Objective
There is an urgent need for new therapies for people with T1DM that work alongside insulin to lower blood sugar without causing hypos and weight gain.
As part of a JDRF-funded project, we have discovered that a hormone, naturally released by the brain and called alpha-melanocyte stimulatory hormone (α-MSH), can do just that. We administered α-MSH in animals and healthy humans and found it to be safe and effective in reducing blood sugar without causing hypos. By using a technique also known as “clamp”, we also demonstrated that α-MSH lowers blood sugar by increasing the amount of sugar that is taken up by muscles. As part of our ongoing work, we are now administering α-MSH to people with T1DM to find out if it has similar beneficial effects as in healthy participants.
The aim of this proposal is to develop detailed knowledge on the biological mechanism through which α-MSH works, as this is an essential element of developing a new medication for people with T1DM.
Our objectives are the following:
Objective 1: Determine if α-MSH increases uptake of glucose by muscle in people with T1DM.
24 people with T1DM will undergo a procedure referred to as a “clamp” during which they receive glucose, insulin and α-MSH or placebo (saline) to measure if and how much blood sugar is taken up by muscles. Participants will be asked to attend on two occasions, one for the α-MSH infusion and one for the placebo (saline) infusion. This technique has been used for decades in the field of diabetes research and is safe when used by experienced researchers.
Infusion of α-MSH did not result in any side effects (e.g. hypos) in our healthy volunteer study. We will continue to be vigilant and as previously, we will ask participants on the proposed study to rate any feelings of nausea or flushing, while monitoring their blood pressure and heart rate. A doctor will always be available in the unlikely event of any side effects.
Objective 2: Understand how α-MSH works to increase the uptake of blood sugar by muscle.
9 people with T1DM and 9 healthy participants will ingest a sugary drink whilst receiving an infusion of α-MSH or placebo (saline) in their bloodstream. Participants will be asked to attend on two occasions, one for the α-MSH infusion and one for the placebo (saline) infusion. A different group of 6 people with T1DM will also attend the research facility fasted only for the purposes of the muscle biopsy. Muscle samples will be collected from all participants using a biopsy of the leg. Muscle samples will be analysed to find out the exact “machinery” α-MSH activates in muscle to reduce blood sugar. The analyses will take place in our state-of-the-art scientific laboratories using the latest technologies in order to produce accurate and meaningful results.
Muscle biopsies are commonly performed in diabetes research and our team has expertise in this procedure. We will make sure that the participants receive enough local anaesthetic to reduce or eliminate any discomfort during the procedure. Pain killers and appropriate dressings will be provided to minimise discomfort and ensure rapid healing after the biopsy.
Each participant will be reimbursed with £100 ($122) per visit for their time and effort.
Background Rationale
Type 1 Diabetes (T1DM) is an autoimmune disease that 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 T1DM to manage their insulin levels with an external supply in the form of an injection or pump. However, in an attempt to optimise their sugar control, patients frequently receive more insulin than they need, and this can lead to dangerously low levels of blood sugar (hypos) or weight gain.
Many pharmaceutical companies have pursued add-on therapies to insulin in the management of T1DM. None of them currently meet the needs of people with T1DM. The available add-on therapies lower blood glucose only marginally; they cause frequent side effects to the patient and are expensive to healthcare systems.
There is an urgent need for new add-on therapies for people with T1DM that work alongside insulin to lower blood sugar without causing hypos and weight gain.
Our research has discovered that the brain can detect an increase of blood glucose levels, and as a response to this, secretes a hormone called alpha-melanocyte stimulatory hormone (α-MSH). α-MSH has been studied in the past for its actions on skin pigmentation, weight loss and inflammation, but the association with diabetes is a new research development that we have led in.
As part of a JDRF-funded project, we have taken the first critical step in targeting α-MSH as a new add-on therapy in T1DM by infusing the hormone into both animals and healthy humans. We found that α-MSH infusion lowered blood sugar levels after a meal, without causing hypos or an increase in food intake. We also showed that α-MSH works by increasing the amount of sugar taken out of the blood and into muscle. Currently, we are infusing α-MSH in people with T1DM to find out if it can lower blood sugar after a meal, like it does in healthy participants.
Our healthy participants tolerated the infusion well and did not report any side effects. These data provide significant assurance that a positive finding from our proposed studies will translate into an effective and tolerable therapy for T1DM.
In our journey to develop α-MSH into a new add-on treatment for diabetes, we want the take the next step and:
i. Determine if α-MSH increases the amount of glucose taken up by muscle in people with T1DM and
ii. Understand how α-MSH works to increase the uptake of blood sugar by muscle.
Description of Project
Management of blood glucose for people with Type 1 Diabetes (T1DM) can be challenging. When individuals have too much glucose in the body, or too little insulin, high blood sugar can occur. In the long term, high blood sugar can lead to kidney failure, blindness, and amputations. Conversely, the risk of low blood sugar (hypo) can occur if the insulin dose is too high for the amount of glucose in the body. This common and severe side effect can lead to unconsciousness, brain damage or death.
There is an urgent need for new therapies for people with T1DM that work alongside insulin to lower blood sugar without causing hypos and weight gain.
As part of a JDRF-funded project, we have discovered that a hormone, naturally released by the brain and called alpha-melanocyte stimulatory hormone (α-MSH), can do just that. We administered α-MSH in animals and healthy humans and found it to be safe and effective in reducing blood sugar without causing hypos. We also demonstrated that α-MSH lowers blood sugar by increasing the amount of sugar that is taken up by muscles. As part of our ongoing work, we are currently administering α-MSH to people with T1DM to find out if it has similar beneficial effects.
The aim of this proposal is to understand how α-MSH works, as this is an essential element of developing a new medication for people with T1DM.
Our objectives are the following:
Objective 1: Determine if α-MSH increases uptake of glucose by muscle in people with T1DM.
24 people with T1DM will undergo a procedure referred to as a “clamp” during which they receive glucose, insulin and α-MSH or placebo (saline) in order to measure if and how much blood sugar is taken up by muscles.
Objective 2: Understand how α-MSH works to increase the uptake of blood sugar by muscle.
9 people with T1DM and 9 healthy participants will ingest a sugary drink whilst receiving an infusion of α-MSH or placebo (saline). A different group of 6 people with T1DM will also attend the research facility but will not have the sugary drink or any infusions. We will take muscle biopsies from the leg from all these participants and analyse them in our state-of-the-art laboratories to find out the exact “machinery” α-MSH activates in muscle to reduce blood sugar.
We have the necessary experience to conduct these studies that are safe and used for years in diabetes research.
Our research is important because it will address a major unmet need in the care of people with T1DM. The proposed research studies will provide vital evidence to decide whether α-MSH holds promise as a potential new add-on treatment for T1DM. If our findings are positive, we will be well positioned to seek further funding to develop and optimise a medication that works on the α-MSH receptor in muscle to reduce blood glucose in people with T1DM.
In addition, the proposed work on the muscle samples will generate detailed information on the molecular “machinery” used by muscle to take up glucose from the bloodstream in people with T1DM. These muscle samples will be a unique and invaluable resource that could help other scientists around the world also develop new treatments for T1DM.
Our research could have a major positive impact on the lives of people living with T1DM, their families and carers. A safe and effective treatment would enable people with T1DM to improve their sugar control without the addition of more insulin. Better glucose control could reduce the risk of life-threatening diabetes complications, and the risk of hypos and weight gain.
Anticipated Outcome
Our research is important because it aims to address a major unmet need in the care of people with T1DM. The proposed research studies will provide us with the vital evidence to decide whether α-MSH holds promise as a potential new add-on treatment for T1DM. If we show glucose uptake in muscle with α-MSH, we can proceed with optimising a medication that works on the α-MSH receptor in muscle to reduce blood glucose in people with T1DM. A negative finding will also be important as it will divert the investment of resources away from a treatment that is unlikely to work, to other targets for drug development that we identify during this project.
In addition, the proposed work on the muscle biopsies will generate detailed information on the molecular “machinery” used by muscle to take up glucose from the bloodstream in people with T1DM. The muscle samples will be a unique and invaluable resource for scientists. This output will be completely independent of whether our findings regarding the effects of α-MSH are positive or negative.
Our research could have a major impact on the lives of people living with T1DM, their families and carers. A safe and effective treatment would enable patients to improve their sugar control despite lower insulin doses. Better glucose control could reduce the risk of life-threatening diabetes complications, and the risk of hypos and weight gain.
Our proposed research is still in the early stages of the drug development pathway and therefore its outcomes will not impact on existing models of care in the short term. The innovation lies in our quest to develop medications that work via α-MSH receptors and can be taken ideally as a tablet, or alternatively an injection, alongside short-acting insulin injections or insulin boluses through pumps. In the long term we envisage that, whilst complementing insulin therapies, such medications will lead to a novel model of care for people with T1DM.
Relevance to T1D
Management of blood glucose for people with Type 1 Diabetes (T1DM) can be challenging. When individuals have too little insulin, high blood sugar can occur. In the long term, high blood sugar can lead to kidney failure, blindness, and amputations. Conversely, the risk of low blood sugar (hypo) can occur if the insulin dose is too high for the amount of glucose in the blood. This common and severe side effect can lead to unconsciousness, brain damage or death.
Our research has shown that α-MSH, a hormone produced in the brain and can reduce blood glucose levels without causing hypos or hunger. We have shown that α-MSH can be given before a meal to reduce blood glucose in healthy participants, by increasing the amount of glucose taken up by muscles. This action of α-MSH may be utilized for the development of a new add-on treatment that can be taken by people with T1DM, ideally as a tablet, to reduce their insulin doses.
Our research could have a major positive impact on the lives of people living with T1DM, their families and carers. A safe and effective treatment would enable them to improve their sugar control despite lower insulin doses. Better glucose control would reduce the risk of life-threatening diabetes complications, and the risk of hypos and weight gain.