Objective
Insulin administration remains the cornerstone therapy for people living with type 1 diabetes (T1D) and tight glucose control, through intensive insulin therapy, reduces the risk of developing long-term complications. However, the role of the higher insulin doses often required to maintain tight glycemic control is poorly understood. Higher insulin doses to maintain glycemic control have been associated with an increased risk of hypoglycemia, weight gain, and insulin resistance, which is when the cells in the body become less responsive to insulin, raising the insulin dose required to maintain glucose control. Insulin resistance increases the risk of heart disease, although whether high insulin dose itself is associated with increased risk of complication development is not well understood. As adjunctive (i.e., non-insulin) therapies can lower insulin requirements, there is a critical need to determine whether lowering insulin dose, while maintaining glycemic control, is beneficial for reducing long-term complications and hypoglycemia. The objective of this project is to isolate the role of insulin dose from that of insulin resistance and HbA1c as a cause of complication development in persons living with T1D. We will do this with two parallel studies. First, we will use existing data from a large cohort of people with childhood-onset T1D that have been followed prospectively for 37 years. Importantly, this study has already collected data on insulin dose, HbA1c, insulin resistance, and other risk factors and has followed persons with T1D prospectively to observe the development of long-term complications (e.g., heart disease, kidney disease, eye disease, etc.) as they occur. We will use novel statistical analysis techniques to provide a comprehensive picture of the long-term risks and benefits of higher insulin doses in T1D, that are independent of insulin resistance and HbA1c. We will then validate our results in another large cohort of people living with T1D. Second, in a subset of these study participants with T1D, we will collect new data on contemporary insulin therapy and use of other medications. We will also collect data on subclinical (i.e., early-stage, before symptom onset) heart disease and kidney disease. Data collected will be used to determine if insulin dose in a contemporary setting, using modern T1D management regimens/technology is associated with early stages of heart disease and/or kidney disease.
Background Rationale
In the past 30 years, there have been dramatic improvements in the management of Type 1 Diabetes (T1D) and it is now well understood that tight control of glucose through intensive insulin therapy reduces the risk of developing long-term complications. However, intensive insulin therapy can have some unintended consequences. It can increase the risk of hypoglycemia and promote weight gain. Insulin treatment in people living with T1D may also contribute to insulin resistance, which is when the cells in the body become less responsive to insulin. Insulin resistance in turn leads to a requirement for even higher doses of insulin to control glucose levels. In this vicious cycle, it is difficult to disentangle the role of insulin dose from that of insulin resistance. Although insulin resistance is associated with an increased risk of heart disease, whether high insulin dose also increases the risk of long-term complications is not well understood. Adjunctive (i.e., non-insulin) therapies, used in persons living with type 2 diabetes (T2D), can lower insulin requirements and may offer additional protection against heart and kidney disease. However, evidence is lacking on whether insulin dose can be safely lowered while maintaining good glycemic control in people living with T1D. Furthermore, whether such lowering of insulin dose would reduce long-term complications in people living with T1D is also unknown. Yet, such evidence would be essential in guiding new, non-insulin, treatment strategies to improve acute (e.g., hypoglycemia) and long-term health in people living with T1D. Existing studies which have prospectively followed people living with T1D for many years and have collected data on insulin dose, HbA1c, measures of insulin resistance as well as the development of complications, have the ability to evaluate risks and benefits of higher doses of insulin in maintaining glycemic control. These studies can help researchers, clinicians, and regulators assess the benefit (if any) of lowering insulin dose while initiating non-insulin treatment, even if HbA1c remains similar.
Description of Project
Tight control of glucose through intensive insulin therapy reduces the risk of developing long-term complications in people living with Type 1 Diabetes (T1D). However, intensive insulin therapy can have some unintended consequences, including increasing the risk of hypoglycemia and promoting weight gain. Insulin treatment in people living with T1D may also contribute to insulin resistance, which is when the cells in the body become less responsive to insulin. Insulin resistance in turn leads to a requirement for even higher doses of insulin to control glucose levels. In this vicious cycle, it is difficult to disentangle the effect of higher insulin dose itself from that of insulin resistance. Although insulin resistance is associated with an increased risk of heart disease, whether high insulin dose also increases the risk of long-term diabetes complications is not well understood. Adjunctive (i.e., non-insulin) therapies, used in persons living with type 2 diabetes (T2D), can lower insulin requirements and may offer additional protection against heart and kidney disease. However, evidence is lacking on whether insulin dose can be safely lowered while maintaining good glycemic control in people living with T1D. Furthermore, whether such lowering of insulin dose would reduce long-term complications in people living with T1D is also unknown. Yet, such evidence would be essential in guiding new, non-insulin, treatment strategies to improve acute (e.g., hypoglycemia) and long-term health in people living with T1D. Existing studies which have prospectively followed people living with T1D for many years and have existing data on insulin dose, HbA1c, measures of insulin resistance, as well as information on the development of complications, have the ability to evaluate risks and benefits of higher doses of insulin in maintaining glycemic control. These studies can help researchers, clinicians, and regulators assess the benefit (if any) of lowering insulin dose while initiating non-insulin treatments. The objective of this project is to isolate the role of insulin dose from that of insulin resistance and HbA1c as a cause of complication development in persons living with T1D. We will do this with two parallel studies. First, we will use existing data from a large cohort of people with T1D that have been followed for 37 years. Importantly, this study has already collected data on insulin dose, HbA1c, insulin resistance, and other risk factors and has followed persons with T1D prospectively to observe the development of long-term complications (e.g., heart disease, kidney disease, eye disease, etc.) as they occurred. We will use novel statistical analysis techniques to provide a comprehensive picture of the long-term risks and benefits of higher insulin doses in T1D, that are independent of insulin resistance and HbA1c. We will then repeat the same analysis in another large cohort of people living with T1D to validate our findings. Second, to determine if the findings from the historical data seem to reflect the modern experience, we will collect new data on contemporary insulin therapy and use of other medications in a subset of the same study participants with T1D. We will also collect data on subclinical (i.e., early-stage, before symptom onset) heart disease and kidney disease. Data collected will be used to determine if people using higher insulin doses in a contemporary setting, with modern T1D management regimens/technology, are more likely to have early stages of heart disease and/or kidney disease.
Anticipated Outcome
We hypothesize that, after accounting for treatment history, glycemic control, and insulin resistance, higher insulin doses will be associated with an increased risk of heart and kidney disease (addressed in Aim 1). We further hypothesize that, for a given level of glycemic control, higher insulin dose will be causally associated with worse subclinical (i.e., early-stage, before the onset of symptoms) heart and kidney health (addressed in Aim 2). Aim 1 will rely on existing data from a large cohort of people with childhood-onset T1D who have been followed prospectively for 37 years. Novel statistical analysis techniques will be used to provide a comprehensive understanding of the long-term risks and benefits of higher insulin doses in T1D, independent of HbA1c and insulin resistance. Results will be validated in another large cohort of people living with T1D. For Aim 2, we will select a subset of study participants with T1D and collect new data on contemporary insulin therapy and use of other medications, as well as measures of subclinical heart disease and kidney disease. Our analysis will assess if insulin dose in a contemporary setting, using modern T1D management regimens/technology, is associated with early stages of heart disease and kidney disease. The results of our study will provide evidence to further study the effect of lower insulin requirements with use of adjunctive (non-insulin) therapies on acute (e.g., hypoglycemia) and long-term (heart, kidney disease) health outcomes in people living with T1D. The results will also highlight the need to develop new glucose-lowering therapies for people living with T1D.
Relevance to T1D
The effect of exposure to insulin differs dramatically between persons living with T1D and those living with T2D. Unlike T2D, which is characterized by high production of insulin in the body and insulin resistance (the state in which the cells in the body become less responsive to insulin), in T1D, the pancreas produces very little to no insulin, requiring life-long insulin therapy. Although unequivocally lifesaving, insulin therapy requires the body to process the administered insulin differently than it would process insulin produced by the body, and this difference has some unintended side-effects, such as weight gain and hypoglycemia. Adjunctive (i.e., non-insulin) therapies can lower insulin requirements and may offer additional protection against heart and kidney disease. However, studies conducted thus far have shown that the effect of such therapies is smaller in people living with T1D than in those living with T2D. This is likely because in these studies, participants with T1D were required to reduce insulin dose while taking adjunctive medications to avoid hypoglycemia, thus limiting the potential improvement in glycemic control. Therefore, data derived from T2D populations cannot be reliably extrapolated to T1D populations, and dedicated studies of insulin dose and complications in people living with T1D are critically needed.