Objective
Multiple studies by our team and others have shown that obesity is a risk factor for T1D. However, this knowledge has not yet led to clinical trials testing whether preventing or treating obesity could prevent T1D because key questions remain unanswered. The overall goal of this project is to provide critical information needed to determine whether obesity treatment could play a role in T1D prevention.
To achieve this, we propose studying participants in the T1D TrialNet Pathway to Prevention study who are positive for islet autoantibodies (a marker of T1D risk), have been followed over time, and have data and samples available for analysis. Using these resources, we aim to address the following three research questions:
1. Do obesity-related processes –such as insulin resistance, reduced insulin production, beta cell stress and inflammation– contribute to the progression to clinical T1D?
2. Does reducing BMI to a normal range lower the risk of T1D?
3. Do race, ethnicity, genetic ancestry, sex, and age influence the relationship between obesity, islet autoantibodies, and T1D risk?
We hypothesize that greater insulin resistance, lower insulin production, higher beta cell stress and increased inflammation –driven by obesity– will raise T1D risk. We also expect that individuals who reduce their BMI to a normal range will have a lower risk of progressing to T1D. Finally, we anticipate that obesity will have a stronger effect on T1D risk, and obesity treatment larger benefits on T1D risk, in individuals who are Black, Hispanic, of non-European ancestry, female, or adolescents compared to other groups.
Background Rationale
Individuals with T1D face significant hurdles in their daily lives despite advances in technology and improved insulin therapies. Thankfully, T1D prevention has been shown to be possible. We can now identify people at risk for T1D and have treatments available to delay its onset. However, these treatments are not effective for everyone, and their benefits may diminish over time. Thus, research is needed to find new strategies.
T1D is now understood as a condition that begins long before symptoms appear. The first sign of the attack on the beta cells (the cells that make insulin) by the immune (defense) system is the appearance of a single islet autoantibody in the blood (referred to as stage 0 T1D). The disease then progresses to multiple autoantibodies (stage 1), followed by abnormal blood glucose levels that are not yet in the diabetic range (stage 2), and finally to glucose levels in the range of diabetes, often accompanied by symptoms (stage 3).
Using data from participants in the T1D TrialNet Pathway to Prevention study, we demonstrated that obesity and overweight accelerate the progression from one to multiple autoantibodies, and the risk of stage 3 T1D. Other investigators have observed similar findings in different populations and with various methods. This research has produced robust evidence that obesity triggers the appearance of autoantibodies and accelerates the progression toward T1D. However, it is not clear how this happens, whether normalizing body weight decreases the risk of T1D, and who is most susceptible to these effects. These questions must be answered before clinical trials can test whether treating obesity prevents T1D.
Obesity is known to cause another type of diabetes (type 2) through multiple processes. There is also evidence that similar events are triggered by obesity in people at risk for T1D and may contribute to the development of T1D. Obesity causes insulin resistance (when insulin is less effective), decreased insulin production relative to the body’s needs, beta cell stress (when beta cells overwork to produce insulin), and inflammation. These processes disrupt the balance between insulin production and the body’s insulin needs to maintain a normal blood glucose level. Additionally, beta cell stress and inflammation damage beta cells, making them more visible and vulnerable to the immune attack. Since there are available drugs that preferentially target each of those processes, better understanding their role will allow us to select the best treatment.
Although we and others have demonstrated that increased BMI accelerates the progression through T1D stages, it remains unclear whether reducing BMI to a normal range will lower T1D risk. Demonstrating this is essential before we can propose a clinical trial to prevent T1D by treating obesity.
Finally, some groups of people may be more susceptible to the effects of obesity and overweight on T1D risk. We found this to be the case for Hispanic participants. However, race and genetic ancestry (now measured in TrialNet) were not studied. We also observed that girls younger than 12 years of age experienced increased T1D risk at lower BMI than boys over 12. A similar pattern was present in adults younger or older than 35. Therefore, there are strong data to suggest that obesity could be particularly harmful for specific groups of individuals. Improving this knowledge will identify those who might benefit the most from targeting obesity for T1D prevention.
Description of Project
Type 1 diabetes (T1D) has both genetic and environmental causes. Since genetic effects take longer, the rapid surge in the frequency of T1D during the past decades suggests an environmental influence. In parallel, there has been a rise in obesity, partly because of increasing availability of food and decreasing need for physical exercise in populations around the world.
We and others have demonstrated that obesity and overweight increase the risk of T1D. Individuals with elevated body mass index (BMI) –a measure of weight relative to height– are more likely to develop islet autoantibodies –blood markers that signal the beginning of T1D–, and then progress to having high blood glucose and symptoms of T1D. Despite this knowledge, no clinical trials have yet tested whether preventing or treating obesity could prevent T1D. This is because key questions to design such trials remain unanswered. The goal of this project is to address these unanswered questions.
It is not known how obesity contributes to the development of T1D. Early evidence suggests that some of the processes linking obesity to another type of diabetes, namely, type 2, might also play a role in T1D. These processes include insulin resistance (insulin being less effective than it should), reduced insulin production, stress on beta cells (the cells in the pancreas that make insulin), and inflammation. In addition, although we know that obesity or overweight increase T1D risk, it is unclear whether reducing body weight to a healthy range lowers this risk. Finally, we observed that in some groups, such as Hispanic individuals, obesity or being overweight has an even greater impact on T1D risk. We believe that other groups may also be particularly vulnerable.
Therefore, the first goal of this project is to determine whether obesity-related factors –such as insulin resistance, insulin production, beta cell stress and inflammation– cause an increase in the risk of T1D. The second goal is to evaluate whether reducing BMI to a healthy range can lower the risk of developing T1D. The third goal is to assess whether certain characteristics, such as race, ethnicity, genetic ancestry, sex, or age, make some individuals more susceptible to the effects of obesity on T1D risk.
We will leverage unique, existing data and stored blood samples from participants in the TrialNet Pathway to Prevention study, which has tracked individuals over time. Using these resources, we will measure markers of inflammation and beta cell stress and analyze information related to insulin resistance, insulin production, BMI and whether participants developed additional islet autoantibodies or progressed to clinical T1D. Our research team is uniquely qualified to carry out this project, thanks to our extensive experience in T1D prediction and prevention, as well as our work on the relationship between obesity, ethnicity and T1D risk. We have also a proven history of successful collaboration on similar studies, ensuring the expertise and teamwork needed for this project.
Through these groundbreaking studies, we expect to uncover how obesity influences the development of T1D, whether reducing BMI can lower T1D risk, and which groups are most vulnerable to these effects. This research will provide crucial new insights to guide the design of future studies aimed at preventing T1D by addressing obesity, possibly in combination with other preventive treatments. The relevance of this work is heightened by the availability of approved medications and strategies to treat obesity. In addition, this project will highlight that people may develop T1D through different pathways and require different treatments for effective and safe T1D prevention.
Anticipated Outcome
In Specific Aim 1, we anticipate finding that processes triggered by obesity, such as insulin resistance (insulin being less effective than it should), reduced insulin production relative to the body’s needs, beta cell stress (when beta cells overwork to produce insulin), and inflammation, will increase the risk of developing T1D in individuals at risk for the disease. In addition, we expect these processes to intensify the attack of the immune (defense) system against the pancreatic beta cells that produce insulin, accelerating progression through the stages that lead to clinical T1D.
In Specific Aim 2, we anticipate that participants who were obese at the start of the study but reduced their body weight to a healthy range during follow-up will have a lower risk of developing T1D compared to those who remain in the obesity range. We also expect to find that improvements in insulin resistance, insulin production, beta cell stress, and inflammation are predictors of a reduced risk of T1D.
In Specific Aim 3, we hypothesize that race, ethnicity, ancestry, sex, and age influence how obesity affects the risk of T1D. Specifically, we expect obesity to be more strongly linked to insulin resistance, decreased insulin production, beta cell stress, and inflammation in participants who are Hispanic (compared to non-Hispanic), Black (compared to White), of non-European ancestry (compared to European), females (compared to males), and adolescents (compared to younger children and adults). We also anticipate these groups may progress more rapidly when exposed to obesity and obesity-linked processes. Finally, we expect that normalizing BMI benefits participants who are Hispanic, Black, non-European ancestry, females, and adolescents more than other participants in terms of their T1D risk.
In sum, this research will address critical questions on the effect of obesity on T1D so that a clinical trial for T1D prevention can be designed. This research is groundbreaking because it seeks to leverage a new approach to T1D prevention that may help individuals who do not respond to current strategies.
Relevance to T1D
Despite recent advances in diabetes technology and insulin formulations, individuals living with T1D and their families continue to face a significant burden. In addition, people with T1D remain at risk for acute and chronic complications. Decades of research have made it possible to identify individuals at high risk of developing T1D, and drugs that can delay its onset have been developed and approved. However, these treatments are not effective for everyone or their effects may diminish over time. This highlights the need for research to find new prevention strategies. This project seeks to generate the evidence needed to test a new approach to T1D prevention. In particular groups of individuals, this new approach could be complementary to treatments that modulate the immune system.
Obesity has been shown to increase the risk of T1D. However, current knowledge is insufficient to design a clinical trial to prevent T1D by treating obesity. We need to understand how obesity accelerates the progression of T1D, demonstrate that reducing obesity reduces T1D risk, and identify the individuals most susceptible to the detrimental effects of obesity on T1D risk and who would benefit most from targeted treatment. This project seeks to cover these key knowledge gaps and inform the design of clinical trials to prevent the progression of islet autoimmunity and T1D by treating obesity.