Objective
This proposal aims to test if a naturally produced small protein from the pituitary gland in the brain, alpha-Melanocyte-stimulating hormone (α-MSH), reduces blood glucose in Type 1 Diabetes (T1D) animal models and people with T1D without affecting basal glucose levels. In parallel, we aim to generate stable, specific, analogues of the Melanocortin 5 Receptor (MC5R) as lead drug development candidates.
The hypotheses we will test are:
i) α-MSH improves glucose tolerance in T1D animal models and in humans
ii) The glycemic effects of α-MSH in animal models are mediated by MC5R
iii) MC5R agonists improve glucose tolerance in T1D animal models
Specifically, we will:
i) Determine the glycemic effects of α-MSH in rodent and non-human primate (NHP) T1D models
ii) Determine the effects of α-MSH on fasting glucose and oral glucose tolerance in people with T1D
iii) Create selective, long-lasting, orally available MC5R agonists and characterize in vitro
iv) Determine the glycemic effects of novel MC5R agonists in rodent and NHP T1D models.
Background Rationale
Diabetes is recognised as the fasted growing chronic condition in the world. It develops through the body’s failure to properly regulate blood glucose levels. Type 1 Diabetes (T1D), is an autoimmune disease and develops when beta cells in the pancreas are destroyed and the ability to produce insulin is switched off. As insulin allows the body to process sugar and create energy, it is important for people living with T1D to manage their insulin levels with an external supply in the form of an injectable or pump. However, sometimes patients receive more insulin than they need, and this can lead to dangerously low levels of blood glucose.
Our research has discovered that the brain can also detect an increase of blood glucose levels, and as a response to this, secretes a small protein called alpha-Melanocortin-stimulating hormone (α-MSH). α-MSH has been studied in the past for its actions on pigmentation, weight loss and inflammation, but the association with diabetes is a new research development.
For proteins to have a functional effect on the body, like regulating glucose, they need to tightly bind to a receptor which sits on the outside of a cell. α-MSH is able to bind to the Melanocortin Receptor (MCR) family, of which there are 5 different subtypes. When α-MSH binds to the MC1R, there is an effect on skin colour, when it binds to MC4R weight loss occurs. However, we believe that the effect that α-MSH can play in lowering blood glucose levels is when it binds to the MC5R. This specific receptor can be found on skeletal muscle cells, and when bound by α-MSH, result in glucose being transported into the cell, effectively clearing it from the blood and turning it into energy for the body to use.
α-MSH has a proven safety record as it has been tested in clinical trials for its ability to increase skin pigmentation. The outcome of these trials indicate that α-MSH is well tolerated, with side effects of potential nausea and/or facial warmth/flushing. These data provide some assurance that a positive finding from our proposed clinical study will translate into a useful and tolerable therapy for T1D in humans.
This research proposal is looking to determine if α-MSH will reduce blood glucose levels following a meal in volunteers with T1D. In conjunction with this, we will produce new compounds based on the design of α-MSH that bind only to the MC5R and screen its’ activity in cell-based and animal studies. If we can achieve this, it will help to produce a drug that only targets the MC5R and will therefore not have any unwanted effects associated with binding to the other Melanocortin receptors. This is an important step in the development of a new adjunctive therapeutic for T1D.
Description of Project
Medication in the form of insulin, is critical in the management of Type 1 Diabetes (T1D), but it remains imperfect, and individuals face difficult choices in the day to day control of their diabetes. Individuals must choose either less glucose control leading to risks associated with high blood glucose, or tight glucose control leading to risks of hypoglycaemia, which can be catastrophic. There is a clear need for additional therapies to be taken in combination with insulin which allows for a lower insulin dose, but better glucose control. Currently there are no such therapies available on the market that fit the needs of people living with T1D.
Our research has recently shown that in humans and animals the alpha-Melanocyte-stimulating hormone (α-MSH) is produced by the brain in response to an injection of glucose or when a meal is consumed. In animal studies, α-MSH reduces the levels of glucose in the body following a meal, but does not modify resting glucose levels. This effect is facilitated by the binding of α-MSH to its receptor Melanocortin 5 Receptor (MC5R). This receptor is found on skeletal muscle cells, and when α-MSH interacts with MC5R, glucose is transported into the muscle from the blood stream. This novel way of lowering blood glucose levels could be harnessed to develop a new therapeutic to be taken with a lower dose insulin for better treatment of T1D.
We have clearly demonstrated the glucose lowering effects of α-MSH in both cell-based and animal studies. Through independent funding, our collaborators in Dublin, Ireland, plan to test if α-MSH can reduce blood glucose in healthy humans. Following the completion of this trial, and if successful with JDRF funding, we wish to see if α-MSH can reduce blood glucose in individuals with T1D. This clinical study will be conducted at the Melbourne Health on glucose tolerance in volunteers with T1D. Volunteers will be given a dose of either α-MSH or placebo, and then undergo an oral glucose tolerance test, which mimics the effect of a meal by raising glucose levels in the blood. We will test if treatment with α-MSH causes lower glucose levels during the glucose tolerance test.
The Melanocortin Receptor family has five subtypes, and α-MSH is able to bind to most of these, resulting in many different effects (from skin colour changes to weight loss). Therefore, to generate a more effective and tolerable therapeutic for use in T1D it will be necessary to generate a compound which binds tightly to the MC5R only (MC5R agonist). In parallel with the clinical trial, we will develop novel MC5R agonists and evaluate their improved efficacy over the native α-MSH, in cell based and animal studies. We seek to perform these bridging studies in both mice-models of T1D and a unique non-human primate model of T1D. After the successful conclusion of these studies, we will be well positioned to seek further funding to optimise a lead novel, MC5R agonist that is orally available, that is, it can be taken as a tablet rather than an injection. This follow-on work will be conducted in partnership with industry, and it is anticipated that clinical trials of a successful therapeutic would be conducted in the T1D clinical trials network in Australia and at international sites.
Anticipated Outcome
Over the last decade, a number of non-insulin glucose-lowering therapies have been approved to treat Type 2 Diabetes. To date, only one has been approved to treat Type 1 Diabetes (T1D). α-MSH presents an opportunity to explore a new pathway that may be helpful to people living with T1D. Understanding the effects of α-MSH in humans through controlled clinical studies is a key step in this journey.
We expect that the clinical research proposed will establish that α-MSH can reduce blood glucose levels in individuals with T1D, independently of insulin. This will establish the role for specific MC5R compounds as a therapeutic in combination with insulin for T1D care, because it will reduce glucose without risking hypoglycaemia, and allow for reduced total insulin use.
In parallel, we will begin research into the production and testing of compounds that specifically bind to the MC5R, the receptor of interest. We expect this program to yield data supporting our hypothesis that the glucose modulating effects are mediated through the MC5R in cell-based studies and replicated in animal-based studies. We plan that these studies will produce a molecule that is orally available, that is, it can be taken as a tablet, rather than as an injection.
Data generated from the clinical and lab-based studies together, will be attractive for new partnerships that will progress this treatment through the research and development pipeline and to those that need it most: people living with T1D.
Relevance to T1D
Management of blood glucose for people with Type 1 Diabetes (T1D) is difficult, and conditions dangerous to their health can develop as a consequence of too high or too low blood glucose levels. When individuals have too much food or glucose in the body, or too little insulin, hyperglycaemia can occur. This condition is a key driver of microvascular (diabetic nephropathy, neuropathy and retinopathy) and macrovascular (coronary artery disease, peripheral arterial disease and stroke) complications. Conversely, the risk of hypoglycaemia can occur if the insulin dose is too high for the amount of glucose in the body. This common and severe adverse effect can lead to unconsciousness/coma and possible brain damage or death.
Our research has shown that α-MSH, which is produced in the brain and acts through an alternative pathway to insulin in the body, can help to manage blood glucose levels. We have shown that α-MSH can be given before a meal and help glucose be processed in the body to make energy. The specific actions of α-MSH may be harnessed for the development of a new therapeutic that can be taken by people with T1D in conjunction with insulin at a lower dose.
This could have a major positive impact on the lives of people living with T1D and their families. With a successfully developed treatment, it would enable people with T1D to improve their glucose control despite lower insulin doses. Better glucose control would reduce the risk of life threatening vascular complications, and lower insulin doses would reduce weight gain and the risk of hypoglycaemia.