Objective
The main goal of our MetMod-T1D study is to test whether a medication called AMX0035 can improve metabolism in adults with type 1 diabetes. While most diabetes treatments focus on controlling blood sugar, our study takes a different approach by targeting how cells handle stress and produce energy.
People with type 1 diabetes often develop "insulin resistance," meaning their bodies don't respond as well to insulin, even when they take the right doses. They also experience problems with their cells' energy factories (mitochondria). These issues contribute to difficulties managing diabetes and may increase the risk of complications, yet current treatments don't address them directly.
AMX0035 combines two compounds that work together: (a) Phenylbutyrate, which helps cells properly fold proteins and reduces cellular stress, (b) TUDCA, which protects cellular energy production and prevents premature cell death. This combination has shown promising results in other conditions, including a rare form of diabetes called Wolfram Syndrome. Our study will be the first to test whether it can help people with the more common type 1 diabetes.
Specifically, we want to determine:
(1) Whether AMX0035 improves how well insulin works in muscle, liver, and fat tissues;
(2) If it enhances energy production in cells;
(3) Whether it affects blood sugar control, body composition, and markers of inflammation;
(4) If it's safe and well-tolerated by people with type 1 diabetes.
To answer these questions, we'll conduct a carefully designed clinical trial with 60 adults with type 1 diabetes. Participants will be randomly assigned to receive either AMX0035 or a placebo for 24 weeks. We'll use advanced testing methods to measure insulin sensitivity and cellular energy production before and after treatment.
Our study team includes experts in diabetes research from the University of Washington in Seattle and the Diabeter Clinic in Amsterdam. This international collaboration allows us to recruit diverse participants and leverage specialized expertise from both centers.
By investigating AMX0035, we hope to develop a new treatment approach that complements insulin therapy by addressing the underlying metabolic abnormalities in type 1 diabetes. If successful, this could lead to better management of diabetes and potentially reduce the risk of long-term complications, ultimately improving quality of life for people with type 1 diabetes.
Background Rationale
Type 1 diabetes has traditionally been understood as a condition where the immune system mistakenly destroys the insulin-producing cells in the pancreas. Without insulin, blood sugar levels rise to dangerous levels, which is why insulin replacement is the cornerstone of treatment. However, research over the past decade has revealed that type 1 diabetes involves more complex metabolic problems that insulin alone doesn't fix.
Many people with type 1 diabetes develop "insulin resistance," which means their bodies don't respond normally to insulin, similar to what happens in type 2 diabetes. This occurs even in people who maintain healthy weight and good blood sugar control. Our research team has shown that this insulin resistance affects multiple organs—muscle doesn't take up glucose efficiently, the liver produces too much glucose, and fat tissue releases too many fatty acids into the bloodstream.
Another important discovery is that the tiny powerhouses within cells, called mitochondria, don't function properly in type 1 diabetes. These mitochondria are responsible for converting nutrients into energy, and when they malfunction, it affects metabolism throughout the body.
Modern diabetes management has brought significant advances. Continuous glucose monitors and automated insulin delivery systems have made it easier to maintain target blood sugar levels. However, these technologies haven't eliminated the underlying metabolic problems. In fact, when insulin is delivered under the skin rather than through the natural pathway via the liver, it can actually worsen some aspects of metabolism.
Current medication options have limitations. SGLT2 inhibitors can cause dangerous ketoacidosis in type 1 diabetes. GLP-1 receptor agonists help with weight management but don't fully address insulin resistance. Metformin offers modest benefits but doesn't significantly improve glucose control in most people with type 1 diabetes. This is why we're investigating AMX0035, a medication that combines two compounds with complementary effects: (a) Phenylbutyrate helps cells properly fold proteins and reduces stress in a cellular component called the endoplasmic reticulum; (b) TUDCA protects mitochondria and prevents cellular stress from triggering premature cell death.
Early evidence from laboratory studies and from people with Wolfram Syndrome (a rare genetic form of diabetes) suggests this combination might improve metabolism and preserve insulin-producing function. In animal models of diabetes, these compounds improved glucose control, enhanced insulin secretion, and protected insulin-producing cells.
The MetMod-T1D study represents a fundamentally different approach to treating type 1 diabetes. Rather than focusing exclusively on blood sugar control, we're targeting the underlying cellular processes that contribute to metabolic dysfunction. If successful, this could open the door to more comprehensive treatment strategies that address the full spectrum of metabolic abnormalities in type 1 diabetes.
Description of Project
People with type 1 diabetes (T1D) face many challenges managing this disease. While modern insulin therapy and glucose monitoring have improved care, we now understand that T1D involves more than just insulin deficiency. Many people with T1D develop "insulin resistance," meaning their bodies don't respond as well to insulin, even when they have normal weight. They also experience problems with how their cells produce energy, particularly in the tiny cellular powerhouses called mitochondria.
Current treatments focus mainly on replacing insulin but don't address these underlying metabolic problems. Our research team is launching a new clinical trial called MetMod-T1D to test whether a medication called AMX0035 can improve metabolism in people with type 1 diabetes. AMX0035 combines two compounds that work together to reduce cellular stress and improve energy production in cells.
This medication has shown promising results in other conditions. Studies in Wolfram Syndrome (a rare form of diabetes) and in laboratory models showed improvements in blood sugar control and insulin production. Now we want to see if these benefits extend to people with type 1 diabetes.
Our study will include 60 adults with type 1 diabetes from clinics in Seattle, USA and Amsterdam, Netherlands. Half will receive the actual medication and half will get a placebo (inactive pill) for 24 weeks. Neither the participants nor the researchers will know who is receiving which treatment until the study ends.
We'll use advanced testing methods to measure how well insulin works in different body tissues and how efficiently cells produce energy. Participants will undergo comprehensive evaluations including specialized scans to measure body composition, detailed blood glucose monitoring, and small tissue samples to examine cellular function. We'll also track standard measures like HbA1c and time spent in healthy blood glucose ranges.
If successful, this study could open the door to a new treatment approach for type 1 diabetes that goes beyond insulin replacement. By addressing the underlying metabolic problems, we hope to improve overall health and potentially reduce long-term complications. Our research team has extensive experience conducting metabolic studies in type 1 diabetes. The international collaboration ensures we can recruit a diverse group of participants and apply the highest standards of research methodology.
This innovative approach represents an important shift in how we think about treating type 1 diabetes. Rather than focusing solely on blood sugar control, we're targeting the fundamental cellular processes that affect metabolism throughout the body. We believe this holistic approach could lead to better outcomes and quality of life for people living with type 1 diabetes.
Anticipated Outcome
The MetMod-T1D study could fundamentally change our approach to treating type 1 diabetes by addressing metabolic problems beyond blood sugar control. Here's what we hope to accomplish:
First, we expect to demonstrate whether AMX0035 improves how well insulin works in the body—what scientists call "insulin sensitivity." This is important because many people with type 1 diabetes develop insulin resistance, meaning they need higher doses of insulin to achieve the same effect. If AMX0035 makes insulin work more efficiently, people might need less insulin to maintain good blood sugar control, potentially reducing weight gain and the risk of low blood sugar episodes.
Second, we anticipate learning whether AMX0035 enhances cellular energy production by improving mitochondrial function. Mitochondria are the tiny powerhouses within cells that convert nutrients into energy. When they don't work properly, it affects metabolism throughout the body. By measuring energy production in muscle tissue before and after treatment, we'll determine if AMX0035 helps restore normal cellular energy balance.
Third, we'll discover if AMX0035 affects body composition, particularly the accumulation of fat in the liver and other organs where it doesn't belong. This "ectopic fat" is associated with insulin resistance and increased inflammation. Our advanced imaging techniques will detect even small changes in fat distribution that could have meaningful health benefits.
Fourth, we'll evaluate whether AMX0035 influences various measures of blood sugar control, including HbA1c (the 3-month average) and time spent in healthy blood sugar ranges as measured by continuous glucose monitors. While insulin will remain the primary treatment for controlling blood sugar, AMX0035 might make this control easier to achieve and maintain.
Fifth, we'll establish the safety profile of AMX0035 specifically in people with type 1 diabetes. Although this medication has been studied in other conditions, each population may experience different side effects, so careful monitoring is essential.
Beyond these direct results, our study will generate a wealth of data about metabolism in type 1 diabetes. The comprehensive testing we're conducting—including advanced scans, tissue samples, and detailed blood analysis—will help us better understand the relationships between cellular stress, energy production, and clinical outcomes in type 1 diabetes.
If successful, this study could pave the way for larger clinical trials of AMX0035 in type 1 diabetes, potentially leading to FDA approval of a new treatment option. More broadly, it could spark increased interest in developing other medications that target metabolism rather than focusing solely on blood sugar control.
Relevance to T1D
Despite remarkable advances in insulin formulations, glucose monitoring technologies, and insulin delivery devices, people with type 1 diabetes still face significant challenges. Many struggle to maintain optimal blood sugar control despite their best efforts, and even those who achieve excellent control remain at increased risk for long-term complications affecting the heart, kidneys, eyes, and nerves. The MetMod-T1D study addresses these challenges by exploring a fundamentally different approach to treatment.
Current management of type 1 diabetes focuses primarily on replacing insulin and monitoring blood sugar. While essential, this approach doesn't address the underlying metabolic abnormalities that contribute to disease progression and complications. Research has shown that insulin resistance—where the body doesn't respond normally to insulin—is common in type 1 diabetes and associated with higher rates of heart disease, kidney disease, and mortality. Similarly, dysfunction in mitochondria (the cellular energy factories) contributes to tissue damage throughout the body.
By targeting these metabolic abnormalities directly, AMX0035 could complement insulin therapy in several important ways:
First, improved insulin sensitivity could make diabetes management easier and more predictable. When insulin works more efficiently, people may need lower doses to achieve the same blood sugar control, potentially reducing both high and low blood sugar episodes. This could translate to less daily burden in managing the condition.
Second, by addressing fundamental cellular stress processes, AMX0035 might help prevent or slow the development of diabetes complications. Many complications stem from cellular damage caused by metabolic abnormalities beyond high blood sugar alone. By improving how cells handle stress and produce energy, AMX0035 could help protect organs throughout the body.
Third, this study introduces a personalized medicine approach to type 1 diabetes. Our comprehensive assessments will help identify which individuals benefit most from metabolic modulation therapy, potentially allowing for more tailored treatment recommendations in the future.
Fourth, the MetMod-T1D study could shift the research focus in type 1 diabetes. While efforts to prevent or cure type 1 diabetes through immune intervention remain essential, our study highlights the importance of also developing treatments for the millions of people currently living with the condition.
Finally, this research directly addresses an unmet need in type 1 diabetes care. While several adjunctive therapies have been studied, none have been specifically developed to target the combination of insulin resistance and mitochondrial dysfunction that characterizes type 1 diabetes. AMX0035's dual mechanism of action makes it uniquely suited to address these interconnected problems.
The MetMod-T1D study represents more than just testing another medication—it embodies a paradigm shift in how we conceptualize and treat type 1 diabetes. By recognizing that type 1 diabetes affects metabolism throughout the body and developing treatments that address these widespread effects, we hope to improve both the daily management experience and long-term health outcomes for people living with this challenging condition.