Researchers say they have developed the first "comprehensive roadmap" detailing protein interactions that enable pancreatic cells to produce, store and secrete insulin. This is according to a study published in Cell Reports.
The research team from The Scripps Research Institute (TSRI) says their finding may lead to a better understanding of the insulin secretion process and how this plays a part in insulin disorders, such as type 2 diabetes.
Type 2 diabetes is caused by a weakened insulin response from cells throughout the body, meaning blood glucose levels remain high for too long.
The researchers note that one therapeutic strategy for treating the condition would be to boost or repair the process in which insulin is produced and secreted through pancreatic cells known as "beta cells." These are the cells that make insulin.
However, the researchers say that due to lack of understanding regarding how beta cells generate and release sufficient insulin levels, there are no drugs as of yet that can improve efficiency.
Insulin 'the dominant protein of beta cells'
For their study, conducted in a mouse cell model of human beta cells, the researchers used antibodies that bind to early and late forms of insulin during the synthesis and secretion process.
They explain that through drawing proteins "out of the soup" of the beta cell molecules, this allows the antibodies to isolate any proteins that have bound to or had interaction with insulin.
The researchers then identified these proteins using mass spectrometry. This allowed the researchers to discover what insulin-interacting proteins were in the beta cells.
Additionally, this process enabled the researchers to distinguish the insulin-interacting proteins - that appear to play a part in the early phase of the insulin synthesis process - from those that appear to work in the later stages of insulin storage and secretion.
From this, the scientists were able to create a "biosynthetic interaction network." In other words, a map showing insulin's protein interactions with pancreatic cells.
"Until now we were identifying one insulin-interacting protein at a time, but this study provides the first systems-wide insights into the insulin synthesis pathway," says Pamela Itkin-Ansari, a beta cell researcher at the University of California, San Diego, the Sanford Burnham Research Institute and co-author of the study.
William E. Balch, professor and member of the Skaggs Institute for Chemical Biology at TSRI, notes that one thing the "roadmap" shows is that insulin effectively runs the beta cell:
"It is by far the dominant protein in the beta cell and the activities within the cell are largely geared towards its processing and secretion."
TMEM24 provides potential for new drug target
Beta cells grown in culture show the importance of TMEM24 in 'mature storage container granules' (yellow) that regulate a slower, chronic form of insulin release.
Image courtesy of the Balch lab, The Scripps Research Institute.
The research team also discovered that another protein found in the beta cells, called TMEM24, had a significant ability to bind insulin.
Further research into the protein showed that TMEM24 is involved in the insulin pathway. The protein was found to regulate a slower, chronic form of insulin release, compared with beta cells that usually secrete a brief burst of insulin before embarking on a longer, lower-intensity release.
He says that this discovery represents a big breakthrough in the discovery of new drug targets:
"This chronic insulin release appears to be more important for human health compared to the acute release of insulin that protects us from the sugar rush of, say, a Snicker's bar, yet almost nothing has been known about this part of the release pathway."
Prof. Balch says the research team plans to conduct further studies looking at both normal and diabetic human beta cells:
"In general, we want to understand more fully what components of this pathway are instrumental in healthy management of insulin production in response to a healthy diet or mismanagement in response to the current unhealthy diets of modern lifestyles leading to disease, and then of course we want to find ways to target those components with therapies."
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