Does an infusion of alpha-melanocyte stimulating hormone reduce blood sugar after a sugary drink in healthy people and those with type 1 diabetes mellitus?
| ISRCTN | ISRCTN26265036 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN26265036 |
| IRAS number | 275910 |
| Secondary identifying numbers | CPMS 45135, IRAS 275910 |
- Submission date
- 26/06/2020
- Registration date
- 02/07/2020
- Last edited
- 23/06/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Current plain English summary as of 19/11/2021:
Background and study aims
Patients with type 1 diabetes and advanced type 2 diabetes commonly have high blood glucose levels after eating. This can injure body organs resulting in complications such as heart attacks, blindness and kidney failure. They require life-long treatment with the hormone insulin. While insulin therapy is effective it can come with significant side-effects like very low sugar levels (hypoglycaemia) and excessive weight gain. Researchers have discovered that a hormone from the brain called alpha melanocyte-stimulating hormone (α-MSH) reduces blood glucose in mice and sheep by making them more sensitive to insulin. Researchers now wish to find out for the first time if this is true in humans. They propose to infuse this hormone and measure blood glucose levels in healthy humans to determine whether α-MSH improves their insulin sensitivity.
Who can participate?
In parts one and two of the study, adults aged 18-50 who are healthy with no history of diabetes, who have had a stable body weight for at least 3 months and a BMI of ≥18 < 30 (i.e., not underweight or obese) will be eligible to take part. In part three the study will recruit adults aged 18-50 who have type 1 diabetes mellitus but are otherwise healthy, who have had a stable body weight for at least 3 months and a BMI of ≥18 < 30 (i.e., not underweight or obese).
What does the study involve?
There are three parts to the study.
In part one, healthy participants will attend four visits where they will receive an infusion of either α-MSH or saline (saltwater) at one of three concentrations. During the infusion, participants will have their glucose tolerance tested by drinking a cup of water with 75 g of sugar in it. Blood samples will be collected over this time (4 hours). Then participants will attend two visits where they will receive an infusion of either saline or α-MSH at the concentration found in part one to have the greatest effect on glucose tolerance. As well as the α-MSH infusion, they will also undergo a test that infuses insulin and glucose to very precisely measure the effect of the α-MSH infusion on their insulin sensitivity. Over this time (6 hours) blood samples will be collected. Blood samples will be used to measure blood sugar, insulin, α-MSH, and gut hormones.
In part two, healthy participants will attend two visits where they will undergo glucose tolerance tests as described above while receiving an infusion of either high dose alpha-MSH or saline.
In part three, participants with type 1 diabetes mellitus attend two visits where they will undergo glucose tolerance tests as described above while receiving an infusion of either high dose alpha-MSH or saline.
What are the possible benefits and risks of participating?
There are no direct benefits to the participants medically. The risks are very low as the alpha-MSH peptide has been used in humans previously and has minimal side effects. Some facial flushing may occur for a few minutes, and potentially some nausea. A physician will be present during the infusion to manage these should they occur.
Where is the study run from?
Imperial College London (UK) and Ulster University (UK)
When is the study starting and how long is it expected to run for?
May 2019 to December 2024
Who is funding the study?
Investigator initiated and funded
Who is the main contact?
Brett Johnson
brett.johnson@nhs.net
Previous plain English summary:
Background and study aims
Patients with type 1 diabetes and advanced type 2 diabetes commonly have high blood glucose levels after eating. This can injure body organs resulting in complications such as heart attacks, blindness and kidney failure. They require life-long treatment with the hormone insulin. While insulin therapy is effective it can come with significant side-effects like very low sugar levels (hypoglycaemia) and excessive weight gain. Researchers have discovered that a hormone from the brain called alpha melanocyte-stimulating hormone (α-MSH) reduces blood glucose in mice and sheep by making them more sensitive to insulin. Researchers now wish to find out for the first time if this is true in humans. They propose to infuse this hormone and measure blood glucose levels in healthy humans to determine whether α-MSH improves their insulin sensitivity.
Who can participate?
Adults age 18-50 who are healthy with no history of diabetes, who have had a stable body weight for at least 3 months and a BMI of ≥18 < 30 (i.e., not underweight or obese)
What does the study involve?
There are two parts to the study. In part one participants will attend four visits where they will receive an infusion of either α-MSH or saline (saltwater) at one of three concentrations. During the infusion, participants will have their glucose tolerance tested by drinking a cup of water with 75 g of sugar in it. Blood samples will be collected over this time (4 hours).
In the second part of the study, participants will attend two visits where they will receive an infusion of either saline or α-MSH at the concentration found in part one to have the greatest effect on glucose tolerance. As well as the α-MSH infusion, they will also undergo a test that infuses insulin and glucose to very precisely measure the effect of the α-MSH infusion on their insulin sensitivity. Over this time (6 hours) blood samples will be collected. Blood samples will be used to measure blood sugar, insulin, α-MSH, and gut hormones.
What are the possible benefits and risks of participating?
There are no direct benefits to the participants medically. The risks are very low as the alpha-MSH peptide has been used in humans previously and has minimal side effects. Some facial flushing may occur for a few minutes, and potentially some nausea. A physician will be present during the infusion to manage these should they occur.
Where is the study run from?
Imperial College London (UK)
When is the study starting and how long is it expected to run for?
May 2019 to July 2022
Who is funding the study?
Investigator initiated and funded
Who is the main contact?
Brett Johnson
b.johnson@imperial.ac.uk
Contact information
Public
Department of Metabolism, Digestion and Reproduction
6th Floor Commonwealth Building
Imperial College London
Hammersmith Hospital
Du Cane Road
London
W12 0NN
United Kingdom
 ORCID ID |
0000-0002-2902-1919 |
|---|---|
| Phone | +44 (0)7592589553 |
| Brett.johnson@nhs.net |
Scientific
Department of Metabolism, Digestion and Reproduction
6th Floor Commonwealth Building
Imperial College London
Hammersmith Hospital
Du Cane Road
London
W12 0NN
United Kingdom
| ORCID ID |
0000-0003-3830-3173 |
|---|---|
| a.miras@nhs.net |
Study information
| Study design | Randomised; Both; Design type: Not Specified, Not Specified, Cross-sectional |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A physiological study of the effect of alpha-MSH on glucose clearance in healthy participants and those with type 1 diabetes mellitus |
| Study acronym | Alpha-MSH |
| Study objectives | Current study hypothesis as of 19/11/2021: Alpha-melanocyte stimulatory hormone (alpha-MSH) is a hormone that is produced by the brain and released into the bloodstream. It has multiple functions in the body, such as reducing inflammation, promoting skin pigmentation and controlling energy balance. It has recently been shown that in animals, infusion of alpha-MSH increases glucose clearance by promoting its uptake in skeletal muscle, thus lowering circulating blood sugar. Human studies to understand this action of alpha-MSH is a critical next step. This study aims to observe the effect of alpha-MSH on increasing glucose clearance from the blood by promoting its uptake into skeletal muscle in healthy humans and those with type 1 diabetes mellitus Hypothesis: Alpha-melanocyte stimulating hormone improves post-prandial glucose clearance versus saline in healthy humans and those with type 1 diabetes mellitus Previous study hypothesis: Alpha-melanocyte stimulatory hormone (alpha-MSH) is a hormone that is produced by the brain and released into the bloodstream. It has multiple functions in the body, such as reducing inflammation, promoting skin pigmentation and controlling energy balance. It has recently been shown that in animals, infusion of alpha-MSH increases glucose clearance by promoting its uptake in skeletal muscle, thus lowering circulating blood sugar. Human studies to understand this action of alpha-MSH is a critical next step. This study aims to observe the effect of alpha-MSH on increasing glucose clearance from the blood by promoting its uptake into skeletal muscle in healthy humans. Hypothesis: Alpha-melanocyte stimulating hormone improves post-prandial glucose clearance versus saline. |
| Ethics approval(s) | Approved 19/05/2020, London - Fulham Research Ethic Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)2071048235; fulham.rec@hra.nhs.uk), REC ref: 20/LO/0355 |
| Health condition(s) or problem(s) studied | Glucose clearance from the blood |
| Intervention | Current intervention as of 19/11/2021: For this prospective double-blinded (both the researchers and study participants are unaware of the intervention) randomised control trial (RCT) the researchers plan to recruit 15 healthy volunteers from the general public for work package 1, 22 of the same for work package 2, and patients with type 1 diabetes mellitus for work package 3. The participants will be healthy male and female volunteers or those with type 1 diabetes mellitus above the age of 18 with no major medical conditions. Prior to being accepted into the study, participants will first be screened by a member of the research team to ensure they meet the inclusion and exclusion criteria. At this screening visit, participants will be informed about the study and have the opportunity to ask questions. They will be given a detailed participant information sheet which they may keep to review. Once the participant has been given a minimum of 24 h to consider their entry into the study, informed consent in person will be obtained. Work package 1: This work package will be comprised of two sub-studies run sequentially, to find the most effective dose of alpha-MSH, and then to assess its effect on whole body insulin sensitivity. We will conduct a prospective randomised double-blinded physiological study to recruit 15 healthy participants from either sex from the community. On each of these four study visits, participants will undergo an oral glucose tolerance test and will be randomized to either a placebo infusion or infusion of alpha-MSH, at one of three doses (15, 150, 1500 ng/kg/hr). Each participant will be studied at least 2 days apart in a randomized, double blind, placebo-controlled, crossover manner. On completion of dose-finding, a euglycaemic hyperinsulinaemic clamp will be conducted with placebo and the dose of alpha-MSH observed to induce the maximal change in the area under the curve of glucose and/or insulin concentration during an OGTT, and as long as it does not cause hypoglycaemia. Each participant will be studied at least 2 days apart in a randomized, double- blinded, placebo-controlled, crossover manner. Work package 2: Participants will undergo two OGTT visits, at least 2 days apart, during which they will be randomised to receive either saline or 1500 ng/kg/hr alpha-MSH. Work package 3: Participants will undergo two OGTT visits, at least 2 days apart, during which they will be randomised to receive either saline or 1500 ng/kg/hr alpha-MSH. The blood collected throughout the infusions will be analysed in the lab for relevant hormones and proteins. Previous intervention: For this prospective double-blinded (both the researchers and study participants are unaware of the intervention) randomised control trial (RCT) the researchers plan to recruit 15 healthy volunteers from the general public. The participants will be healthy male and female volunteers (we aim to recruit 8 males and 7 females) above the age of 18 with no major medical conditions. Prior to being accepted into the study, participants will first be screened by a member of the research team to ensure they meet the inclusion and exclusion criteria. At this screening visit, participants will be informed about the study and have the opportunity to ask questions. They will be given a detailed participant information sheet which they may keep to review. Once the participant has been given a minimum of 24 hours to consider their entry into the study, informed consent in person will be obtained. Every participant will then attend 4 separate morning visits at Hammersmith Hospital after an overnight fast (fasted since 10 pm the night before). Each visit will last approximately 4 hours and take place at a minimum of 1-week intervals. At each of these visits the participants will be randomised (assigned at random by a computer programme) to infusions of one of three doses of alpha-MSH or placebo (normal saline - 0.9% sodium chloride (salt) solution). These infusions will last for 150 minutes and will be delivered through an intravenous cannula placed in the arm. A second cannula will be inserted into the other arm to enable extraction of blood samples. Thirty minutes after each infusion begins, participants will be asked to consume a sugary drink which will raise their blood sugar levels. Throughout the infusion, blood will be drawn and circulating blood glucose measured. This will allow the researchers to measure the body’s response to glucose under each of the doses and compare this to the placebo in order to identify the dose at which alpha-MSH acts to reduce blood sugar. Once all participants have completed four infusion visits (three doses of alpha-MSH and one placebo visit) with oral glucose tolerance tests, they will be invited back for a further two morning fasted visits at Hammersmith Hospital. Each visit will last approximately 4 hours, during which participants will undergo what is known as a 'glucose clamp' where their blood glucose is maintained at a stable level during an infusion of insulin with alpha-MSH or placebo. The participant will require three separate intravenous lines (one for insulin, one for either alpha MSH or placebo and one for extracting blood samples). During one of these visits, the dose of alpha-MSH administered will be that which is observed to cause the greatest change in blood glucose levels during the glucose tolerance test visits. In the other visit, saline will be administered as placebo. At the first of these two visits, the participant will be randomised to alpha-MSH or placebo, with the second visit administering the infusion not given in the first. Both the researchers and participant will be unaware of the treatment during these visits. This glucose clamp technique will allow the researchers to quantify the amount of glucose that is being used by the body in response to an infusion of alpha-MSH. The study will conclude when participants complete two glucose clamp visits. If any of the expected side effects (nausea, facial flushing, general discomfort) are present at any dose they will be assessed via the Visual Analogue Scale provided, where the participant will rate each sensation by marking with a dash along a 10 cm line. The blood collected throughout the infusions will be analysed in the lab for relevant hormones and proteins. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Alpha-MSH |
| Primary outcome measure | Current primary outcome measure as of 19/11/2021: Work Package 1: 1. Difference in the total or incremental area under the curve of glucose concentration at an OGTT during saline vs. alpha-MSH infusion at 0-180 minutes 2. Difference in the total or incremental area under the curve of insulin concentration at an OGTT during saline vs. alpha-MSH infusion at 0-180 minutes 3. Difference in the glucose infusion rate at the euglycaemic hyperinsulinaemic clamp during saline vs. alpha-MSH infusion Work Package 2: 1. Difference in the total or incremental area under the curve of glucose concentration at an OGTT during saline vs. 1500 ng/kg/hr alpha-MSH infusion at 0-180 minutes 2. Difference in the total or incremental area under the curve of insulin concentration at an OGTT during saline vs. 1500 ng/kg/hr alpha-MSH infusion at 0-180 minutes Work Package 3: 1. Difference in the total or incremental area under the curve of glucose concentration at an OGTT during saline vs. 1500 ng/kg/hr alpha-MSH infusion at 0-180 minutes Previous primary outcome measure: 1. Area under the curve of glucose concentration measured using blood tests at an OGTT during saline vs. alpha-MSH infusion visits at 0-180 minutes 2. Glucose infusion rate measured using blood tests at the euglycaemic hyperinsulinaemic clamp during saline vs. alpha-MSH infusion visits at 0-240 minutes |
| Secondary outcome measures | Current secondary outcome measures as of 19/11/2021: Work Package 1: 1. Difference in the total or incremental area under the curve of the concentration of the following metabolites during OGTT and clamp with saline or alpha-MSH infusion at 0-180 minutes: 1.1. Insulin measured using blood tests 1.2. C-peptide measured using blood tests 1.3. Glucagon measured using blood tests 1.4. GLP-1 measured using blood tests 1.5. α-MSH measured using blood tests 2. Adverse events (including flushing) as reported by the participant using visual analogue scales at -30 to 180 minutes Work Package 2: 1. Difference in the total or incremental area under the curve of the concentration of the following metabolites during OGTT and clamp with saline or 1500 ng/kg/hr alpha-MSH infusion at 0-180 minutes: 1.1. Insulin measured using blood tests 1.2. C-peptide measured using blood tests 1.3. Glucagon measured using blood tests 1.4. GLP-1 measured using blood tests 1.5. α-MSH measured using blood tests 2. Adverse events (including flushing) as reported by the participant using visual analogue scales at -30 to 180 minutes Work Package 3: 1. Difference in the total or incremental area under the curve of the concentration of the following metabolites during OGTT and clamp with saline or 1500 ng/kg/hr alpha-MSH infusion at 0-180 minutes: 1.1. Insulin measured using blood tests 1.2. C-peptide measured using blood tests 1.3. Glucagon measured using blood tests 1.4. GLP-1 measured using blood tests 1.5. α-MSH measured using blood tests 2. Adverse events (including flushing) as reported by the participant using visual analogue scales at -30 to 180 minutes Previous secondary outcome measures: 1. Area under the curve for the following metabolites during OGTT and clamp during saline or alpha-MSH infusion visits at 0-180 minutes: 1.1. Insulin measured using blood tests 1.2. C-peptide measured using blood tests 1.3. Glucagon measured using blood tests 1.4. GLP-1 measured using blood tests 1.5. α-MSH measured using blood tests 2. Adverse events (including flushing) as reported by the participant using visual analogue scales at -30 to 180 minutes |
| Overall study start date | 05/05/2019 |
| Completion date | 31/12/2024 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 50 Years |
| Sex | Both |
| Target number of participants | 59 |
| Key inclusion criteria | Current participant inclusion criteria as of 19/11/2021: Work Package 1 and 2: 1. 18-50 years old 2. Normal fasting glucose (< 5.6 mmol/l) 3. Stable body weight for at least 3 months 4. BMI ≥18 and <30 kg/m² 5. The participant is capable of giving written informed consent 6. The participant is able to read, comprehend and record information written in English Work Package 3: 1. 18-50 years old 2. Diagnosis of T1DM with low/undetectable plasma C-peptide 3. Stable body weight for at least 3 months 4. BMI ≥18 and <30 kg/m² 5. The participant is capable of giving written informed consent 6. The participant is able to read, comprehend and record information written in English Previous participant inclusion criteria: 1. 18-50 years old 2. Normal fasting glucose (< 5.6 mmol/l) 3. Stable body weight for at least 3 months 4. BMI > = 18 < 30 kg/m² 5. The participant is capable of giving written informed consent 6. The participant is able to read, comprehend and record information written in English |
| Key exclusion criteria | 1. Previous or current psychiatric diagnosis listed in DSM-V Axis 1 2. Significant current or past medical or psychiatric history that, in the opinion of the investigators, contraindicates their participation 3. History of type 1 or type 2 diabetes mellitus 4. History of endocrine disorder 5. History of ischaemic heart disease, hypertension, heart failure, cardiac arrhythmia, peripheral vascular or cerebrovascular disease. 6. History or presence of significant respiratory, gastrointestinal, hepatic, oncological, neurological or renal disease or other condition that in the opinion of the Investigators may affect participant safety or outcome measures 7. Unwillingness or inability to follow the procedures outlined in the protocol 8. History of sensitivity to any of the peptides, or components thereof, or a history of drug or other allergy that, in the opinion of the investigators, contraindicates their participation 9. Use of current regular prescription or over-the-counter medications that in the opinion of the Investigators may affect participant safety or outcome measures 10. Clinically significant abnormalities in screening electrocardiogram (ECG) or blood tests abnormalities which in the opinion of the study physician, is clinically significant and represents a safety risk 11. Current pregnancy or breast-feeding in female participants (the Investigators would advise on using contraception for the duration of the visits) 12. Pulse rate < 40 or > 100 beats per minute OR systolic blood pressure > 160 and < 100 and a diastolic blood pressure > 95 and < 50 in the semi-supine position 13. The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the first experimental visit in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) 14. Exposure to more than 3 new investigational medicinal products within 12 months prior to the screening 15. Participants who have donated, or intend to donate, blood within three months before the screening visit or following study visit completion |
| Date of first enrolment | 15/09/2020 |
| Date of final enrolment | 31/10/2024 |
Locations
Countries of recruitment
- England
- Northern Ireland
- United Kingdom
Study participating centres
Praed Street
London
W2 1NY
United Kingdom
Du Cane Road
London
W12 0NN
United Kingdom
Coleraine
BT52 1SA
United Kingdom
Sponsor information
University/education
c/o Keith Boland
Clinical Trials Manager
Room 221, Level 2
Medical School Building
Norfolk Place
London
W2 1PG
England
United Kingdom
| Phone | +44 (0)20 7594 9480 |
|---|---|
| k.boland@imperial.ac.uk | |
| Website | http://www3.imperial.ac.uk/ |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Other
No information available
Results and Publications
| Intention to publish date | 31/12/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal. No additional files currently available. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
23/06/2023: The following changes were made to the study record:
1. The recruitment end date was changed from 15/01/2023 to 31/10/2024.
2. The intention to publish date was changed from 30/06/2023 to 31/12/2023.
20/06/2023: The overall study end date was changed from 30/06/2023 to 31/12/2024.
26/01/2023: The following changes were made to the trial record:
1. The overall end date was changed from 31/01/2023 to 30/06/2023.
2. The intention to publish date was changed from 01/12/2022 to 30/06/2023.
3. The plain English summary was updated to reflect these changes.
30/06/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2022 to 15/01/2023.
2. The overall trial end date was changed from 31/07/2022 to 31/01/2023.
19/11/2021: The following changes have been made:
1. The study hypothesis has been updated.
2. The overall trial end date has been changed from 31/07/2022 to 30/06/2022.
3. The intervention has been updated.
4. The primary outcome measure has been updated.
5. The secondary outcome measures have been updated.
6. The participant inclusion criteria have been updated.
7. The participant type has been changed from Healthy volunteer to Mixed.
8. The target number of participants and the total target enrolment number have been changed from 15 to 59.
9. The recruitment end date has been changed from 26/02/2021 to 30/06/2022.
10. The plain English summary has been updated.
11. The scientific title has been changed from "A physiological study of the effect of alpha-MSH on glucose clearance in healthy participants" to "A physiological study of the effect of alpha-MSH on glucose clearance in healthy participants and those with type 1 diabetes mellitus".
12. The public title has been changed from "Does an infusion of alpha-melanocyte stimulating hormone reduce blood sugar after a meal in healthy people?" to "Does an infusion of alpha-melanocyte stimulating hormone reduce blood sugar after a sugary drink in healthy people and those with type 1 diabetes mellitus?".
13. The trial participating centre "Ulster University" has been added.
21/07/2021: The following changes have been made:
1. The overall trial end date has been changed from 31/07/2021 to 31/07/2022 and the plain English summary has been updated to reflect this change.
2. The intention to publish date has been changed from 01/07/2022 to 01/12/2022.
08/03/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 28/02/2021 to 26/02/2021.
2. The total final enrolment was added.
10/12/2020: The funder was changed from Health Research Board (Republic of Ireland); Grant Codes: ILP-HSR-2017-007 to Investigator initiated and funded.
27/08/2020: The recruitment start date was changed from 01/08/2020 to 15/09/2020.
26/06/2020: Trial's existence confirmed by the NIHR.
