Objective
The goal of this project is to understand how a gene called GLP1R, which makes the receptor for a hormone that regulates blood sugar and appetite, affects the development and long-term complications of type 1 diabetes (T1D). In T1D, the body’s immune system attacks and destroys the insulin-producing beta cells in the pancreas. Although new insulin and glucose-monitoring technologies have improved daily management, many people with T1D still face serious challenges, including unstable blood sugar levels, heart and kidney problems , and other complications that shorten life expectancy.
Drugs that activate GLP1R are already approved for type 2 diabetes and obesity, where they lower blood sugar, reduce body weight, and protect the heart and kidneys. Because of these benefits, many people with T1D are now using them “off-label,” even though the FDA has not approved them for T1D and it is not yet known who benefits or whether the drugs are completely safe in this population.
This project will use large-scale human genetic data to test whether natural genetic differences that increase or decrease GLP1R activity influence T1D risk, beta-cell function, and related complications. The findings will guide the development of safer, more precise GLP1R-based therapies for people living with T1D.
Background Rationale
Type 1 diabetes (T1D) develops when the body’s immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. Without these cells, the body cannot make insulin to control blood sugar levels, leading to lifelong dependence on insulin therapy. While insulin replacement is life-saving, it does not prevent long-term complications such as heart and kidney disease, nerve damage, or cognitive decline. Despite decades of research, there are still no approved treatments that protect or restore the function of the body’s own beta cells and development of complications. One promising direction comes from a gene called GLP1R, which makes the receptor for a hormone called GLP-1. This hormone helps the body control blood sugar, reduce appetite, and protect multiple organs from metabolic stress. Drugs that activate this receptor, called GLP1R agonist, are widely used for type 2 diabetes and obesity and have shown benefits for heart and kidney health. However, their effects in people with T1D are not yet well-characterized, and it remains unclear which patients with T1D might benefit from these drugs and how these drugs influence disease progression and complications.
By studying how natural genetic differences in the GLP1R gene affect T1D risk and complications, this project will reveal whether GLP1R signaling plays a protective or harmful role in T1D. The results will guide future precision therapies aimed at improving long-term outcomes for people living with T1D.
Description of Project
Type 1 diabetes (T1D) develops when the body’s immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. Without these cells, the body cannot make enough insulin to control blood sugar, leading to lifelong dependence on insulin therapy. Although advances in insulin delivery and glucose monitoring have improved daily management, many people with T1D still struggle to maintain stable blood-sugar levels and face serious complications such as heart and kidney disease, vision loss, and cognitive changes.
A major unanswered question is why some individuals with T1D develop these complications while others remain relatively protected. One promising lead comes from a gene called GLP1R, which makes the receptor for glucagon-like peptide-1 (GLP-1), a hormone that helps the body to regulate blood sugar, appetite, and metabolism. Medications that activate GLP1R, known as GLP-1 receptor agonists (GLP1RAs), are already approved to treat type 2 diabetes (T2D) and obesity, where they lower blood sugar, promote weight loss, and reduce the risk of heart and kidney disease. These drugs also promote brain health and function and are being tested for neurocognitive and psychiatric conditions. Because of these benefits, many people with T1D are now using GLP1RA drugs “off-label,” even though these medications have not yet been approved or fully studied for T1D.
This project asks a simple but important question: Does lifelong activation or suppression of GLP1R signaling protect or harm people with T1D? To answer this question, we will take advantage of a natural experiment provided by human genetics. Each of us is born with small inherited differences in the GLP1R gene that slightly change how strongly this receptor works. By studying how these natural genetic differences influence the risk of developing T1D and its complications, we can safely predict the potential long-term effects of GLP1R-based drugs without exposing patients to risk.
We will analyze genetic and clinical data from several of the world’s largest and most informative studies: the UK Biobank (over 500,000 participants), FinnGen (hundreds of thousands of individuals with genetic and health-record data), and the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC), which has followed people with T1D for more than 30 years. Together, these resources allow us to track how GLP1R-related genetic differences affect: (1) the risk of developing T1D and the age when it begins; (2) the preservation of beta-cell function after diagnosis, measured by blood C-peptide levels; and (3) long-term outcomes such as cardiovascular disease, kidney function, vision problems, and cognitive health.
We will use modern and advanced statistical tools to compare the outcomes of these medical outcomes in individuals whose genetics naturally make GLP1R more versus less active. This approach, often a “natural clinical trial”, will help reveal cause-and-effect relationships that ordinary observational studies cannot. We expect our analyses to reveal whether GLP1R activation helps preserve beta-cell health or influences how rapidly T1D progresses. Additionally, we anticipate finding which complications (for example, heart or kidney disease) are most improved or worsened by lifelong GLP1R activation. We expect to also identify which organs, such as the pancreas, brain, or kidneys, are most responsible for these effects. This project is very important because understanding how GLP1R signaling affects T1D will fill a critical gap between genetics and clinical therapy. The results could identify people who might benefit or be harmed from GLP1R-based treatments, guiding safer and more precise use of these drugs. In the end, this study may help transform GLP1R medications from general metabolic therapies into personalized tools that protect beta-cell health, reduce complications, and improve quality of life for people living with T1D.
Anticipated Outcome
This project is expected to uncover whether natural differences in the GLP1R gene influence the development and long-term complications of type 1 diabetes (T1D). By combining modern genetic analyses with large human datasets, the study will determine whether people who naturally have higher or lower GLP1R activity experience differences in their risk of developing T1D, in how long their insulin-producing cells remain functional, and in their risk of developing complications such as heart, kidney, or nerve problems.
We anticipate the findings to show that enhanced GLP1R activity is linked to better protection of insulin-producing beta cells and reduced risk of certain T1D complications, echoing the positive effects of GLP1R-based drugs already seen in people with type 2 diabetes. The project will also help identify whether these benefits are mediated mainly through pancreatic effects or through the brain, heart, or other organs that also use GLP1R signaling.
In summary, the findings from this will provide the first genetic evidence clarifying how GLP1R activity influences T1D outcomes and guide safer and more effective use of existing GLP1R-based drugs in people with T1D, laying the groundwork for precision therapies that strengthen beta-cell health, improve metabolic control, and reduce complications.
Relevance to T1D
Type 1 diabetes (T1D) remains a lifelong condition with no definitive cure. Although insulin therapy sustains survival, it does not fully prevent swings in blood glucose levels and long-term complications that affect the heart, kidneys, eyes, and brain in patients with T1D.
Drugs that activate the GLP1R receptor, the target in this study, have revolutionized the treatment of type 2 diabetes (T2D) and obesity. These drugs lower blood sugar, promote weight loss, and reduce the risk of cardiovascular and kidney disease in people with T2D. Because of these benefits, many people with T1D have begun using them “off-label,” even though these medicines are not yet approved for T1D. There is an urgent need to understand whether GLP1R activation helps protect beta cells and improve outcomes in T1D and whether its effects differ in people with this disease. This research will use genetics to answer that question. By studying how natural differences in the GLP1R gene influence T1D risk, progression, and complications, we will determine whether the same biological pathways that help people with T2D also apply to those with T1D. These insights will help guide future clinical trials and lead to safer, more targeted therapies to protect and preserve beta-cell health in people with T1D.