THADA inhibition in mice protects against type 2 diabetes mellitus by improving pancreatic β-cell function and preserving β-cell mass

Yuqing Zhang, Shan Han, Congcong Liu, Yuanwen Zheng, Hao Li, Fei Gao, Yuehong Bian, Xin Liu, Hongbin Liu, Shourui Hu, Yuxuan Li, Zi-Jiang Chen (), Shigang Zhao () and Han Zhao ()
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Yuqing Zhang: Shandong University
Shan Han: Shandong University
Congcong Liu: Shandong University
Yuanwen Zheng: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Hao Li: Shandong University
Fei Gao: Chinese Academy of Science
Yuehong Bian: Shandong University
Xin Liu: Shandong University
Hongbin Liu: Shandong University
Shourui Hu: Shandong University
Yuxuan Li: Shandong University
Zi-Jiang Chen: Shandong University
Shigang Zhao: Shandong University
Han Zhao: Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Impaired insulin secretion is a hallmark in type 2 diabetes mellitus (T2DM). THADA has been identified as a candidate gene for T2DM, but its role in glucose homeostasis remains elusive. Here we report that THADA is strongly activated in human and mouse islets of T2DM. Both global and β-cell-specific Thada-knockout mice exhibit improved glycemic control owing to enhanced β-cell function and decreased β-cell apoptosis. THADA reduces endoplasmic reticulum (ER) Ca2+ stores in β-cells by inhibiting Ca2+ re-uptake via SERCA2 and inducing Ca2+ leakage through RyR2. Upon persistent ER stress, THADA interacts with and activates the pro-apoptotic complex comprising DR5, FADD and caspase-8, thus aggravating ER stress-induced apoptosis. Importantly, THADA deficiency protects mice from high-fat high-sucrose diet- and streptozotocin-induced hyperglycemia by restoring insulin secretion and preserving β-cell mass. Moreover, treatment with alnustone inhibits THADA’s function, resulting in ameliorated hyperglycemia in obese mice. Collectively, our results support pursuit of THADA as a potential target for developing T2DM therapies.

Date: 2023
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DOI: 10.1038/s41467-023-36680-0

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