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Single-cell transcriptome profiling of pancreatic islets from early diabetic mice identifies Anxa10 for Ca2+ allostasis toward β-cell failure

Version 2 2023-11-17, 20:03
Version 1 2023-10-23, 17:23
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posted on 2023-11-17, 20:03 authored by Kaori Motomura, Takashi MatsuzakaTakashi Matsuzaka, Shigeyuki Shichino, Tatsuro Ogawa, Hao Pan, Takuya Nakajima, Yasuhito Asano, Toshitsugu Okayama, Tomoyo Takeuchi, Hiroshi Ohno, Song-iee Han, Takafumi Miyamoto, Yoshinori Takeuchi, Motohiro Sekiya, Hirohito Sone, Naoya Yahagi, Yoshimi Nakagawa, Tatsuya Oda, Satoshi Ueha, Kazuho Ikeo, Atsushi Ogura, Kouji Matsushima, Hitoshi Shimano

Type 2 diabetes (T2D) is a progressive disorder denoted by hyperglycemia and impaired insulin secretion. Although a decrease in β-cell function and mass is a well-known trigger for diabetes, the comprehensive mechanism is still unidentified. Here we carried out single-cell RNA sequencing (scRNA-seq) of pancreatic islets from prediabetic and diabetic db/db mice, an animal model of T2D. We discovered a diabetes-specific transcriptome landscape of endocrine and nonendocrine cell types with subpopulations of β and α cells. We recognized a new prediabetic gene, Anxa10, that was induced by, and regulated Ca2+ influx from metabolic stresses. Anxa10-overexpressed β cells displayed suppression of glucose-stimulated intracellular Ca2+ elevation and potassium-induced insulin secretion. Pseudotime analysis of β cells predicted this Ca2+-surge responder-cluster proceeded to mitochondria dysfunction and also endoplasmic reticulum stress. Other trajectories comprised dedifferentiation and transdifferentiation, emphasizing acinar-like cells in diabetic islets. Altogether, our data provides a new insight into Ca2+ allostasis and β cell failure processes.

Funding

This work was supported by research funds from the grants-in-aid for Scientific Research on Innovative Areas program (Inflammation Cellular Sociology) JP17H06395 (to H.S.) and JP17H06391 (to K. Matsushima) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Tatsuro Ogawa is currently an employee of Daiichi Sankyo Co., Ltd.

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