The Insulin Signaling Paradox in Beta Cells

The Insulin Signaling Paradox in Beta Cells

By: Tiffany Richardson

The regulation of glucose levels relies on a concert of signals spread across various organ systems such as the liver, muscle, fat, and pancreas. Insulin signaling in the muscle, fat, and liver leads to glucose disposal into these tissues for either energy of storage. Insulin deficiency in Type 1 diabetes (T1D) eliminates the signaling facilitated by insulin. Furthermore, insulin has been shown to impact other cellular functioning such as cellular growth, metabolism, and survival. 

But how does insulin affect its producer? Paracrine effects of other islet endocrine cells on beta cells have been studied but the autocrine effects of insulin on beta cells is not well understood. Previous investigations have revealed that insulin signaling in beta cells helps to facilitate compensatory beta cell proliferation in diabetic mouse models. In order for insulin to initiate these functions, a functioning insulin receptor must be present on these cells. The following investigation will help to demystify the paradox of insulin signaling in insulin producing cells.

Insulin Signaling Inception: The Inceptor Receptor

Ansarullah and colleagues linked a new receptor to beta cell insulin signaling and beta cell function. Upon querying to find new pancreatic regulators, they discovered that 5330417C22Rik mRNA was highly expressed in embryonic mouse pancreas. The human variant of this gene is oestrogen-induced gene (or EIG121 or ELAPOR1 or KIAA1324). Because of this protein’s similarities to the insulin receptors, these investigators took the liberty to bestow a new name onto KIAA1324: insulin inhibitory receptor or inceptor. The authors then set out to investigate the function of inceptor in beta cells and whole-body glucose homeostasis. Read on to find out more about these exciting new discoveries!

 Mice with the inceptor genetically deleted exhibit:

  • Early onset mortality – mice usually die within a few hours of being born
  • Hyperinsulinemia (increased blood insulin levels) & hypoglycaemia (decreased blood glucose levels)
  • Increased activation of insulin receptor and IGF1 receptor signaling
  • Increased proliferation of beta cells leading to increased beta cell mass

Mice with the inducible genetic deletion of inceptor in beta cells exhibit:

  • Increased activation of insulin receptor and IGF1 receptor signaling
  • Increased proliferation of beta cells
  • Improved in vivo glucose tolerance 

How can inceptor cause these changes? It was described that the interaction of inceptor and insulin receptor and Insulin Like Growth Factor 1 (IGF1) receptor signaling can lead to clathrin-mediated endocytosis further resulting in desensitization of insulin and IGF1 receptors. When this interaction was prohibited with monoclonal antibodies, inceptor and insulin receptors were not endocytosed leading to sustained receptor activity in beta cells. The researchers concluded that this newly found receptor, inceptor, reduces the potential for insulin to constantly signal onto beta cells through clathrin-mediated endocytosis. Thus, inceptor reduces the activation of downstream insulin signaling pathways in beta cells.

The Takeaway: The discovery of inceptor helps to uncover clues of how insulin could be behaving in an autocrine manner to affect beta cell function. What remains to be uncovered is how the local environment of secreted insulin in disease states such as T1D or T2D in which local concentrations of insulin are high could disrupt proper beta cell insulin signaling. Additionally, there could be physiological cases in which inceptor is malfunctioning leading to inappropriately high insulin signaling in the beta cell. There is much to learn about this new player in insulin signaling and we will need to keep our ears to the ground to see what’s next.

Sources

  • Ansarullah, Jain, C., Far, F.F. et al. (2021). Inceptor counteracts insulin signalling in β-cells to control glycaemia. Nature. https://doi.org/10.1038/s41586-021-03225-8.
  • Kulkarni, R. (2021). New-found brake calibrates insulin action in β-cells. Nature. https://doi.org/10.1038/d41586-021-00141-9
  • Leibiger, I. B., Leibiger, B., and Berggren, P. (2008). Insulin Signaling in Pancreatic β-cells. Annual Review of Nutrition, (28). https://doi.org/10.1146/annurev.nutr.28.061807.155530.
  • Image credit: Helmholtz Zentrum München

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