Single-Cell Transcriptome Profiling of Pancreatic Islets From Early Diabetic Mice Identifies Anxa10 for Ca2+ Allostasis Toward β-Cell Failure
Kaori Motomura, Takashi 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
Abstract
Type 2 diabetes 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 performed single-cell RNA sequencing of pancreatic islets from prediabetic and diabetic db/db mice, an animal model of type 2 diabetes. 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 that this Ca2+-surge responder cluster would proceed to mitochondria dysfunction and endoplasmic reticulum stress. Other trajectories comprised dedifferentiation and transdifferentiation, emphasizing acinar-like cells in diabetic islets. Altogether, our data provide a new insight into Ca2+ allostasis and β-cell failure processes. ARTICLE HIGHLIGHTS: The transcriptome of single-islet cells from healthy, prediabetic, and diabetic mice was studied. Distinct β-cell heterogeneity and islet cell-cell network in prediabetes and diabetes were found. A new prediabetic β-cell marker, Anxa10, regulates intracellular Ca2+ and insulin secretion. Diabetes triggers β-cell to acinar cell transdifferentiation.