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18-12-2024 | Insulins | Article

Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress

Authors: Wenyue Yin, Suyun Zou, Min Sha, Liangjun Sun, Haoqiang Gong, Can Xiong, Xinyue Huang, Jianan Wang, Yuhan Zhang, Xirui Li, Jin Liang, Xiaoai Chang, Shusen Wang, Dongming Su, Wanhua Guo, Yaqin Zhang, Tijun Wu, Fang Chen

Published in: Diabetologia | Issue 3/2025

Abstract

Aims/hypothesis

The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes.

Methods

SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions.

Results

SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA–HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells.

Conclusions/interpretation

Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.

Graphical Abstract

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Title: Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress
Authors: Wenyue Yin
Suyun Zou
Min Sha
Liangjun Sun
Haoqiang Gong
Can Xiong
Xinyue Huang
Jianan Wang
Yuhan Zhang
Xirui Li
Jin Liang
Xiaoai Chang
Shusen Wang
Dongming Su
Wanhua Guo
Yaqin Zhang
Tijun Wu
Fang Chen
Publication date: 18-12-2024
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Insulins
Published in: Diabetologia / Issue 3/2025
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-024-06343-w

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Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Graphical Abstract

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