The American Diabetes Association’s Scientific Sessions is here! Until June 29, scientists will present some of the most updated topics, from beta cell replacement to immune therapies to complications, all with the result to change things for the type 1 diabetes (T1D) community. Here are Drs. Danny Chou, Peter Arvan, Jeffrey Millman, and Efsun Arda, who will share their key takeaways from day 2, with their commentary in the video and below:
Danny Chou, Ph.D.
Assistant Professor of Biochemistry, Stanford University
The Pros and Cons of New Approaches to Prevent and Manage Hypoglycemia in Diabetes Therapies
Dr. Chou talked about his efforts in reducing hypoglycemia. Hypoglycemia is one of the more dangerous episodes for people with diabetes, because when you accidentally overdose insulin, hypoglycemia is a serious event. They developed a few different approaches that he believes that can make inserting insulin to be more responsive to the circulating blood-glucose levels. Dr. Chou designed it in a way that the solubility will increase when your circulation level is higher, instantly reaching the blood stream in the way that induces glucose uptake and reduces blood glucose levels. He showed that he can inject a huge dose of insulin, somewhere around 20 times to 30 times more than what would have injected in this specific model, and blood glucose levels will stay at around a hundred milligrams per day per deciliter. “So,” said Dr. Chou, “this is great.”
Peter Arvan, M.D., Ph.D.
Chief of the Division of Metabolism, Endocrinology & Diabetes, University of Michigan
Insulin at Its 100th Birthday
Dr. Arvan’s interest is in the biosynthesis of insulin. He talked about the different steps that are needed to manufacture the protein, which turn out to be a very complicated process, very much like an assembly line at a factory. An initial protein is made, which is larger than the final insulin product. The initial protein is called pre-proinsulin, and it has to be delivered into a special compartment of the cell in order to begin its journey, to be made into insulin and to be sent to the bloodstream in response to glucose. As it turns out, there are a number of defects that can lead to the protein never even reaching the initial compartment.
It also turns out that the delivery of the newly made insulin molecule into that initial compartment is itself regulated by glucose, and the inability to regulate certain proteins that are needed to make the insulin product will result in a failure to make insulin, and that will result in diabetes.
Dr. Arvan also discussed the idea that after the early precursor of insulin, which is known as proinsulin, after that protein is inside the initial compartment for which insulin biosynthesis is needed, the protein has to fold into a certain shape, and failure to do so results in an inability of the protein to ever move through the pancreatic beta cell in order to become insulin. He demonstrated a number of different mutations that relate to the inability to fold the protein and deliver it through the beta cell to make insulin, and that can result in a form of diabetes that is extremely severe, including diabetes that can occur during the very first 30 days of life.
Jeffrey Millman, Ph.D.
Associate Professor of Medicine and Biomedical Engineering, Washington University School of Medicine in St. Louis
Generation of Beta Cells from Stem Cells—State of the Art
Over the last several years, there have been many groups that have reported procedures for essentially manufacturing insulin-secreting cells and tissues in the laboratory. This includes recent work from my own group which reported on at the session today that we’re now able to manufacture these cells at a such a high number and a such a high quality in terms of their ability to respond to sugar and secrete insulin that we’re actually able to transplant these cells and functional cure diabetes in mice. That’s a major takeaway of the session today, is the work of my group that, and many others who spoke at the session, including a Julie Sneddon, Paul Cadue, and Jim Wells, that this technology has really advanced, so that cell replacement therapy is looking much more like a possibility that is on the near horizon.
The basic idea here is that instead of a patient needing to manually check their sugars and inject themselves with insulin multiple times a day, or using a pump of course, instead these transplanted cells would be able to replace the function that’s occurring here and do these actions naturally inside of the body without the recipient needing to think about that. Recent advances have made this a real possibility for us. There is still a lot of work to be done on this. The big major thing that came from the session on that front was that we still don’t have a really good solution to the problem of dealing with the immune system.
And that’s where a lot of the focus of the field is going right now, is to figure out what is a good approach that we should be taking with data about developing these stem cell-derived insulin-secreting cells and tissues in order to protect them from the immune system. Some of the approaches that are being investigated right now are to put a physical barrier between the transplanted cells and the immune cells that are in the body to make it so the immune cells can not physically interact with the insulin-secreting cells to provide protection. Another approach, touched on today in the session, was the idea of genetically engineering these cells, so that they are essentially cloaked from the immune system and therefore cannot be destroyed by the immune system. Both of these are very active areas of research going on in the field currently and we’ll have to see what comes of that research over the next several years.
Another major aspect of the session today that was very exciting to learn about was the utilization of these stem cell technologies for modeling a disease on a dish, in particular trying to model the causes of diabetes. These talks focus on some of the genetic causes of diabetes with people with certain mutations in genes that are important for normal instigating cell behavior causing those cells to either not form when their children or to cause them to fail when they are older. A lot of progress has been made taking this technology and essentially using the procedure that we as a field use to generate and screening cells and tissues for cell therapy to a say, “Look at what, how that process is progressing in the laboratory with these mutations and seeing what goes wrong,” and with the understanding of what goes wrong, hopefully being able to design a cure for what happened, for what ended up causing the failure for the insulin-producing cell to be developed there. An additional aspect of that, of course, as well as received a lot of attention in the scientific literature over the last few years, is the idea of actually going in directly genetically engineering these diabetes causing mutations to fix them outright.
The final topic that I think it’s worth noting from today’s session is the advances that bioinformatics has made in terms of how we as scientists study these cells. The technology has advanced so far that we can actually, on a single cell level, measure all the genes that are active or inactive in a population of cells. This has recently exploded over the last few years to give us such an immense amount of information that would have been science fiction five or eight years ago. It’s really changing the way that we’re thinking about how we as scientists are studying diabetes and developing cures here. There are associated computational methods that are quite complicated associated with trying to deal with these very large datasets, but the point here is that they are leading to new insights into how in screening cells are developed and how to improve the process of making this in screening cells, and then, three, in the case of the mutations that cause diabetes, how can we potentially design interventions to overcome that pathogenic mutation. These are huge datasets and are providing new insights that are just simply impossible with the way that we were doing this research a few years ago.
I think the overall lesson that I’ve taken away from the session is that it’s a very exciting time to be working in the space. There are many groups across the U.S. and across the world that are working on this problem of finding a cure for type 1 diabetes.
Efsun Arda, Ph.D.
Stadtman Investigator and Head, Developmental Genomics Group, National Institutes of Health
Beyond Genome-Wide Association Studies—Understanding the Function of Variants Associated with Diabetes
I thought this was a fantastic session and we kicked it off with Dr. Klaus Kaestner talk about the human pancreas program called HPAP. In his talk, Dr. Kaestner mainly gave us an overview about this human pancreas analysis program. This program was established to tackle the issues involving human pancreas research, because historically most of the pancreas research has focused on the rodent models, but we know that those models do not recapitulate the entirety of the human pancreas development or physiology, or are not a hundred percent effective modeling the diseases.
This program was established back in 2016 and it focuses on procuring human pancreas tissue from donors with type 1 and type 2 diabetes, in addition to donors with normal pancreas. The goal is to improve and standardize data collection, processing, and sharing. Dr. Kaestner mentioned several studies that use the HPAP resource to uncover unexpected findings about islet biology and diabetes research. For instance, through this workday reported first evidence of alpha cell dysfunction and the activation of immune response genes in duct cells in type 1 diabetes. We usually don’t think about the these cells. When we think about diabetes, we usually think about beta cells. So it’s interesting to find the evidence of contribution of these other cell types to type 1 diabetes. Therefore, these findings are certainly interesting and warrant many follow-up studies.
Dr. Kaestner also mentioned a plethora of -omix data that they’ve collected, including single cell chromosome accessibility and gene expression, which are available to the community with registration. In summary, HPAP is a great resource. Please, please check it out by Googling HPAP.
Next speaker was Dr. Inês Barroso, who studies the genetic variance with obesity. Her lab has been a part of several important large-scale genome-wide association studies addressing obesity and late traits. In their recent work, called Scoop, they focused on severe childhood obesity and recruited clinically obese participants, less than 10 years old. They performed whole exome sequencing and followed by a targeted sequencing to uncover several loci that have an effect on body mass index at mass and also developmental delays. Dr. Barroso suggested genetic testing for some of these genes that they identified in order to choose appropriate treatment options.
I was the next speaker in the session after Dr. Barroso, and I talked about my group’s work on identifying the enhancer elements in purified human pancreas cells. One of the key challenges in the field is that we know that genetic variants have a role in diabetes risk, but we don’t know which ones have the most significant effect and what the underlying mechanisms are. We try to tackle these challenges by characterizing or categorizing regulatory genetic elements in purified pancreas populations and analyze the 3D structure of the chromatin to solve gene expression. Through our work, we’ve identified thousands of these regulatory regions and cell type specific chromatin interactions. We hope to leverage this information to predict disease, risk variance, and, including diabetes risk variance, develop prognostic tools and improve precision medicine approaches.
The last speaker in the session was Dr. Michael Stitzel. Dr. Stitzel talked about his labs work on looking at the effects of genetic variance on islet open chromatin regions. The previously showed that different individuals have a lot of variability in distal regions, and they tend to coincide with variance linked to type 2 diabetes risk, as well as transcription factor binding sites that are important for islet biology. In their new work, they wanted to study the effect of genetic variance under stress conditions, for instance, high glucose, or the plasmic reticulum stress. They found that about 30% of regulatory elements containing the variance actually had an effect under stress conditions, highlighting the fact that we should consider conditions that mimic the pathological state to uncover the effects of some of these genetic variants that normally may not have an a phenotype under normal homeostatic state.
In summary, it was a great session.
