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

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

  • Nat Commun. 2023 Feb 23;14(1):1020. doi: 10.1038/s41467-023-36680-0.
Yuqing Zhang # 1 2 3,  Shan Han # 1 2 3,  Congcong Liu 1 2 3,  Yuanwen Zheng 4,  Hao Li 5,  Fei Gao 6,  Yuehong Bian 1 2 3,  Xin Liu 1 2 3,  Hongbin Liu 1 2 3,  Shourui Hu 1 2 3,  Yuxuan Li 1 2 3,  Zi-Jiang Chen 7 8 9 10 11,  Shigang Zhao 12 13 14,  Han Zhao 15 16 17
Affiliations

Affiliations

  • 1 Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China.
  • 2 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China.
  • 3 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China.
  • 4 Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, Jinan, Shandong, China.
  • 5 Shandong Provincial Qianfoshan Hospital, Shandong University, 250014, Jinan, Shandong, China.
  • 6 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Science, 100101, Beijing, China.
  • 7 Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. chenzijiang@hotmail.com.
  • 8 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. chenzijiang@hotmail.com.
  • 9 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. chenzijiang@hotmail.com.
  • 10 Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, 200135, Shanghai, China. chenzijiang@hotmail.com.
  • 11 Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Shandong, 250012, Jinan, China. chenzijiang@hotmail.com.
  • 12 Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. zsg0108@126.com.
  • 13 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. zsg0108@126.com.
  • 14 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. zsg0108@126.com.
  • 15 Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. hanzh80@sdu.edu.cn.
  • 16 Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. hanzh80@sdu.edu.cn.
  • 17 Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. hanzh80@sdu.edu.cn.
  • # Contributed equally.
PMID: 36823211 DOI: 10.1038/s41467-023-36680-0
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.

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