Objective
Type 1 diabetes develops due to destruction, by the body's own immune system, of insulin-producing beta-cells in the pancreas. Our previous work has shown that a protein called NAMPT may play an important role in the death of insulin-producing cells in type 1 diabetes.
The objective of this study is to build on these initial findings and use models of type 1 diabetes to investigate whether drugs which block the action of NAMPT (some of which can be taken orally as a pill or capsule) can:
1) Prevent death of insulin-producing cells
2) Increase function of insulin-producing cells
3) Lower blood sugar levels in diabetic mice
If successful, this study will have identified a possible new drug for type 1 diabetes, which may be taken forward into clinical trial.
Background Rationale
Type 1 diabetes develops when insulin-producing cells, known as beta-cells, are attacked by the body's immune system and destroyed. Since the main role of insulin is to reduce blood sugar levels, this lack of insulin production leads to abnormally high blood sugar levels and increased risk of developing complications including heart and kidney disease, blindness and increased risk of lower-limb amputations.
Currently the main way to treat type 1 diabetes is to inject insulin, which lowers blood sugar levels. However daily insulin injections are inconvenient and uncomfortable and are associated with risk of hypoglycemia (very low levels of blood sugar) which can sometimes cause comas and death. Additionally, injected insulin does not control blood sugar as well as the body’s own insulin. This means that even with life-long insulin therapy, diabetic complications still develop. Therefore, new drugs which can increase the survival and overall number, and function of insulin-producing cells are urgently required. Such drugs would ideally treat the underlying disease, allowing the body being able to produce more of its own insulin, which would in turn reduce the requirement for insulin injections.
This project will focus on a protein called NAMPT. NAMPT is involved in regulation and function of the body’s immune system. Previous work has shown that when NAMPT levels are too high, this can cause an abnormal immune response leading to inflammation and cell death, similar to what is observed in type 1 diabetes. When we increased activity of NAMPT in mouse insulin-producing cells in laboratory experiments, we observed that this caused insulin-producing cells to die. Importantly, this is consistent with what is observed in type 1 diabetes. We have also conducted some preliminary experiments in models of type 1 diabetes, which have shown that lowering the activity of NAMPT can prevent death and increase function of insulin-producing cells.
This suggests that blocking the action of NAMPT may be an exciting new approach for treating type 1 diabetes which could prevent death of insulin-producing beta-cells, and as a result allow the body to produce more of its own insulin.
Drugs which target NAMPT already exist and have been shown to be effective in other inflammatory and autoimmune diseases. The next steps, and the objectives for this study are to test drugs which block NAMPT function in mouse models of type 1 diabetes and in human insulin-producing beta-cells to see if we can increase the numbers of insulin-producing cells in these type 1 diabetes models.
If successful, this study will have identified an attractive novel type 1 diabetes drug which can potentially treat the underlying disease by increasing numbers of functional insulin-producing cells. This will reduce the need for daily insulin injections and provide significant patient benefits. Some NAMPT blocking drugs can be taken orally, potentially as a pill or capsule which would benefit people in terms of increased convenience. The next steps after these experiments will be to progress to human clinical studies to assess whether NAMPT inhibiting drugs are safe and effective in people with type 1 diabetes.
Description of Project
Type 1 diabetes is caused by destruction of insulin-producing cells. This means that to control their blood sugar, people with type 1 diabetes must inject insulin, to replace the insulin normally produced by the body. However, injected insulin does not control blood sugar levels as well as the bodies own insulin. Insulin injection can also cause blood sugar levels to become too low (hypoglycaemia), which in some cases can be life threatening. Therefore, new drugs which can prevent of type 1 diabetes are needed to reduce requirement for injected insulin and improve treatment options for people with type 1 diabetes.
This project will use human tissue and animal models to investigate whether new drugs which block the action of a protein called NAMPT can be used to prevent type 1 diabetes. Some of these drugs can be taken orally, either as tablets or capsules. This could be a major benefit for people with type 1 diabetes, potentially reducing need for insulin injections and allowing better control of blood sugar levels, using a drug available in a convenient form which can be taken orally.
Anticipated Outcome
If successful, this project will have identified a novel drug that can prevent death of insulin-producing cells, and as a result potentially be used to prevent type 1 diabetes. Importantly, by increasing function and survival of insulin-producing beta-cells cells, this drug will treat the underlying disease and therefore will reduce the requirement for daily insulin injections.
Reducing the need for insulin would help people in several different ways. Daily insulin injections can be painful and inconvenient, often leading to underuse of insulin and worsening of blood sugar levels. Less need for insulin would also lower the risk of hypoglycemia, which is associated with insulin injections. Increasing the body’s own insulin levels could also result in better control of blood sugar over the long-term, leading to reduced risk of diabetic heart and kidney disease. The fact that some of the drugs to be tested in this project can be taken orally as a pill or capsule, would provide even greater benefit in terms of convenience.
Success of the current project would allow us to potentially move forward into clinical trials, with the aim of evaluating whether the drug works in people with type 1 diabetes, and rapidly making this therapy available to patients with type 1 diabetes.
Relevance to T1D
This study is highly relevant to type 1 diabetes. Type 1 diabetes occurs due to death of insulin-producing cells, because of the actions of the body’s own immune system. The resulting lack of insulin production leads to uncontrolled increases in blood sugar levels and an associated increased risk of developing complications such as heart and kidney disease.
Currently, the main treatment for type 1 diabetes is insulin injection. This aims to manage symptoms of diabetes (i.e. by controlling blood sugar levels) but does not increase numbers or survival of insulin-producing cells, and therefore does not increase levels of the body’s own insulin. Insulin injection can also lead to several problems. Firstly, over the long-term insulin injections do not always control blood sugar that well, and people taking insulin can still develop diseases linked to high blood sugar such as heart and kidney disease. Secondly, in the short term, insulin injections can cause blood sugar levels to become very low - known as hypoglycaemia. This is a dangerous side-effect and can cause symptoms ranging from nausea and dizziness to seizures, coma and death.
Additionally, people with type 1 diabetes cite reducing complexity and burden of disease management, especially in response to meals and exercise, as a priority for research efforts. In addition, current insulin delivery technology is not considered to be discrete, low enough burden or sufficiently reliable.
Our work has the potential to address these issues by identifying a drug which can prevent death of insulin-producing cells (reducing insulin requirements and improving blood sugar control) and is low-burden (can be taken orally).
This study will focus on testing whether blocking the actions of a protein called NAMPT can increase survival and function of insulin-producing cells. We have already shown that NAMPT plays a role in the death of insulin-producing cells in models of type 1 diabetes and our preliminary experiments show that drugs which block NAMPT action can prevent death of insulin-producing cells.
If successful, this project could lead to identification of new drugs for prevention of type 1 diabetes, some of which can be taken orally as a pill or capsule. This could represent a major improvement in treatment options for people with type 1 diabetes, leading to reduced need for insulin injections and better control of blood sugar levels.