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.
GrantsEuropean 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