Three years ago, the inceptor protein was discovered and its role as an inhibitor of the insulin signaling pathway was described. Inceptor and the insulin receptor are located on the surface of beta cells, where Inceptor can act as a negative regulator of insulin receptor (INSR) and insulin-like growth factor 1 receptor (IGF1R) signaling. Inceptor’s role in blocking the insulin receptor and reducing the cells’ insulin sensitivity and weakening the signaling pathway was described in the 2021 Nature paper, “Inceptor counteracts insulin signalling in β-cells to control glycaemia.”
Now, new work shows that Inceptor binds excess insulin within beta cells and directs it towards degradation. “This knowledge about Inceptor’s function gives us a deeper understanding of how beta cells regulate their insulin homeostasis,” says Heiko Lickert, PhD, director of the Institute of Diabetes and Regeneration Research at Helmholtz Munich and professor at the Technical University of Munich (TUM).
This work is published in Nature Metabolism in the paper, “Inceptor binds to and directs insulin towards lysosomal degradation in β-cells.”
Insights into the regulation of insulin homeostasis might open new insights into replenishing insulin and restore β cell function. Inceptor (encoded by the gene IIR/ELAPOR1) is a transmembrane protein that has roles in lysosomal degradation, autophagy, zymogenic granule maturation and acrosome formation.
The increased presence of Inceptor in beta cells suggests that the receptor plays a role in insulin secretion, which is regulated by beta cells. This process is often impaired in diabetes, leading to elevated blood sugar levels.
By blocking Inceptor, the researchers were able to refill beta cells’ insulin stores, enhance insulin release, and prevent beta cell death. “Especially in already damaged cells, blocking Inceptor could help boost insulin production and protect the beta cells,” explains Lickert.
Using human induced pluripotent stem cell (SC)-derived islets, the authors showed that the IIR knockout (KO) “results in enhanced SC β cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC β cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS).”
More specifically, they found that inceptor “localizes to clathrin-coated vesicles close to the plasma membrane and in the trans-Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation.”
The findings suggest that specifically targeting Inceptor could be a promising strategy for improving the function of insulin-producing cells in people with diabetes. “Our goal is to develop new medications that support the cells’ insulin balance and prolong their viability, based on our discovery” says Lickert. Such a therapy could especially help individuals in the early stages of type 2 diabetes to slow disease progression and reduce the risk of complications.
To translate these findings from the lab to real-world applications, Lickert has founded a start-up working on developing drugs that specifically block Inceptor to protect or regenerate beta cells. Preclinical studies are initially needed to test the safety and efficacy of these new therapeutic approaches. “Our goal is to pave the way for clinical trials and thereby contribute to the treatment, and hopefully even the cure, of diabetes,” says Lickert.
