Objective
Our proposed study has two primary goals. The first is to determine if glucagon receptor antagonist (GRA) therapy improves insulin resistance and markers of cardiovascular disease (CVD) in participants with type 1 diabetes (T1D). To do this, we will use state-of-the-art clinical research techniques to measure the insulin sensitivity of important metabolically active tissues (fat, liver, and muscle). We will also measure markers of cardiovascular disease (CVD) and inflammation in the peripheral blood, and evaluate vascular health using forearm blood flow measurements. The second goal is to determine if GRA therapy reduces the risk of DKA by inhibiting ketone body formation. To do this, we will measure free fatty acid and ketone levels during a six-hour period of acute insulin withdrawal (insulin stopped). All tests will be done at baseline and again after twelve weeks of therapy (GRA or placebo) in order to quantify the effects of glucagon blockade.
Background Rationale
In contrast to the ever-expanding toolbox of medications available for type 2 diabetes, treatment options for type 1 diabetes (T1D) remain limited. People living with T1D are affected by insulin resistance and increased rates of cardiovascular disease (CVD), and the majority are unable to achieve blood glucose targets. Diabetic ketoacidosis (DKA), the most common cause of diabetes-related death in children, remains a major concern and affects roughly 7% of individuals with T1D each year. Increased levels of the hormone glucagon, secreted by the pancreas, contribute to many of these problems.
Glucagon secretion by the cells of the pancreas is normally tightly controlled by nearby cells. However, in T1D the cells are destroyed, and glucagon is released in an uncontrolled fashion. Glucagon hypersecretion causes higher blood glucose levels, which require greater doses of insulin. Over time, high levels of insulin in the body lead to an insulin resistant state, meaning more insulin is needed to achieve desired glucose control. Thus, dysregulated glucagon contributes to a feedback loop of higher glucose, increased insulin levels, and insulin resistance. Glucagon hormone also promotes the formation of ketone bodies and is essential to the development of DKA. Blocking the action of glucagon using a glucagon receptor antagonist (GRA) may reduce insulin resistance and associated CVD risk, while also decreasing ketone formation and lowering the risk for DKA.
In a previously published study, we demonstrated that a single dose of a GRA medication reduced insulin requirements by ~26% while simultaneously improving glucose control (projected A1c improvement of 1.0% with no increase in hypoglycemia). Treatment with GRA also reduced the levels of free fatty acids, which can be made into ketones. The study demonstrated the ability of glucagon blockade in T1D to reduce insulin levels and decrease the precursors for ketones. Further research is needed to understand the effect of GRA medication on insulin resistance, and to directly measure its ability to inhibit ketone formation.
Description of Project
Type 1 diabetes (T1D) is the most common form of diabetes in children, and accounts for 5-10% of diabetes worldwide. Living with T1D is an ever-present burden for those who are affected. Over 1.3 million Americans with T1D labor daily to control their blood glucose and prevent complications including diseases of the eye, kidney, and heart. Additionally, people living with T1D have an increased risk of developing cardiovascular disease (CVD) compared to those without diabetes, and CVD remains the leading cause of death for individuals living with T1D. Good control is difficult to maintain, and the majority do not achieve blood glucose goals. Due to the destruction of their insulin-producing cells, individuals with T1D are fully dependent on insulin therapy. Long-term insulin use and elevated levels of the hormone glucagon lead to insulin resistance, an independent marker of cardiovascular disease. Furthermore, rates of diabetic ketoacidosis (DKA), one of the most dangerous acute complications of diabetes, remain unacceptably high. There is a clear unmet need for treatments that improve glucose control, decrease insulin resistance and CVD, and reduce the risk of life-threatening DKA.
A new experimental treatment approach – blocking the effect of the hormone glucagon – may offer hope. Glucagon is a hormone that opposes the activity of insulin. Under normal conditions its release is tightly regulated. But in T1D glucagon levels are inappropriately high, stimulating the release of glucose from the liver and promoting the formation of ketone bodies. This in turn contributes to high blood glucose, insulin resistance, and an increased risk for DKA. A glucagon receptor antagonist (GRA) medication, which blocks glucagon activity at its receptor, may be able to improve blood glucose, reduce insulin resistance, and inhibit ketone formation, possibly preventing DKA.
We aim to study the effect of a GRA medication on glucose, insulin sensitivity, CVD risk, and ketone levels in individuals with T1D. To do this, we will enroll 30 participants who will be randomized to receive either GRA or placebo. We will use state-of-the-art clinical research techniques to measure changes in insulin resistance and glucose release from the liver. Blood samples will be analyzed for markers of CVD before and after treatment. We will also measure ketone body formation during insulin withdrawal, simulating a low-insulin state that can lead to DKA. Ultimately, our goal is to clarify the potential role of glucagon blockade as a novel treatment approach for the T1D population.
Anticipated Outcome
We hypothesize that twelve weeks of glucagon receptor antagonist (GRA) therapy will lead to decreased insulin requirements and improved glycemic control (A1c and time-in-range) in participants with type 1 diabetes (T1D), consistent with our previously published proof-of-concept single-dose study. Furthermore, we hypothesize that blocking glucagon action will improve insulin sensitivity, decrease markers of cardiovascular disease and inflammation, and inhibit ketone body formation during insulin withdrawal.
Relevance to T1D
Cardiovascular disease (CVD) is the leading cause of death in people with type 1 diabetes (T1D). This population has an increased CVD risk, which is not fully explained by traditional risk factors or by hyperglycemia. Insulin resistance, known to occur in individuals with T1D, is associated with CVD and may contribute to increase rates of heart and vascular disease. There are no FDA-approved diabetes treatments that target insulin resistance or CVD in T1D. Insulin therapy itself causes high peripheral insulin concentrations and leads to insulin resistance. Dysregulated secretion of the hormone glucagon by the pancreatic cells further contributes to insulin resistance, and also promotes ketone body formation, which can lead to diabetic ketoacidosis (DKA).
The proposed study is designed to evaluate the effect of glucagon blockade – using a glucagon receptor antagonist (GRA) – on insulin resistance and ketone body formation in T1D. If successful, GRA treatment has the potential to improve glucose control, lower insulin requirements, and decrease CVD risk by reducing insulin resistance. Furthermore, it would be the first treatment to reduce ketone body formation and lower the risk of DKA, making it a potential paradigm-shifting therapy for T1D.