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
  • 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. [email protected].
  • 8. Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. [email protected].
  • 9. Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. [email protected].
  • 10. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, 200135, Shanghai, China. [email protected].
  • 11. Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Shandong, 250012, Jinan, China. [email protected].
  • 12. Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. [email protected].
  • 13. Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. [email protected].
  • 14. Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. [email protected].
  • 15. Center for Reproductive Medicine, Shandong University, 250012, Jinan, Shandong, China. [email protected].
  • 16. Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, 250012, Jinan, Shandong, China. [email protected].
  • 17. Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250012, Jinan, Shandong, China. [email protected].
  • # 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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