Understanding islet cells in type 1 diabetes

We've posted a new paper online, which you can find here.

This is one of the larger projects we've come out with in recent years, a tremendous amount of work by PhD student Theo dos Santos, Research Associate Dr. Xiao Qing Dai and others from our group, along with collaborators at Stanford, Vanderbilt, and UC San Diego, among others. The work combines some really cool approaches such as electrical recordings, molecular profiles, and imaging data from pancreas samples and islet cells of organ donors with autoimmune type 1 diabetes, mostly from our human research islet program. Collecting data from so many islet cells is a massive feat by Xiao Qing, and bringing it all together has been a huge effort by Theo.
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So what did we do, and what does it mean? In recent years, there have been interesting new discoveries about 'islets in type 1 diabetes'. Firstly, although the insulin-producing beta-cells are destroyed by autoimmunity, this is actually 'incomplete' and most people living with type 1 diabetes actually do have some 'surviving' beta-cells (although often very few). It is somewhat debated about whether these surviving beta-cells behave abnormally. Are they the same as the beta-cells in people without diabetes? Secondly, glucagon secretion from pancreatic alpha-cells is disrupted in type 1 diabetes and can contribute both to high glucose after meals and low glucose events called hypoglycaemia. The reason(s) for these changes are not entirely clear, although some recent work suggests that alpha-cell immaturity or so-called 'plasticicity' could contribute. What are the pathways that contribute to altered alpha-cells in type 1 diabetes?

To answer these questions, we measured the electrical properties that define beta- and alpha-cells from human organ donors, in concert with the expression of thousands of genes (something we call pancreas patch-seq). Using machine learning approaches, we studied differences and similarities between the cells from organ donors with and without type 1 diabetes. These are very rare samples, and very few studies have actually managed to study live islets from donors with type 1 diabetes - in fact, when we first started this project, we were unsure whether we could even isolate islets or islet cells from these donors. Somewhat surprisingly, we could find islets that could be isolated from type 1 diabetes donors - some of these were almost entirely alpha-cells (because the beta-cells had been destroyed), but in some cases, we could find islets that also contained beta-cells!

In short, the results of this work show that beta-cells from donors with type 1 diabetes are electrically quite different from 'typical' beta-cells from donors without diabetes, and these changes seemed linked to the immune response and altered metabolism. This is not particularly surprising to be honest. Somewhat more interestingly (and since there were more alpha-cells this was a bit easier to study), altered alpha-cell electrical responses were consistent with a 'hyperactivity' and linked to molecular pathways that include immune signalling, but also much more (for example cell maturity, metabolism, and amino acid signals). Some of this even appears linked to the genetics of type 1 diabetes, suggesting that alterations in alpha-cells might not simply be secondary to the destruction of neighboring beta-cells. Theo followed up on some of the interesting pathways to validate these findings.

 So in short, this work provides new insight into exactly how and why islet cells change in type 1 diabetes beyond the 'autoimmune killing' of them. This provides some basis for thinking about new approaches to treating the disease, for example through the modulation of the amino acid pathways that I mentioned above.

As always, much more work is needed - but we continue to add new pieces to the puzzle.