膵β細胞が増えるための新しいしくみを解明―ストレスへの適応が生存と増殖をうまく調整

2026-04-22

2026-04-21 京都大学

京都大学の研究チームは、インスリンを分泌する膵β細胞が増える新たな仕組みを解明した。糖尿病では膵β細胞の減少が問題となるが、本研究は小胞体ストレス応答に関わる転写因子ATF6αに着目。マウス実験により、高脂肪食や妊娠などのストレス環境下で、ATF6αが細胞の生存と増殖を同時に調整し、膵β細胞量の増加に不可欠であることを示した。さらに単一細胞RNA解析から、ATF6α欠損では増殖しにくい状態へ変化する可能性も判明した。本成果は膵β細胞量維持の分子機構理解を進め、糖尿病の新たな治療戦略開発につながると期待される。

＜関連情報＞

ATF6αは膵β細胞の増殖と生存を協調的に制御してストレス適応性の膵β細胞量増加を司る
Activating Transcription Factor 6α Governs Stress-Adaptive Pancreatic β-Cell Mass Expansion by Coordinating Proliferation and Survival

Daisuke Otani;Takaaki Murakami;Muhammad Fauzi;Ainur Botagarova;Sho Sekito;Hisato Tatsuoka;Shinsuke Tokumoto;Ryota Usui;Masahito Ogura;Taro Toyoda;Yasuhiro Murakawa;Daisuke Yabe;Nobuya Inagaki
Diabetes Published:April 17 2026
DOI:https://doi.org/10.2337/db26-0048

Progressive loss of pancreatic β-cell mass (BCM) is a hallmark of type 2 diabetes, yet strategies to preserve or restore BCM remain elusive due to incomplete understanding of the molecular mechanisms governing β-cell proliferation in adults. The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis, but the in vivo role of activating transcription factor 6α (ATF6α), the most recently evolved UPR branch, in β-cell proliferation and survival is unclear. Here, we investigated the role of ATF6α in β-cell adaptation under chronic metabolic and physiological stress. We demonstrated that β-cell–specific ATF6α knockout mice exhibited impaired BCM expansion accompanied by reduced β-cell proliferation and increased apoptosis during high-fat diet feeding and pregnancy, but not under basal conditions. In vitro, ATF6α knockdown suppressed proliferation and enhanced apoptosis in chronically stressed MIN6^Akita cells, but not in MIN6 cells, whereas ATF6α overexpression promoted β-cell proliferation. Single-cell transcriptomic analysis further revealed that ATF6α directs proliferative transcriptional states in β-cells under metabolic stress, while its absence diverts cells toward nonproliferative states. Together, these findings establish ATF6α as a coordinating regulator of adaptive β-cell proliferation and survival that supports BCM expansion under sustained stress.

Article Highlights

The role of activating transcription factor 6α (ATF6α) in the stress-adaptive regulation of pancreatic β-cell mass (BCM) in vivo remains incompletely defined.
We investigated the role of ATF6α in the regulation of BCM, β-cell proliferation, and survival under sustained stress using in vivo and in vitro models.
Loss of ATF6α consistently impaired BCM expansion through reduced β-cell proliferation and increased apoptosis across models.
Our findings establish ATF6α as an important regulator of stress-adaptive BCM expansion through coordinating β-cell survival and proliferation under sustained stress.