A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
(https://pubmed.ncbi.nlm.nih.gov/38184650/)

The development of insulin resistance occurs often — it's a normal part of pregnancy, and it often occurs with aging. Obesity is one such case where insulin resistance is well-known. We also know that obesity and insulin resistance are important risk factors for the development of type 2 diabetes. What is less well-appreciated is that most people with insulin resistance don't actually go on to develop diabetes! Why?

In short, the islet cells that make insulin are, under most circumstances, really good at adapting their production of insulin to the body's needs. If insulin resistance goes up, islets typically increase their insulin output to match. Increasing insulin production by islets in the face of insulin resistance helps to keep blood sugar in the normal range.

There are three ways that insulin can be increased with 'increased metabolic demand'. One classic view is that islets grow in size. This clearly happens in mice. Evidence in humans is harder to come by, and it may be more likely to happen in obesity that occurs during childhood. Secondly, insulin clearance from the blood is reduced; in this case, it's not actually an increase in islet insulin production that happens, but insulin is not removed from the blood as quickly (essentially leading to more 'build up'). Thirdly, and less-well-understood, is that islets simply crank out more insulin. This is actually a very early response to metabolic challenges, and occurs before increased insulin content of the islets or pancreas. A great study several years ago demonstrated this effect in islets transplanted into the eye (so they could be visualized directly)!

​It's that last study that inspired our work that was just published, led by Frank Lin and Kuni Suzuki. In that paper, we showed that the ability of islets to secrete insulin is increased in human obesity (particularly in islets from younger organ donors) and in islets from mice fed a high fat diet for as little as two days! We used mice to study how this happens. We find that some signals inside the insulin-secreting cells when mice are fed high fat act to increase the ability of islets to secrete insulin. We think that this signal acts on a specific protein (called SENP1) which plays an important role helping islet cells release insulin into the blood. When we remove that protein from mice, they are much more likely (and much more quickly) to have high blood sugar when fed a high fat diet because they can't increase their insulin very well.

What does this mean for diabetes? It is important for us to understand how islets can up-regulate their production of insulin when needed. This research tells a bit more about that puzzle, and in particular provides new insight into early responses to 'metabolic stress' that might be seen in obesity. Hopefully, this will help us to eventually develop strategies to reduce or delay reduced insulin responses that occur in type 2 diabetes.

Patrick

A bit less than a year ago, I decided to try to add some functionality to this website that would help people learn about our research and the kinds of things that we are interested in. For a while I tested out various automated artificial chat bots that would allow interested people to ask questions about our work and get answers. That worked OK... but in response to questions it too often came back with strange answers or simply with: 'I don't know'.

I have been wanting to provide some venue for short lay summaries of our work, and perhaps more about the lab as well. Am going to start providing summaries of our work, starting with our latest paper from Dr. Frank Lin published just this month. I might also post about older papers or other things of interest as well.

I hope that this will be of use to anyone interested. Colleagues, students, those interested in biomedical science, and people living with diabetes.

If you want to know some very specific details of our work, you can find it by clicking on 'Research' above!

​Patrick