Objective
This project focuses on understanding how the liver changes over the course of type 1 diabetes (T1D) and whether a new type of insulin—designed to reach the liver more effectively—can improve metabolic health. Although people with T1D rely on insulin every day, the way insulin is delivered under the skin does not match how the body naturally sends insulin directly to the liver. This mismatch may contribute to insulin resistance, a condition where the body becomes less responsive to insulin over time.
The study has three main objectives:
Objective 1: Understand how liver metabolism changes early vs. late in T1D
People who are newly diagnosed with T1D and those who have lived with the disease for decades may have very different liver metabolism. Early in the disease, the liver may work harder to compensate for low insulin levels in the portal vein, while later in the disease, the liver may become less efficient and show signs of mitochondrial stress. To investigate this, the study will use advanced imaging tools—such as PET scans and MRI—to measure liver blood flow, oxidative metabolism, fat content, and insulin sensitivity. By comparing people with recent-onset T1D to those with long-standing T1D, the research team aims to map out how liver function evolves over time and identify early warning signs of metabolic decline.
Objective 2: Test whether a liver targeted insulin (HDV insulin) can improve liver metabolism and insulin sensitivity
A new insulin formulation called HDV insulin is designed to deliver a portion of injected insulin directly to the liver, more closely mimicking natural physiology. This may help correct the long standing imbalance between high insulin levels in the bloodstream and low insulin levels in the liver. In this part of the study, adults with long standing T1D will be randomly assigned to receive either HDV insulin or standard insulin for 26 weeks. The research team will measure whether HDV insulin:
• improves liver oxidative metabolism
• increases liver blood flow
• enhances insulin sensitivity
• affects glucose control or reduces hypoglycemia
This will be the first trial to directly test whether restoring insulin delivery to the liver can improve metabolic health in T1D.
Objective 3: Explore the biological mechanisms behind these effects using mouse models
To better understand why liver targeted insulin might work, the study will also include experiments in mice with insulin deficient hyperglycemia. These experiments will test how HDV insulin affects liver metabolism and whether hormones like glucagon influence the liver’s response to insulin. This mechanistic work will help clarify the pathways involved and guide future therapeutic strategies.
Why these objectives matter
Together, these objectives aim to answer a critical question: Can restoring a more natural insulin balance protect the liver and improve insulin sensitivity in people with T1D?
If successful, this research could:
• reveal new mechanisms driving insulin resistance in T1D
• identify a window for early intervention
• support a new insulin formulation that better mimics natural physiology
• reduce long term complications linked to metabolic stress
• improve quality of life for people living with T1D
This project combines cutting edge imaging, clinical trials, and mechanistic biology to address a long standing gap in T1D research—how to protect the liver and improve insulin action in a disease where insulin is essential but imperfectly delivered.
Background Rationale
People with type 1 diabetes (T1D) depend on insulin delivered under the skin because their pancreas no longer produces it. While modern automated insulin delivery systems have dramatically improved glucose control, they still cannot mimic one key feature of natural insulin biology: in people without diabetes, insulin travels directly to the liver first, where about half of it is used before the rest enters the bloodstream. This natural “portal-first” delivery is essential for regulating how the liver processes glucose and fats.
In T1D, insulin delivered under the skin circulates mainly in the bloodstream instead of the liver. This creates too much insulin in the body’s peripheral tissues and too little reaching the liver. Over time, this imbalance is believed to contribute to insulin resistance, a condition where the body becomes less responsive to insulin. Unlike type 2 diabetes, insulin resistance in T1D occurs even in people who are young, lean, and have excellent glucose control. This suggests that the cause is not obesity or inactivity, but rather the biology of insulin delivery itself.
Research shows that insulin resistance in T1D affects many organs—including muscle, fat, kidneys, and especially the liver. The liver plays a central role in controlling blood sugar, breaking down fats, and producing energy. When the liver does not receive enough insulin, it continues releasing glucose even when blood sugar is already high, and it relies more heavily on burning fatty acids for fuel. This can place extra stress on liver mitochondria, the structures responsible for producing energy.
Recent imaging studies from our group uncovered a surprising pattern in young adults with T1D:
• Liver blood flow is reduced, suggesting early vascular changes.
• Liver oxidative metabolism is unusually high, meaning the liver is working harder than expected.
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These findings suggest that the liver may initially “overcompensate” to maintain normal function despite low insulin levels. But over many years, this extra workload may lead to mitochondrial strain and declining energy production. Indeed, people with long standing T1D show reduced liver ATP production, a sign of mitochondrial dysfunction and impaired insulin action.
Together, these observations point to a possible progression from early metabolic overactivity to mitochondrial stress to eventual long term liver dysfunction and insulin resistance.
Despite decades of research, no study has directly tested whether restoring insulin delivery to the liver can protect liver metabolism or improve insulin sensitivity in T1D. A new insulin formulation—HDV insulin—offers a promising solution. It uses tiny vesicles to direct a portion of injected insulin specifically to the liver, partially restoring the natural portal to peripheral insulin balance. Early clinical trials show that HDV insulin is safe and may reduce hypoglycemia and insulin needs in people with higher HbA1c levels. However, its effects on liver metabolism, mitochondrial function, and insulin sensitivity have never been evaluated.
This study is designed to fill that critical gap. By combining advanced imaging, metabolic testing, and clinical intervention, the project aims to determine whether targeting insulin to the liver can correct the underlying metabolic stress that contributes to insulin resistance in T1D.
Description of Project
People living with type 1 diabetes rely on insulin delivered under the skin, rather than through the pancreas as in people without diabetes. While today’s automated insulin delivery systems have dramatically improved glucose control, they still cannot mimic the body’s natural way of delivering insulin directly to the liver. As a result, people with type 1 diabetes experience too much insulin in the bloodstream and too little in the liver. This imbalance is increasingly recognized as a major contributor to insulin resistance, a condition where the body becomes less responsive to insulin over time.
Insulin resistance in type 1 diabetes is common—even in people who are young, lean, and have excellent glucose control. It affects many organs, but the liver appears to play a particularly important role. Our recent research uncovered a surprising pattern: young adults with type 1 diabetes show reduced blood flow but preserved liver oxidative metabolism, a sign that there may be gradual impairments in metabolism due to low insulin levels in the portal vein. Over many years, this may continue to deteriorate and contribute to mitochondrial stress, declining control of liver energy production, and worsening insulin resistance. This project aims to understand these changes more clearly and test a promising new approach to restore a more natural insulin balance.
What is HDV‑insulin and why might it help?
HDV‑insulin is a new formulation that attaches a small portion of insulin to tiny vesicles designed to deliver insulin directly to the liver—more closely mimicking natural physiology. Unlike previous liver-directed insulins, HDV‑insulin still leaves most insulin available to act in the rest of the body, potentially avoiding past safety issues. Early clinical studies show that HDV‑insulin is safe and may reduce hypoglycemia and insulin needs in people with higher HbA1c levels. But no study has yet examined whether it can improve liver metabolism and restore insulin sensitivity that deteriorates over time.
We will recruit adults with recently diagnosed type 1 diabetes (<5 years) and long‑standing type 1 diabetes (≥25 years) to understand how liver metabolism changes over time. Using advanced imaging tools such as PET scans and MRI, along with detailed metabolic testing, we will:
(1) Aim to understand how liver metabolism differs early vs. late in the natural evolution of type 1 diabetes.
We expect that people early in the disease will show higher normal oxidative metabolism, yet reduced tissue perfusion, while those with long-standing T1D will show reduced mitochondrial energy production. These differences may reveal when and how insulin resistance develops.
(2) Test whether HDV‑insulin can improve liver metabolism
Adults with long-standing T1D will be randomly assigned to receive either HDV‑insulin or standard insulin for 26 weeks. We will measure whether HDV‑insulin:
- increases liver oxidative metabolism
- improves liver blood flow
- enhances insulin sensitivity
- improves glycemic control or reduces hypoglycemia
(3) Examine the biology behind these effects
Using mouse models, we will test how HDV‑insulin affects liver metabolism and whether hormones like glucagon play a role.
Why this matters
This will be the first clinical trial to deeply investigate how liver metabolism changes across the lifespan of diabetes and whether a liver‑targeted insulin can correct these abnormalities. The results could:
- reveal a new mechanism driving insulin resistance in diabetes
- identify a critical window for early intervention
- support a new insulin formulation that better mimics natural physiology
- reduce long‑term complications linked to insulin resistance
- improve quality of life by reducing insulin doses, hypoglycemia, and metabolic stress
Importantly, this project is being developed with patient‑partners across Canada, Europe, and the United States, ensuring that the perspectives of people living with T1D guide the research and its real‑world relevance.
Anticipated Outcome
This study is designed to answer an important question for people living with type 1 diabetes (T1D): How does the liver change over the course of the disease, and can a new type of insulin help protect it? By combining advanced imaging, metabolic testing, and a clinical trial of a liver targeted insulin, the project aims to generate several key outcomes that could reshape how we understand and treat insulin resistance in T1D.
1. A clearer picture of how the liver changes in T1D
The study is expected to provide the most detailed look to date at how liver metabolism evolves from early to long standing T1D. We anticipate discovering:
• Higher or preserved liver oxidative metabolism early in the disease, suggesting the liver is working harder to compensate for low insulin levels in the portal vein.
• Reduced mitochondrial energy production in long standing T1D, indicating that this early “overwork” may eventually lead to metabolic strain and dysfunction.
These findings will help identify when liver stress begins and how it progresses, offering a roadmap for earlier intervention.
2. Evidence on whether liver targeted insulin can improve liver health
The trial will test whether HDV insulin—a new insulin designed to deliver more insulin directly to the liver—can correct the long standing imbalance created by subcutaneous insulin delivery. We expect to learn whether HDV insulin:
• Improves liver oxidative metabolism, helping the liver produce energy more efficiently
• Enhances liver blood flow, which may support healthier tissue function
• Improves insulin sensitivity, reducing the metabolic burden on the liver
• Influences glucose control, including time in range and hypoglycemia
If successful, this would be the first demonstration that adjusting where insulin goes in the body—not just how much is given—can improve metabolic health in T1D.
3. New insights into the biology behind insulin resistance in T1D
The mouse studies will help clarify why liver targeted insulin works and how hormones like glucagon influence liver metabolism when insulin is low. These mechanistic insights could reveal new therapeutic targets and deepen our understanding of the metabolic stress that develops in T1D.
4. A foundation for new treatment strategies
Together, the findings could support a new approach to insulin therapy—one that restores a more natural insulin balance and reduces the long term metabolic strain on the liver. This could lead to:
• Better insulin sensitivity
• Lower insulin requirements
• Reduced risk of long term complications
• Improved quality of life for people with T1D
5. A patient informed path forward
Because the study is being developed with patient partners across multiple countries, the anticipated outcomes will also include insights into how people with T1D perceive liver targeted insulin, how it fits into real world diabetes management, and what barriers or opportunities exist for future adoption.
Relevance to T1D
For people living with type 1 diabetes, insulin is essential for survival—but the way insulin is delivered today is far from how the body naturally works. Even with the most advanced automated insulin delivery systems, insulin is still injected under the skin rather than released directly into the liver, as it would be in someone without diabetes. This difference has major consequences for long term health.
In type 1 diabetes, insulin delivered under the skin leads to too much insulin circulating in the bloodstream and too little reaching the liver, the organ responsible for regulating blood sugar, burning fats, and producing energy. Over time, this imbalance is believed to contribute to insulin resistance, a condition where the body becomes less responsive to insulin. Insulin resistance in type 1 diabetes is surprisingly common—even in people who are young, lean, active, and managing their glucose well. It increases insulin requirements, raises the risk of complications, and adds to the daily burden of diabetes management.
This project directly addresses this long standing problem by investigating how the liver changes over the course of type 1 diabetes and whether a new type of insulin—HDV insulin, designed to reach the liver more effectively—can help restore a more natural insulin balance.
The relevance to type 1 diabetes is significant for several reasons:
1. It targets a root cause of insulin resistance in type 1 diabetes
Instead of treating symptoms or adding more medications, this project focuses on the underlying biology of insulin delivery. If the liver receives the insulin it needs, it may function more normally, reducing the metabolic stress that contributes to insulin resistance.
2. It may improve glucose control and reduce insulin needs
By improving how the liver responds to insulin, HDV insulin could help people with type 1 diabetes use insulin more efficiently. This may lead to lower insulin doses, fewer highs and lows, and better overall metabolic stability.
3. It addresses long term complications at their source
Insulin resistance is linked to higher risks of cardiovascular disease, steatotic liver, and kidney problems. Improving liver metabolism early—and preserving it over time—could help reduce these risks.
4. It fills a major knowledge gap in T1D research
Although insulin resistance is well recognized in type 1 diabetes, the liver’s role has been understudied. This project uses state of the art imaging and metabolic testing to provide the clearest picture yet of how liver function evolves from early to long standing type 1 diabetes.
5. It explores a therapy that could be integrated into existing insulin delivery systems
HDV insulin is designed to be used with current insulin pumps and automated insulin delivery systems. If effective, it could be adopted without requiring major changes to how people manage their diabetes.
6. It is guided by people living with type 1 diabetes
Patient partners across Canada, Europe, and the United States are helping shape the study to ensure that the research addresses real world needs, concerns, and priorities.
Overall, this project aims to transform our understanding of insulin resistance in T1D and test a therapy that could bring insulin delivery closer to natural physiology. If successful, it could lead to better metabolic health, fewer complications, and a meaningful improvement in quality of life for people living with type 1 diabetes.