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journal article·2024-04Open access

Beta‐Cell Tipe1 Orchestrates Insulin Secretion and Cell Proliferation by Promoting Gαs/cAMP Signaling via USP5

Lu Ding, Yang Sun, Yan Liang, Jie Zhang, Zhendong Fu, Caiyue Ren, Pengfei Li, Wen Liu, Rong Xiao, Hao Wang, Zhaoying Zhang, Xuetian Yue, Chunyang Li, Zhuanchang Wu, Yuemin Feng, Xiaohong Liang, Chunhong Ma, Lifen Gao

Advanced Science· Volume 11· Issue 16
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Abstract

Abstract Inadequate β‐cell mass and insulin secretion are essential for the development of type 2 diabetes (T2D). TNF‐α‐induced protein 8‐like 1 (Tipe1) plays a crucial role in multiple diseases, however, a specific role in T2D pathogenesis remains largely unexplored. Herein, Tipe1 as a key regulator in T2D, contributing to the maintenance of β cell homeostasis is identified. The results show that the β‐cell‐specific knockout of Tipe1 (termed Ins2‐Tipe1BKO) aggravated diabetic phenotypes in db/db mice or in mice with high‐fat diet‐induced diabetes. Notably, Tipe1 improves β cell mass and function, a process that depends on Gαs, the α subunit of the G‐stimulating protein. Mechanistically, Tipe1 inhibited the K48‐linked ubiquitination degradation of Gαs by recruiting the deubiquitinase USP5. Consequently, Gαs or cAMP agonists almost completely restored the dysfunction of β cells observed in Ins2‐Tipe1BKO mice. The findings characterize Tipe1 as a regulator of β cell function through the Gαs/cAMP pathway, suggesting that Tipe1 may emerge as a novel target for T2D intervention.
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Research context

OpenAlex topics: Pancreatic function and diabetes · Genetics and Neurodevelopmental Disorders · Endoplasmic Reticulum Stress and Disease

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Key Laboratory for Experimental Teratology of Ministry of Education Shandong Key Laboratory of Infection and Immunity and Department of Immunology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China

Department of Endocrinology Yucheng People's Hospital Dezhou Shandong 251200 P. R. China

Key Laboratory for Experimental Teratology of Ministry of Education and Department of Cell Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China

Key Laboratory for Experimental Teratology of Ministry of Education and Department of Histology and Embryology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 P. R. China

Department of Gastroenterology ShengLi Hospital of Shandong First Medical University Jinan Shandong 250012 P. R. China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Shandong Province

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