - JOURNAL ARTICLE
AU  - Mohammad Barghouth
AU  - Xiaoping Jiang
AU  - Mototsugu Nagao
AU  - Ning Chen
AU  - Daowei Yang
AU  - Yingying Ye
AU  - Cheng Luan
AU  - Maria F. Gomez
AU  - Anna M. Blom
AU  - Claes B Wollheim
AU  - Lena Eliasson
AU  - Erik Renström
AU  - Enming Zhang
TI  - The structure of insulin granule core determines secretory capacity being reduced in type-2 diabetes
AID  - 10.1101/2022.02.22.481455
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.22.481455
4099  - http://biorxiv.org/content/early/2022/02/23/2022.02.22.481455.short
4100  - http://biorxiv.org/content/early/2022/02/23/2022.02.22.481455.full
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.