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)^3,4,5,6. 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.

胰岛素抵抗是饮食诱导肥胖 (DIO) 的早期并发症¹ ，可能导致高血糖和高胰岛素血症，并伴有适应性 β 细胞肥大和 2 型糖尿病的发展² 。胰岛素不仅通过胰岛素受体 (INSR) 发出信号，还通过胰岛素样生长因子 1 受体 (IGF1R) 促进 β 细胞存活、生长和功能^3,4,5,6 。我们最近发现胰岛素抑制受体（受体）是 IGF1R 和 INSR 脱敏的关键介质⁷ 。但是，尽管 β 细胞特异性缺失受体可改善瘦小鼠的 β 细胞功能⁷ ，但仍需要澄清受体信号抑制是否也能改善肥胖条件下的血糖。我们评估了雄性小鼠 DIO 条件下大脑或胰腺 β 细胞中靶向受体缺失对糖代谢的影响。在本研究中，我们表明，受体的整体和神经元缺失，以及β细胞中成年发病的缺失，通过增强β细胞的健康和功能来改善葡萄糖稳态。此外，我们证明，受体介导的葡萄糖控制改善并不依赖于表达刺鼠相关蛋白或阿黑皮素原神经元的受体功能。我们的数据表明，受体抑制可改善 DIO 小鼠的葡萄糖稳态，因此证实受体是 INSR 和 IGF1R 信号传导的关键调节因子。