We've just posted a new paper from graduate student Amanda Schukarucha Gomses online!
(www.biorxiv.org/content/10.1101/2024.12.02.626463v1)!

We all know that people are differ from each other, and likewise that patients with diabetes are also different from one another. Not everyone with type 2 diabetes has it in the same waym, or is equally affected by it. In our group, we study the cells in the pancreas that make insulin and other hormones. These cells, called pancreatic beta cells, are also highly variable or heterogeneous - even the (tens of) thousands of beta cells within an individual are highly variable in how they work. Exactly why one beta cell can differ so much from another remains unclear. In fact the differences themselves have not been fully described. What has become increasingly apparent in recent years is that this heterogeneity in beta-cells is important to how a pancreatic islet works (or doesn't work!).

In the paper we’ve just posted, Amanda from our group explores some of this variability between pancreatic beta cells in health and diabetes. For several years now, Amanda has been studying something called glycine, which is an amino acid that acts as a key signal controlling the activity of pancreatic beta cells. It works by tickling specific proteins on the cell called receptors. These receptors are important because they are linked, genetically, to type 2 diabetes and obesity. Previous work from our group showed that these glycine receptors seem to be decreased in type 2 diabetes.

So Amanda wondered, firstly, whether the reduction in these glycine receptors in type 2 diabetes was because of diabetes itself or a consequence of elevated blood sugar. She was able to show that the glycine receptors are downregulated by hyperglycemia. While doing this, she noticed that the activity of these glycine receptors varies tremendously between beta cells, even cells from the same organ donor. Although in general, the activity of these receptors is down in type 2 diabetes, perhaps more surprising was just how different their activity could be between individual beta cells.

To explore what might be responsible for that variation in receptor activity, Amanda performed patch-seq experiments with other members of our team who have used that technique before. She was able to show the relationship between specific genes within a beta cell and the amount of glycine receptor activity in those cells. So what does this mean? Understanding glycine receptors is important because of the link with diabetes, but studying them is also challenging. Because this receptor doesn’t seem so active in mice or rats, we are pretty limited in how we can study it. In short, we need access to human tissue through our tissue bank to study these cells. The results from this study provide a molecular roadmap to understanding the heterogeneity of beta cells and their activity and how this changes in diabetes, thus contributing to our understanding of human insulin secretion in health and diabetes. 

dos Santos et al.,  (2024) Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice. Nature Communications, 15, 9063.

We are fortunate to contribute to lots of different kinds of research studies as collaborators. In this new paper, Rafael Arrojo e Drigo and his team at Vanderbilt University have uncovered some important effects of caloric restriction (CR) that could impact the management of diabetes. This follows previous studies (see for example the DiRECT Trials) that showed in humans that severe caloric restriction can reverse type 2 diabetes. In this new paper, Dr. Arrojo e Drigo demonstrtes some of the impacts of this on insulin secreting pancreatic beta cells.

Caloric restriction, which involves reducing daily calorie intake without malnutrition, has long been known to extend lifespan in various organisms. This study dives deep into how CR influences the function and health of beta cells (see also this paper from the Benninger group). Remarkably, the research demonstrated that CR enhances the beta cells’ ability to maintain glucose homeostasis, which is critical for preventing diabetes. This likely occurs by improving insulin sensitivity, meaning less insulin is needed to control blood sugar levels, thereby reducing the workload on beta cells.

The study utilized advanced imaging and molecular techniques, which the Arrojo e Drigo group and other colleagues at the Salk Institute are experts at, to show that CR helps in maintaining the integrity of beta cell function by reducing cellular stress and preserving mitochondrial health. This aids in delaying the aging process of beta cells, an effect linked to prolonged beta cell health and reduced diabetic risk.

How did we contribute to this work? Often our contributions are for our work in human tissue processing through the ADI IsletCore, or for our expertise in islet cell electrical measurements. That's not the case here. Postdoc Dr. Birbickram Roy has been doing experiments on mouse and human tissue to visualize the expression of certain genes using a technique called RNAscope. This allows us to see expressed genes in pancreas and islet cells. In this particular paper, Birbickram helped out with the visualization of markers for islet growth, stress, and ageing in the CR mice.

For individuals with diabetes or those at risk, these findings highlight a promising avenue for research into how dietary interventions could help maintain the health of beta cells and provides important insight into the mechanism by which trials such as the DiRECT caloric restriction studies may reverse diabetes. By potentially adopting a CR diet, individuals might improve their body’s own ability to regulate glucose, offering a natural buffer against the progression of diabetes.

Even though we played only a small part in this study, it's nice to contribute to something that provides some meaningful insight into how diabetes reversal strategies work. 

A new collaborative paper. See it here!

​One of the more exciting developments in the past decade has been the ability to make insulin-producing pancreatic "beta" cells from stem cells. This is cool for many reasons: they are interesting models to study insulin and diabetes; they are a potential source of cells for transplantation and treatment of diabetes; and they may even eventually allow us to forego the use of immunosuppressants in such transplants.

But you'll notice that I put "beta" cells in quotation marks. That's because no one can currently make 'real' beta cells from stem cells in a dish. The cells that we currently make do produce some insulin, they can secrete that insulin, and to some degree they respond to the normal signals (like sugar) to control the release of insulin. But the current consensus is that stem cell derived beta cells still fall short of being 'real' beta cells - and for this reason they are variously referred to as 'stem-cell-beta cells' or 'beta-like cells'. Basically, the beta cells made from stem cells are usually considered immature, with properties that are more like the beta cells found very early in life!

So how can we tell when a stem cell is becoming a 'mature' beta cell? That's where markers come into the picture. What kinds of molecular signs can tell us whether a "beta" cell is becoming mature? That's the question asked by our friend Dr. Francis Lynn, Carmen Bayly and their team. Prior indications suggested mature "beta" cells have higher levels of something called 'islet amyloid polypeptide' or IAPP (side note - IAPP may actually be involved the development of diabetes - see here). Dr. Lynn and his team wanted to know if the stem-cell derived "beta" cells with higher levels of IAPP are, in fact, more mature. To answer this, they put a red fluorescent indicator that turns on when IAPP goes up into stem cells along with a green fluorescent indicator that turns on when insulin is present. They did this using CRISPR, which you might have heard of since it recently won the Nobel Prize for its discoverers. So, when stem cells are prodded to turn into "beta" cells the green signal turns on to indicate insulin is being made. Then, in some of those green cells, a red signal also turns on to indicate that IAPP is present.

So...what's the difference between the green cells and the green/red cells? When they studied the green and the green/red cells separately, they found that the latter had characteristics that more closely resembled 'mature' beta-cells from human donors. They had better glucose control of insulin secretion and better-regulated electrical activities (that's the work that we contributed). So what this mean? Using IAPP as a 'marker' for more mature beta-cells will be an important tool in discovering approaches (like drugs or other manipulations) that can help make better, more mature, 'beta-like cells' from stem cells for use in transplantation, research studies, and other applications.

Although clinical trials are underway, there is still a long way to go before stem-cell beta-cells will be widely available for transplantation. Improved tools (like the IAPP-reporter cells here) will be essential in making this happen!
​

We've just posted a new study, which you can find here.

One of the most rewarding things we do is provide pancreatic islets from organ donors to researchers around the world, so that the community can learn more about diabetes and transplantation. This program is something we're always looking to improve. By isolating the islets and putting them in a dish or test tube, researchers can perform all kinds of studies aimed at generating new understanding of diabetes, testing new therapies, or approaches to islet transplantation. It might come as no surprise though that when they are taken out of the pancreas, islets don't work the same way that they do while in the pancreas, or even when the pancreas is in the human body! Furthermore, when we keep the islets in a dish, they may change over time, becoming even less like they normally would be in the body.

In order to interpret research studies on isolated islets, it's important to know how they change when sitting in a dish for several days (we call that 'in cell culture'). In fact, we often lose islets from the time they are isolated to the time that we take them out of the dish for experiments or when we ship to other researchers (we don't misplace them! But we also don't really know much about what happens to them either... likely they die or fragment into smaller pieces). This is important since we ship islets all around the world for different studies, and if we isolate islets on a Friday we usually can't ship them out until the following Monday! That's what this study focused on: How much are the islets changing if we have to wait several days? Do we lose more islets if we wait longer?

We looked at how the number and quality of islets changed from the time they were first isolated to the time that we shipped them out of our facility for research studies. We analyzed nearly 200 islet isolations and found that the number of islets often decreased by about 25% during the culture process, likely due to fragmentation (and loss of the smaller fragments). This was particularly significant within the first 24 hours after isolation. Importantly though, the quality, recovery, and functionality of the islets did not deteriorate further with extended culture times up to 136 hours.

Why It Matters: For researchers, understanding the factors that affect islet quality can help in designing better experiments and ensuring that they are working with the best possible materials. We were worried that having to wait (over a weekend for example) to ship islets to researchers for their studies may have detrimental consequences. The bad news: there seems to be islet fragmentation and loss after culture, confirming that islets are not quite the same after isolation as they are when in the pancreas (something that we and others have known for a long time). The good news: Most of these changes happen within 24 hours, with little further negative effect if we have to keep the islets in culture longer. So while we don't love the islet loss and fragmentation that happens, at least it doesn't get any worse if we have to wait a few days longer. 

As we learn more about how to optimize islet isolation and culture, we can improve the outcomes for research studies and, ultimately, for patients who might benefit from these advancements. The work in this study may not be particularly ground-breaking, if I have to be honest, but it's a good example of how our team is continually looking to improve our understanding of what is happening in our processes and make meaningful improvements in the work we do. By identifying the factors that influence islet quality and functionality we can provide valuable insights that can help researchers and clinicians better utilize these important resources.

Update, June 26th: the preprint paper describing this tool is now out here.

We've been working for more than a year on this one, and finally it's out there! HumanIslets.com is a new website that's set to change how we study islets. Developed with grant support from CIHR, JDRF, and Diabetes Canada, this platform brings together a lot of important information about human pancreatic islets isolated by our program. These cells help our bodies manage blood sugar levels, which is crucial for people with diabetes and over many years our goal has been to help other researchers study and learn from human research islets.

Why It Matters for People with Diabetes
The more we understand about how islets work, the better we can treat and maybe even reverse diabetes. This website brings together some of the best in diabetes research (see our team here), allowing us to work together and share our findings, with each other and around the world. This kind of collaboration and openness can lead to breakthroughs that directly benefit patients by providing new ways to manage or treat diabetes. In short, all kinds of diabetes research can be helped by access to data, and HumanIslets.com is a major step in increasing data access and quality.

What is HumanIslets.com?
HumanIslets.com is a free online resource where scientists can explore and analyze a vast amount of data about human islets. Essentially, it is an atlas of information that we are making available to the world. The website currently has data from over 540 organ donors, some with diabetes and some without. This makes it an incredibly valuable tool for studying how islets work and how they are affected by (or contribute to the cause of) diabetes. Researchers can look at information from cells all the way up to data from entire donors.

Why is it Important for Researchers?
For researchers, HumanIslets.com is a treasure trove of information. It helps them understand how islets function in different people and what changes in these cells can lead to diabetes. The site is intended to help scientists answer research questions, and perhaps more importantly  to come up with new questions! One of the best things about HumanIslets.com is that it's designed to be easy to use, even if you're not a computer expert (there are lots of kinds of scientists out there - some experienced with big data analysis and computational biology, and others, like me, who are not!). The website is user-friendly, meaning you don’t need a lot of technical knowledge to start exploring the data. This makes it accessible to a wide range of scientists, from students to medical professionals. For power users, the data can be downloaded directly!

Supporting Transparency and Collaboration
HumanIslets.com also emphasizes the importance of sharing data and making it easy to reproduce research results. This is important because it helps ensure that findings are reliable and can be built upon by other scientists. All the data and analysis methods are available for download, which means that anyone can check the work and even use the data for their own research!

I think this is an important new tool in the fight against diabetes. It offers a wealth of information and makes it easier for researchers to study islet cells. It represents a significant step forward in data quality and transparency, that I really hope will help ultimately to improve the lives of people with diabetes.

​Patrick

Most people likely know that research costs money. Whether it's diabetes research, engineering research, social sciences, or whatever — research costs money. Sometimes lots of it! The equipment used to perform research can also often cost lost of money. So where does all this money come from? And where does it go?

There are several potential sources of research support. This can sometimes come from industry sources, such as pharmaceutical companies. We've had a bit of this, on and off, over the years. Often, for academic research (which is what we do here), the money comes from either federal or provincial governments, or from relevant health charities, in the form of research grants. Some of the relevant ones for our work include the Canadian Institutes of Health Research, Diabetes Canada, JDRF, and the National Institutes of Health in the USA. Now, I'm not going to talk about the 'research funding environment' in Canada —  it's been stagnant for years and you can read about that here (*update April: a glimmer of hope in this year's budget). Instead, I'll tell you a bit about the process, partly because I'm going through it now, trying to get our work on insulin secretion refunded (the subject of this post).

An Idea and Preliminary Data
Perhaps the most important part of putting a research grant together, not surprisingly, is the idea. Much of the work we do up-front involves deciding what question or idea is worth our time. This involves reading and understanding the research literature (hopefully both new and old work), and identifying research gaps. This can include input from patient partners as well, and there is a growing and important role for patient groups in deciding on key questions that researchers should tackle. You can find information on becoming involved here.

It's often not enough to have a great idea, though. Before writing a grant proposal, researchers often must collect preliminary data to support their idea. This data might come from initial experiments, showing that the proposed research is feasible and has the potential to be impactful. These can sometimes be funded by what are called 'Pilot Project' grants which are often local competitions designed to help researchers gather preliminary data. For example, the Alberta Diabetes Institute runs a pilot project program.

Writing and Submitting the Grant Proposal
With an idea and some preliminary support for what you want to do, then comes the writing! For me, this can often be the painful part, and I'll often agonize for days or weeks over some little details. Knowing what you want to do and why you want to do it is all well and good, but it means nothing if you can't convey that in a convincing way! A grant proposal typically includes sections like an introduction, research objectives, methodology, expected outcomes, and a detailed budget. It's important to write a compelling story that highlights the significance and originality of the proposed work, making a strong case for why it should be funded.

Proposals then usually need to be signed-off by the University, then submitted through specific online portals. Some of these portals and online systems have quite the reputation, although they are not all that bad — the kind of things I imagine others run into in different kinds of jobs. Once you do manage to click the 'submit' button, the grant is out of your hands! I recommend not looking at it again, for fear of finding typos!

The Grant Review Process
Once submitted, proposals go through a peer review process where experts in the field evaluate quality, feasibility, and potential impact. The process is slightly different between organizations, but the principle is the same. Usually, a grant is reviewed by two or three reviewers who provide written critiques and scoring based on some predefined criteria. At a meeting, which can be online or in-person, the grant reviewers discuss their criticisms and scores amongst each other and with the larger review committee. A lay reviewer may also be involved. Typically, a final score is arrived at and this is used to rank the grants.

A fact of life is that relatively few grant proposals will get funded. In a recent Canadian Institutes of Health Research Project Grant competition, only 17% of proposals were funded. Mine was not among them! Does that mean I wasted my time? Not at all — reviewers provide detailed feedback, highlighting strengths and suggesting areas for improvement. This feedback is really important for improving research and helping researchers refine their ideas for the next time around.

Revision and Resubmission :(
These days, it's really tough to get a grant funded the first time around. Using the feedback from reviewers, proposals can be revised in an attempt to address any concerns or gaps identified. This may involve clarifying the research plan, enhancing the methodology, or perhaps even performing additional preliminary experiments. Once revisions are made, the proposal can be resubmitted, often (hopefully!) with an improved chance of success. This is what I'm doing right now — I'm working on a grant to resubmit and making lots of changes; dropping a genetically-engineered mouse from the proposed studies and focusing on some more fundamental issues related to how insulin is controlled.

Obtaining the Grant and Managing the Funds
Congratulations! Receiving a grant is a significant milestone for any research team, marking the beginning (or continuation of) a funded project and the potential for important discoveries. You can find our current funding sources listed here. Lots of paperwork may be involved in actually getting access to that money, and typically lots of boxes need to be ticked (applications for research ethics approvals, safety approvals, etc.). Grant management involves careful planning and adherence to the budget and, depending on the granting organization, lots of reporting to ensure that funds are allocated correctly for salaries, equipment, supplies, and other research-related expenses.

What the Grant Pays For
In the grant competition I mentioned above (the one I wasn't successful in), the average value of awards were about $1M Canadian dollars over four to five years, each supporting all kinds of biomedical research in Canada. That's a lot money — let's say about $150-200K per year (it varies by funding organization, of course).

What does this pay for? Grants often cover the salaries of researchers, technicians, and other essential staff who contribute to the project, ensuring that the team has the necessary human resources to carry out the research. Funds are used to purchase essential materials and consumables needed for experiments and data collection, which are critical for conducting the research. Grants can also cover travel expenses for researchers to attend conferences, collaborate with other scientists, and share their findings with the broader scientific community. Finally, grant funds support the publication of research results in scientific journals and other platforms, ensuring that new knowledge is shared with the scientific community and the public, advancing the field and fostering further research. In general, a grant of ~$200K yearly might pay the salaries for one technician and one student, plus the other stuff listed above.

​Patrick

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