Objective
Type 1 diabetes (T1D) is a serious autoimmune disease in which the body’s immune system attacks and destroys insulin-producing cells in the pancreas, called beta cells. Without these cells, the body cannot regulate blood sugar levels, leading to dangerous short-term and long-term health complications. Although people with T1D can manage the disease by taking insulin, this is not a cure—and it does not replace the natural, precise blood sugar control that healthy beta cells provide.
In recent years, researchers have made great progress in creating insulin-producing cells from human stem cells. These lab-grown beta cells offer exciting potential for replacing the lost cells in people with T1D, making it possible to restore the body’s ability to produce insulin. However, there are still major challenges to overcome before this kind of therapy can be widely used. One of the biggest problems is that the lab-grown beta cells are often immature. This means they don’t respond well to changes in blood sugar, and they may not survive for long after being transplanted. In addition, the immune system can still harm these new cells—especially under the inflammatory conditions typical of T1D.
The goal of this project is to find existing drugs that can help lab-grown human beta cells mature, function better, and survive longer—even in the stressful environment caused by T1D. These drugs may already be approved for other diseases, which could make it faster and easier to bring them into clinical use for people with diabetes.
To achieve this, we used a state-of-the-art screening approach that tested more than 300 FDA-approved drugs on a human beta cell line, using advanced single-cell genetic technology. This allowed us to pinpoint which compounds triggered helpful changes in gene activity—such as those linked to improved insulin production, better stress management, or stronger cell survival signals.
This research project is now focused on taking the most promising of these compounds and testing them further in human stem cell–derived beta cells and in mice. We have three main objectives:
1. Find drugs that help beta cells mature and function better. We are testing compounds that appear to push beta cells to become more like their natural, fully developed counterparts. We will measure whether the treated cells show stronger insulin responses to glucose and whether they express key markers of maturity. This would make them better candidates for transplantation.
2. Evaluate how well the treated beta cells work in the body. We will transplant drug-treated beta cells into mice with diabetes to see if they can control blood sugar levels more effectively than untreated cells. We’ll monitor blood sugar over time and look at the transplanted cells to determine how well they survive and function.
3. Identify compounds that protect beta cells from inflammation. Since T1D is driven by inflammation and immune attack, it’s important that replacement beta cells can survive under these conditions. We’ll test whether certain compounds help beta cells resist damage from the types of immune molecules seen in T1D.
Together, these studies will identify drugs that help insulin-producing beta cells grow stronger, function better, and last longer—critical steps toward a real cure for type 1 diabetes. Because we’re focusing on drugs that are already approved for other uses, this research has the potential to accelerate the development of new treatments and move them into clinical testing faster.
Background Rationale
Type 1 diabetes (T1D) is a life-altering autoimmune disease that typically develops in children and young adults. In T1D, the body’s immune system mistakenly attacks insulin-producing beta cells in the pancreas. Insulin is a hormone that helps control blood sugar levels. Without it, glucose builds up in the bloodstream instead of entering cells for energy.
Although insulin therapy is lifesaving and essential for people with T1D, it is not a cure. People must continuously monitor their blood sugar, administer insulin through injections or pumps, and manage their diets and activities around the clock. Even with careful management, many individuals still experience dangerous highs and lows in blood sugar, and long-term complications remain a constant threat.
Scientists have long sought ways to restore insulin production in people with T1D. One of the most promising strategies is beta cell replacement therapy—replacing the destroyed beta cells with healthy, insulin-producing ones. In fact, the U.S. Food and Drug Administration (FDA) recently approved human islet cell transplantation for people with T1D, marking an important milestone in the field. However, the supply of donor islets is extremely limited, making this approach unavailable to most patients.
This is where human pluripotent stem cells (hPSCs) offer new hope. These stem cells can be turned into nearly any cell type in the body—including insulin-producing beta cells. Researchers have made great progress in developing methods to grow beta-like cells from hPSCs in the lab. These lab-grown cells offer a potentially unlimited source for cell replacement therapy.
However, there is a major challenge: the beta cells made from stem cells are not fully mature. They don’t sense and respond to blood sugar changes as well as natural beta cells do. They may also be more fragile and susceptible to stress or immune attack. This immature state limits their ability to function properly and survive after transplantation.
In addition, beta cells in people with T1D live in a highly stressful environment. The immune system produces inflammatory molecules (called cytokines) that damage beta cells even before they are destroyed completely. To be truly effective, replacement beta cells must not only function like healthy cells—they must also be able to resist the stressful conditions that come with T1D.
To address these challenges, our lab developed a cutting-edge screening platform that uses single-cell RNA sequencing to examine how individual human beta cells respond to different chemicals. We recently applied this technique to test over 300 FDA-approved drugs and 46 human hormones on a human beta cell line. This allowed us to identify candidate compounds that could enhance the maturation, function, and survival of beta cells.
We are now focused on understanding how these promising compounds help beta cells grow, produce insulin, and withstand immune-related stress. We will test the best candidates in lab-grown stem cell–derived beta cells and in animal models of diabetes. Some compounds appear to boost beta cell maturity by increasing expression of key genes involved in insulin production. Others appear to help cells better sense glucose or protect themselves from cytokine-induced damage.
This research is especially exciting because it focuses on drugs that are already approved for human use. This means that if a compound proves effective, it may be easier and faster to translate it into a therapy for people with T1D. Our long-term goal is to improve the quality and durability of stem cell–derived beta cells so they can be used safely and effectively in patients.
By overcoming the barriers of immaturity and vulnerability, we aim to bring stem cell–based therapies closer to reality—and move one step closer to a functional cure for type 1 diabetes.
Description of Project
Type 1 diabetes (T1D) is a lifelong autoimmune disease in which the body’s immune system mistakenly attacks and destroys insulin-producing cells—called beta cells—in the pancreas. Without insulin, the body cannot properly control blood sugar levels, leading to serious long-term health complications. While daily insulin injections help manage the disease, they do not cure it or fully replace the natural function of beta cells.
A promising approach for treating T1D is to replace the lost beta cells using laboratory-grown insulin-producing cells derived from human stem cells. These stem cell–derived beta cells offer a potentially unlimited supply for transplantation. However, one major challenge remains: these lab-grown cells are often immature and don’t function as well as natural beta cells. They may not produce enough insulin in response to glucose and can be more vulnerable to damage, especially under the stressful conditions present in T1D.
Our project seeks to solve this problem by identifying existing, safe drugs that can help stem cell–derived beta cells become more mature, function better, and survive longer—especially in the face of the inflammation seen in T1D. Using cutting-edge technology that combines drug screening with single-cell genetic analysis, we recently tested over 300 drugs in human beta cells to see which ones improved cell function or protected them from stress.
This proposal focuses on three goals:
Aim 1 is to test whether the most promising drugs can help lab-grown beta cells become more mature and function more like natural beta cells. We’ll look for changes in important genes and markers that indicate a healthy, insulin-producing state. We’ll also test whether the treated cells produce more insulin in response to glucose—just like natural beta cells do.
Aim 2 is to test whether the drug-treated beta cells actually work in the body. We’ll transplant these cells into diabetic mice and track their ability to regulate blood sugar over time. We’ll test blood sugar responses to meals and analyze the transplanted cells to see if they survive and keep functioning long-term. If successful, this would show that these drugs help make lab-grown cells suitable for future human therapies.
Aim 3 focuses on protecting beta cells from the inflammation that drives T1D. In the body, immune cells release harmful molecules—called cytokines—that cause beta cells to malfunction and die. Some of the drugs we identified appear to help beta cells survive this type of attack. We’ll test these protective compounds on lab-grown beta cells and real human islet cells exposed to cytokines, checking whether the cells stay alive and retain their ability to produce insulin.
Through this work, we hope to find new uses for existing drugs that can support insulin-producing beta cells in three ways: helping them grow into mature, fully functional cells; protecting them from immune attack; and enabling them to control blood sugar effectively in the body. These discoveries will improve the ability of lab-grown beta cells to be used in cell therapy and bring us closer to durable treatments—or even a cure—for people living with T1D.
Anticipated Outcome
Type 1 diabetes (T1D) is caused by the immune system attacking and destroying insulin-producing beta cells in the pancreas. While insulin therapy is essential and lifesaving, it does not restore the body’s natural ability to regulate blood sugar. Researchers around the world are working to develop new treatments that go beyond insulin—treatments that can restore or replace lost beta cells and offer long-term blood sugar control.
One of the most promising approaches is using stem cells to generate new insulin-producing beta cells. These stem cell–derived beta cells could one day be transplanted into patients to take over the role of natural beta cells and produce insulin in response to blood sugar levels. However, the lab-grown cells often remain immature, meaning they don’t function as well as natural beta cells. Additionally, they are vulnerable to stress, particularly in the inflammatory environment that characterizes T1D.
Our project seeks to overcome these hurdles by identifying existing drugs—ones that are already approved for other uses—that can help stem cell–derived beta cells mature, function better, and survive longer. Using a powerful technology called single-cell RNA sequencing, we tested over 300 FDA-approved drugs and 46 hormones on human beta cells. This allowed us to see, in detail, how each cell responded to the treatments and identify compounds that might make the cells stronger, more functional, and more resistant to damage.
We anticipate several major outcomes from this research:
1. Improved Beta Cell Maturity:
We expect to identify compounds that help lab-grown beta cells become more like natural adult beta cells. These mature cells should be better at producing and releasing insulin when blood sugar levels rise. We will validate this by looking at key genes and proteins that are known markers of beta cell maturity, and by measuring insulin secretion in response to glucose.
2. Enhanced Beta Cell Function:
Some compounds may directly improve how beta cells sense glucose and release insulin. Even if the cells are not fully mature, they may still become better at doing their job. We will test this by performing insulin secretion tests in the lab and by examining how treated cells respond to different levels of glucose and other stimuli.
3. Stronger Survival Under Stress:
Importantly, we aim to find compounds that protect beta cells from damage caused by inflammatory molecules, which are common in T1D. These “protective” compounds could help cells survive in the hostile environment of the diabetic pancreas. We will test this by exposing treated cells to cytokines—the same inflammatory molecules involved in T1D—and measuring cell death, stress markers, and whether they maintain their insulin-producing identity.
4. Better Performance in Transplanted Cells:
In animal studies, we will transplant treated stem cell–derived beta cells into diabetic mice to see how well they work in a living system. We expect that cells treated with the most promising compounds will be better at lowering blood sugar, will survive longer, and will function more like natural beta cells. These experiments will provide critical evidence of the potential for real-world applications.
5. A Pathway to New Therapies:
Since many of the drugs we are testing are already approved for human use, any successful findings could move quickly into clinical trials. Our goal is to help speed up the development of better cell-based therapies for people with T1D. The ability to mature and protect beta cells with existing drugs could make transplantation safer, more effective, and more accessible to patients.
In summary, our project will define new ways to make insulin-producing beta cells stronger, smarter, and more resilient—paving the way for long-lasting, life-changing treatments for people living with type 1 diabetes.
Relevance to T1D
Type 1 diabetes (T1D) is a lifelong autoimmune disease that affects millions of people worldwide. It usually begins in childhood or adolescence, but it can occur at any age. In T1D, the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. Without insulin, the body cannot properly regulate blood sugar, which can lead to serious health complications including blindness, kidney failure, heart disease, nerve damage, and even death.
For people with T1D, managing blood sugar levels requires constant effort. This often includes multiple daily insulin injections or use of an insulin pump, frequent blood sugar checks, and careful attention to diet and physical activity. While modern tools and technologies have improved diabetes management, they do not eliminate the disease or prevent its long-term consequences. T1D continues to place a major emotional, physical, and financial burden on individuals and families.
This is why researchers and clinicians are working hard to find better solutions—ideally, ones that could restore the body’s ability to produce insulin naturally. One of the most promising avenues is beta cell replacement therapy. This approach involves giving patients new insulin-producing beta cells to take over the function lost due to autoimmune attack. These replacement cells can come from human donors (cadaveric islets) or be created in the lab from human pluripotent stem cells (hPSCs).
Stem cell–derived beta cells offer a potentially unlimited supply for transplantation. However, current versions of these lab-grown cells are not perfect. Many are immature and do not function as well as natural beta cells. They may not release enough insulin in response to glucose, or they may not survive well in the body—especially when exposed to the inflammatory environment caused by the autoimmune process in T1D.
Our research directly tackles these challenges by focusing on how to make stem cell–derived beta cells more mature, more functional, and more resilient. We are using a state-of-the-art screening approach called single-cell RNA sequencing to study how hundreds of FDA-approved drugs affect human beta cells. This lets us see, at the level of individual cells, which compounds boost insulin production, help the cells mature, or protect them from inflammation.
We have already identified several promising compounds. Some appear to help beta cells develop the characteristics of mature, insulin-producing cells—similar to those found in healthy individuals. Others seem to strengthen the cells’ ability to release insulin when blood sugar levels rise. Still others may help beta cells survive better in the presence of inflammatory molecules like cytokines, which are known to contribute to beta cell destruction in T1D.
Why does this matter for people living with T1D? If we can improve the quality and durability of lab-grown beta cells, we can make cell replacement therapy more effective and more widely available. This means:
• Better insulin control: More mature and functional cells could respond to blood sugar more precisely, reducing the risk of dangerous highs and lows.
• Longer-lasting implants: Cells that survive longer under stress may not need to be replaced as often, making the therapy more sustainable.
• Faster treatment development: Since we are studying drugs that are already FDA-approved, any successful findings could be moved more quickly into clinical trials.
• New pathways to a cure: Even beyond transplantation, understanding how to protect and strengthen beta cells could help scientists develop other strategies to preserve a person’s own cells before they are fully lost.
Ultimately, this research brings us closer to a future where people with T1D can live free from the daily burdens of insulin therapy—achieving lasting blood sugar control through safe, effective, and durable cell-based treatments.