Effect of propionate on mesenteric adipose tissue and insulin sensitivity
| ISRCTN | ISRCTN11187912 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN11187912 |
| IRAS number | 288071 |
| Secondary identifying numbers | 20HH6218, IRAS 288071, CPMS 47793 |
- Submission date
- 17/07/2023
- Registration date
- 27/07/2023
- Last edited
- 08/08/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Metabolic diseases, including obesity, hypertension, and cardiovascular disease, significantly increase the risk of type 2 diabetes. About 25% of adults worldwide suffer from metabolic diseases, leading to 2.8 million deaths each year. The composition of fat in the body is closely linked to metabolic diseases. Recent research has highlighted the role of abdominal adipose tissue, specifically mesenteric adipose tissue (MAT), in causing insulin resistance and type 2 diabetes. MAT surrounds the portal vein, which carries blood from the gastrointestinal tract to the liver, and has the potential to impact insulin responses in both local and systemic ways. However, the exact mechanism by which MAT influences insulin resistance is not well understood. Propionate, a short-chain fatty acid produced during carbohydrate fermentation in the colon, is thought to play a role in reducing the release of free fatty acids (FFA) from adipocytes (fat cells) through receptors FFA2 and FFA3. This, in turn, may decrease hepatic glucose generation and increase insulin utilization. While several studies have demonstrated the effects of propionate on obesity and type 2 diabetes, few have explored its mechanism of action and the specific involvement of MAT during metabolic processes. The goal of this project is to investigate the role of propionate in maintaining a healthy MAT phenotype and to gain a deeper understanding of how mesenteric adipocyte biology influences insulin sensitivity in humans. These findings will be crucial for developing strategies to prevent metabolic syndrome and its associated complications.
Who can participate?
Adult participants aged between 18 and 75 years old chosen because they are scheduled to have an operation that will make it possible to take samples of fat from their waist area
What does the study involve?
The study will investigate the effect of propionate on fat tissue and the cell isolated from the fat tissue. We will culture the tissue and isolate the cells in vitro to detect the metabolite release and histological changes with the propionate treatments.
The study will randomly allocate participants into either of the following two groups to receive:
1. 10 g/day cellulose (poorly fermentable carbohydrate) as a control
2. 10 g/day inulin propionate ester (IPE)
This is the lowest dose that the study team has repeatedly shown has a wide metabolic impact with little adverse event profile. The IPE and control will be given to the participants as 10 g of white powder in a sachet which participants can easily mix into their habitual diet. Participants will receive telephone visits every four weeks to assess progress and compliance. They will receive face-to-face review visits every 4 weeks. At the end of the 12th week, they will undergo their planned surgery and at the time of the operation, tissue samples will be taken for analysis.
What are the possible benefits and risks of participating?
Taking part in the study will provide no direct personal benefit for participants and surgery participants over what they currently have. The information that we gain from this study will help us to better understand metabolic disease. If any of the screening questionnaires or blood tests reveal any medical problems (e.g. diabetes, kidney or liver problems), the participant’s GP will be informed so that they can coordinate participants’ care, arrange any further tests, and refer participants to Hospital Doctors if necessary.
The procedure of taking fat samples will cause an extended operation time of up to 5-10 minutes. There is a small risk of complications. These complications include infection, bleeding, blood clots, and injury to nearby structures, such as the liver and small gut.
Where is the study run from?
Hammersmith Hospital Campus, Imperial College London (UK)
When is the study starting and how long is it expected to run for?
November 2019 to November 2024
Who is funding the study?
BBSRC Strategic Programme in Food Innovation and Health (UK)
Who is the main contact:
Prof Gary Frost, g.frost@imperial.ac.uk (UK)
Contact information
Principal Investigator
Imperial College London
Hammersmith Hospital Campus
6th Floor
Commonwealth Building
Du Cane Road
London
W12 0NN
United Kingdom
| Phone | +44 (0)1273 833 480 |
|---|---|
| g.frost@imperial.ac.uk |
Public
Imperial College London
Hammersmith Hospital Campus
6th Floor
Commonwealth Building
Du Cane Road
London
W12 0NN
United Kingdom
| Phone | +44 (0)7925703916 |
|---|---|
| b.lu18@imperial.ac.uk |
Scientific
Imperial College London
Hammersmith Hospital Campus
6th Floor
Commonwealth Building
Du Cane Road
London
W12 0NN
United Kingdom
| Phone | +44 (0)7925703916 |
|---|---|
| b.lu18@imperial.ac.uk |
Study information
| Study design | Double-blind randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Home, Hospital, Telephone, University/medical school/dental school |
| Study type | Prevention, Quality of life |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Impact of the short chain fatty acid propionate on mesenteric adipose tissue, liver metabolism and insulin sensitivity: The PROMIS study |
| Study acronym | PROMIS |
| Study objectives | The mesenteric adipose tissue will be exposed to high propionate flux following the colonic delivery of propionate to the colon. This will result in multifactorial impacts on mesenteric adipose tissue: 1. Stimulate a change in adipocyte phenotype with an increase in beige and brown adipocyte and a decrease in adipocyte size. 2. Hepatic insulin sensitivity will increase and hepatic glucose output will be suppressed leading to improved metabolic sensitivity. |
| Ethics approval(s) |
Approved 25/01/2021, London - Riverside Research Ethics Committee (Ground Floor Temple Quay House 2 The Square, Bristol, BS1 6PN, United Kingdom; +44 (0)2071048193; riverside.rec@hra.nhs.uk), ref: 20/LO/1297 |
| Health condition(s) or problem(s) studied | Metabolic disease |
| Intervention | Metabolic disease is defined as a range of diseases that increase the risk of type 2 diabetes, such as obesity, hypertension and cardiovascular disease. Worldwide, approximately 25% of the adult population has metabolic diseases and there are 2.8 million deaths annually due to these diseases. There is a strong correlation between fat composition and metabolic diseases. Recent research has demonstrated that abdominal adipose tissue has a causal role in the development of insulin resistance leading to type 2 diabetes. In Vivo Study: 12-week Randomised Controlled Study Participants will be randomized into two groups. In the control arm, participants will be given 10 g/day cellulose (a control fibre supplement that is poorly fermentable) for 12 weeks. In the intervention arm (IA), participants will be given 10 g/day of inulin propionate ester (IPE) (at the dose found in the dose-finding study) for 12 weeks. During 12 weeks, participants will be asked to undergo several assessments including: 1. Two Assessment visits at the beginning of Week 1 and the end of Week 12 • Weight, Height, Body Fat Composition • Mixed meal tolerance test (MMTT) • Blood, BH2, Urine and stool samples 2. Two Review visits in Weeks 4 and 8 • Fasting blood • Receive the intervention compounds 3. Three telephone call visits in Weeks 3,7 and 11 • To guarantee compliance In Vitro Study: Adipose Tissue Study Participants will undergo their planned surgery. At surgery volunteers will undergo three biopsies, these will include subcutaneous, omental and mesenteric close to the colon, mesenteric at the tip furthest away from the colon. Adipose tissue samples will be taken for analysis in vitro. Participants will not be treated with any intervention. The in vivo study will investigate whether long-term raised colonic propionate could cause beneficial changes in adipocyte and insulin sensitivity in humans. Changes in insulin sensitivity were assessed using the Homeostatic model assessment (HOMA-IR) by the following formula: HOMA-IR = (fasting glucose x fasting insulin) / 22.5 (Fasting insulin is in mU/L and fasting glucose in mmol/L). The in vitro study will investigate whether the high concentration of propionate could have a positive effect on the adipose. |
| Intervention type | Supplement |
| Primary outcome measure | 1. Adipose tissue morphology measured using adipose tissue samples fixed for microscopic examination imaging and Haematoxylin and Eosin staining to determine adipocyte cell size, number and histological characteristics at the end of Week 12 after the tissue is collected 2. Insulin sensitivity and liver glucose metabolism measured using the Homeostatic model assessment (HOMA-IR). The blood insulin and glucose levels measured using the corresponding testing reagent kits at 0, 15, 30, 60, 90, 120, 180, 240, and 300 min during each assessment visit. In vitro Study: 1. Adipose tissue gene expression measured using Quantitative polymerase chain reaction (qPCR) after tissue is cultured for 24 h 2. After the preadipocyte is isolated from the tissue, the differentiation function will be measured via lipid accumulation on D14 (The last day of the differentiation period). |
| Secondary outcome measures | In vivo study: Circulating levels of glucose, insulin, free fatty acids, gut hormones and SCFA levels measured using the corresponding testing reagent kits. Venous blood samples will be collected at the fasting state during each review visit. In Vitro Study: Metabolite levels in adipose tissue and preadipocytes after treatment such as triglyceride and free fatty acid levels measured using the corresponding testing reagent kits after 24 h and on Day 14, respectively. |
| Overall study start date | 11/11/2019 |
| Completion date | 11/05/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 18 Years |
| Upper age limit | 75 Years |
| Sex | Both |
| Target number of participants | 56 |
| Key inclusion criteria | In vivo study: 1. The participants on the waiting list for cholecystectomy 2. Male or female 3. Age between 18-75 years (inclusive) 4. Body mass index (BMI) of 18-35 kg/m2 5. Willingness and ability to give written informed consent and willingness and ability to understand, participate and comply with the study requirements In vitro study: 1. The participants on the surgery waiting list of the team with Dr Madhava Pai 2. Male or female 3. Age between 18-75 years (inclusive) 4. Body mass index (BMI) of 18-35 kg/m2 5. Willingness and ability to give written informed consent and willingness and ability to understand, participate and comply with the study requirements |
| Key exclusion criteria | In vivo study: 1. Abnormal ECG 2. Screening blood results outside of normal reference values 3. Weight change of ≥3 kg in the preceding 2 months 4. Current smokers 5. History of substance abuse and/or excess alcohol intake 6. Pregnancy 7. Formal medical diagnosis of Type 2 Diabetes, Cardiovascular disease, Cancer, Gastrointestinal disease (e.g. inflammatory bowel disease or irritable bowel), Kidney disease, Liver disease and Pancreatitis 8. Participation in a research study in the 12-week period prior to entering this study 9. Any blood donation within the 12-week period prior to entering this study 10. Use of antibiotics in the past 3 months 11. New medication in the past 3 months 12. Any other reason in the opinion of the investigator In vitro study 1. Screening blood results outside of normal reference values 2. Weight change of ≥ 3kg in the preceding 2 months 3. History of substance abuse and/or excess alcohol intake 4. Pregnancy 5. Any other reason in the opinion of the investigator |
| Date of first enrolment | 20/02/2021 |
| Date of final enrolment | 11/11/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
St Marys Hospital
South Wharf Road
London
W2 1NY
United Kingdom
Sponsor information
University/education
C/o: Ms Cheuk Fung Wong
Joint Research Compliance Office
Imperial College London and Imperial College Healthcare NHS Trust
Room 221, Level 2
Medical School Building
Norfolk Place
London
W2 1PG
England
United Kingdom
| Phone | +44 (0)2075949832 |
|---|---|
| cheuk-fung.wong@imperial.ac.uk | |
| Website | http://www.imperial.ac.uk/ |
"ROR" |
https://ror.org/041kmwe10 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- UKRI - Biotechnology And Biological Sciences Research Council, BBSRC UK, BBSRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 20/02/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be published as a supplement to the results publication. |
Editorial Notes
08/08/2023: Internal review.
08/08/2023: Internal review.
19/07/2023: Trial's existence confirmed by Health Research Authority (UK).
