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Global, neuronal or β cell-specific deletion of inceptor improves glucose homeostasis in male mice with diet-induced obesity.

Nat. Metab. 6, 448-457 (2024)
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Open Access Gold (Paid Option)
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Insulin resistance is an early complication of diet-induced obesity (DIO)1, potentially leading to hyperglycaemia and hyperinsulinaemia, accompanied by adaptive β cell hypertrophy and development of type 2 diabetes2. Insulin not only signals via the insulin receptor (INSR), but also promotes β cell survival, growth and function via the insulin-like growth factor 1 receptor (IGF1R)3-6. We recently identified the insulin inhibitory receptor (inceptor) as the key mediator of IGF1R and INSR desensitization7. But, although β cell-specific loss of inceptor improves β cell function in lean mice7, it warrants clarification whether inceptor signal inhibition also improves glycaemia under conditions of obesity. We assessed the glucometabolic effects of targeted inceptor deletion in either the brain or the pancreatic β cells under conditions of DIO in male mice. In the present study, we show that global and neuronal deletion of inceptor, as well as its adult-onset deletion in the β cells, improves glucose homeostasis by enhancing β cell health and function. Moreover, we demonstrate that inceptor-mediated improvement in glucose control does not depend on inceptor function in agouti-related protein-expressing or pro-opiomelanocortin neurons. Our data demonstrate that inceptor inhibition improves glucose homeostasis in mice with DIO, hence corroborating that inceptor is a crucial regulator of INSR and IGF1R signalling.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Insulin Action; Receptor; Therapy; Resistance; Expression; Energy; Gene
ISSN (print) / ISBN 2522-5812
e-ISSN 2522-5812
Quellenangaben Volume: 6, Issue: 3, Pages: 448-457 Article Number: , Supplement: ,
Publisher Springer
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Grants European Research Council ERC-CoG Trusted
Helmholtz Alliance ICEMED
DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology
Helmholtz Initiative on Personalized Medicine iMed by Helmholtz Association
Helmholtz Association-Initiative and Networking Fund
Helmholtz cross-programme topic Metabolic Dysfunction
ERC AdG Hypo Flam
ERC (CGC: STG )
DFG under Germany's Excellence Strategy
Alexander von Humboldt Foundation
European Union (ERC)
Neither the European Union
German Research Foundation (DFG)
German Center for Diabetes Research
Helmholtz Munich
Helmholtz Association
DZD