Insulin ResistanceNCT03362554
Identification of New Biomarkers of Insulin Resistance
A study of Insulin Resistance and Diabetes Mellitus, Type 2, run by University of Bath at 1 site in United Kingdom.
Trial summary
Diabetes is a chronic metabolic disease affecting 415 million people worldwide, 90% of cases are type 2 which is frequently associated with obesity and a sedentary lifestyle. In healthy individuals, insulin stimulates increased cell surface expression of a glucose transporter (GLUT4) in muscle and fat tissue. Read more about this study
- Who is it for?
- Ages 40 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Insulin Resistance, Diabetes Mellitus, Type 2, Inflammation
- Type of treatment
- Pill or oral medicine, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Feb 2018to Jan 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Male or female
- Age 40-65
- BMI ≥25 to ≤ 40 kg/m2
- Physical activity level <1.75 (daily average)
- Waist size >80 cm (female) or >94 cm (male)
- Weight stable for >3 months
Who cannot join
- Inability to undertake exercise as determined by PAR-Q
- Diagnosed diabetes
- Ongoing or planned lifestyle changes (diet/exercise)
- Recent large shift in bodyweight (>2.5%) within the last 3 months?
- Smoker (or having ceased <6mo ago)
- Metabolic disorders
Show all 12Show fewer
- Hypertension defined as >160/100
- Use of anti-inflammatory medication: NSAIDs
- Cardiovascular disease
- Any bleeding disorder or taking anticoagulant medication
- Use of antibiotics within the last three months
- Use of pro/pre-biotics within one month of first trial day.
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Department for Health, University of Bath
Bath, BA2 7AY
About this study
Diabetes is a chronic metabolic disease affecting 415 million people worldwide, 90% of cases are type 2 which is frequently associated with obesity and a sedentary lifestyle. In healthy individuals, insulin stimulates increased cell surface expression of a glucose transporter (GLUT4) in muscle and fat tissue. This prevents blood sugar levels becoming dangerously high by taking sugar into the muscle and fat cells. Loss of this response ('insulin resistance') frequently occurs before the development of type 2 diabetes. Understanding the cell biology of insulin resistance is necessary to develop more effective treatments for this condition and prevent further cases of type 2 diabetes. Previous work showed that this movement of GLUT4 is dependent on a small protein called Rab3 which is downregulated in insulin resistance. Rab3 protein levels are also sensitive to inflammation, a state that is exacerbated by obesity.
In order to examine whether Rab3 is an early biomarker of insulin resistance, we aim to measure the levels of this protein and its interactors in fat and muscle samples from insulin resistant individuals. It has been shown that insulin sensitivity can be improved with an intervention as short as three weeks when net energy intake is sufficiently reduced. Therefore, by taking the same measurements before and after this three week intervention we can observe any improvements in Rab3 expression and insulin sensitivity at a cellular level.
There is also evidence for an effect of the gut microbiome on insulin sensitivity so we will measure any changes that take place in the gut microbiome following this intervention, which can be determined from faecal samples taken before and after the three weeks.
Read the detailed description
Diabetes is a chronic metabolic disease affecting 415 million people worldwide and 3.5 million people in the UK, with ninety percent suffering from type 2 diabetes. Type 2 diabetes is characterised by the inability of muscle and fat tissues to adequately respond to physiological levels of insulin (peripheral tissue insulin resistance), and to restore the normal levels of sugars in the bloodstream. Insulin resistance may occur prior to the development of type 2 diabetes and has been shown to be strongly linked to lifestyle and to obesity, although the underlying mechanisms are incompletely resolved. A defining characteristic of insulin resistance is abnormal glucose transport as a result of decreased cell surface expression of the glucose receptor GLUT4. In healthy adipose and skeletal muscle this receptor is trafficked to the cell surface in response to an insulin stimulus. We have shown that this translocation to the cell membrane requires the protein Rab3, and expression levels of this protein are reduced in cell models of insulin resistance.
We hypothesise that this downregulation of Rab3 is associated with the development of insulin resistance and its activity would increase following the restoration of insulin sensitivity. The primary aim of this study is to examine the effect on Rab3 levels and GLUT4 trafficking of a diet and exercise intervention that has been previously shown to increase insulin sensitivity. Additionally, the gut microbiome will be studied before and after the intervention to determine any relationship to insulin sensitivity. Recent evidence suggests the microbiome has a significant role in the development of insulin resistance through a number of potential mechanisms. Infusion of microbiota from lean donors has been shown to result in improved insulin sensitivity in male recipients with metabolic syndrome, with concomitant increases in the prevalence of butyrate-producing intestinal microbiota. Exercise is associated with greater microbial diversity, including increases in butyrate-producing microbes. No study to date has monitored insulin sensitivity and microbiota composition before and after an exercise and diet intervention, and so this will lead to a better understanding of the mechanisms that lead to insulin resistance and subsequently type 2 diabetes.
The study participants will include males and females aged between 40-65 years who fit the criteria for inclusion. After monitoring of normal daily activities for 7 days, volunteers will reduce their calorie intake by 5000 kcal/week and take part in 5 weekly exercise sessions for 3 weeks. Participants will attend one session of laboratory testing before and one after this period which will take place at the University of Bath. This intervention should be sufficient to improve insulin sensitivity and allow us to study the cellular changes that will have taken place during this time.
- Being tested
- Controlled diet and exercise.
- Keywords
- Insulin, Glucose, Rab3
- Medical subject headings
- Insulin Resistance, Diabetes Mellitus, Type 2, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Controlled diet and exercise.Behavioural
The intervention will involve 3 weeks of a diet and exercise program designed to cause a net energy decrease of 7000 kcal/week compared to habitual behaviour. This will be achieved through:
- Five exercise sessions per week at 70% VO2 max, using 400 kcal per session.
- Reduction of their standard diet by 5000 kcal per week
Before and after this intervention period participants will take part in a trial day which includes measurement of body composition (using DEXA) and blood sugar control (oral glucose tolerance test). Samples of blood, adipose, skeletal muscle and faeces will also be taken.
| Study group | Role | What they receive |
|---|---|---|
| Intervention | Experimental | Not described Receives: Behavioral: Controlled diet and exercise. |
| Control | No intervention | Not described |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in insulin sensitivity
Response to oral glucose tolerance test
Measured: 120 min (change after 3 weeks)
Secondary outcomes (8)
Rab3 protein expression
Levels of Rab3 in adipose and muscle samples
Measured: Change after 3 weeks
GLUT4 pathway protein expression
Expression levels of GLUT4 pathway proteins in adipose and muscle samples
Measured: Change after 3 weeks
Metabolic markers
Levels of circulating metabolic markers implicated in insulin resistance
Measured: Change after 3 weeks
Inflammatory markers
Levels of circulating inflammatory cytokines
Measured: Change after 3 weeks
Gut microbiome
Species of microorganisms present in fecal samples
Measured: Change after 3 weeks
Body composition
Assessed by whole body DEXA scan
Measured: Change after 3 weeks
Waist circumference
Measured: Change after 3 weeks
Body mass
Measured: Change after 3 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2017
- Study start1 Feb 2018
- Primary completion31 Jan 2024 (estimated)
- Study completionJan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Insulin ResistanceStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Bath
- Sponsor type
- University, hospital or other
- Collaborators
- Teagasc
- Responsible party
- Principal investigator, Francoise Koumanov, University of Bath
- Investigators
- Francoise Koumanov, PhD, Principal investigator, University of Bath
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03362554
- Sponsor's protocol ID
- RC-FH1158
- Status last verified
- Nov 2023
- First submitted
- 29 Nov 2017
- Last updated
- 28 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
DiabetesUK, Facts and Stats. 2016: https://diabetes-resources-production.s3-eu-west-1.amazonaws.com/diabetes-storage/migration/pdf/DiabetesUK_Facts_Stats_Oct16.pdf.
Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000 Aug;106(4):473-81. doi: 10.1172/JCI10842. No abstract available.
PubMed 10953022Koumanov F, Pereira VJ, Richardson JD, Sargent SL, Fazakerley DJ, Holman GD. Insulin regulates Rab3-Noc2 complex dissociation to promote GLUT4 translocation in rat adipocytes. Diabetologia. 2015 Aug;58(8):1877-86. doi: 10.1007/s00125-015-3627-3. Epub 2015 May 30.
PubMed 26024738Walhin JP, Dixon NC, Betts JA, Thompson D. The impact of exercise intensity on whole body and adipose tissue metabolism during energy restriction in sedentary overweight men and postmenopausal women. Physiol Rep. 2016 Dec;4(24):e13026. doi: 10.14814/phy2.13026.
PubMed 28039399Utzschneider KM, Kratz M, Damman CJ, Hullar M. Mechanisms Linking the Gut Microbiome and Glucose Metabolism. J Clin Endocrinol Metab. 2016 Apr;101(4):1445-54. doi: 10.1210/jc.2015-4251. Epub 2016 Mar 3.
PubMed 26938201Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7. doi: 10.1053/j.gastro.2012.06.031. Epub 2012 Jun 20.
PubMed 22728514Campbell SC, Wisniewski PJ 2nd. Exercise is a Novel Promoter of Intestinal Health and Microbial Diversity. Exerc Sport Sci Rev. 2017 Jan;45(1):41-47. doi: 10.1249/JES.0000000000000096.
PubMed 27782912
Study at a glance
From the registry record, last updated by the sponsor on 28 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of New Biomarkers of Insulin Resistance
- ClinicalTrials.gov ID
- NCT03362554
- Acronym / sponsor ID
- RC-FH1158
- Keywords
- Insulin, Glucose, Rab3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 30 participants (actual)
- Lead sponsor
- University of BathUniversity, hospital or other
- Collaborators
- Teagasc
- Study start
- 1 Feb 2018 (actual)
- Primary completion
- 31 Jan 2024 (estimated)
- Study completion
- Jan 2028 (estimated)
- First posted
- 5 Dec 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Diabetes is a chronic metabolic disease affecting 415 million people worldwide, 90% of cases are type 2 which is frequently associated with obesity and a sedentary lifestyle. In healthy individuals, insulin stimulates increased cell surface expression of a glucose transporter (GLUT4) in muscle and fat tissue. This prevents blood sugar levels becoming dangerously high by taking sugar into the muscle and fat cells. Loss of this response ('insulin resistance') frequently occurs before the development of type 2 diabetes. Understanding the cell biology of insulin resistance is necessary to develop more effective treatments for this condition and prevent further cases of type 2 diabetes. Previous work showed that this movement of GLUT4 is dependent on a small protein called Rab3 which is downregulated in insulin resistance. Rab3 protein levels are also sensitive to inflammation, a state that is exacerbated by obesity.
In order to examine whether Rab3 is an early biomarker of insulin resistance, we aim to measure the levels of this protein and its interactors in fat and muscle samples from insulin resistant individuals. It has been shown that insulin sensitivity can be improved with an intervention as short as three weeks when net energy intake is sufficiently reduced. Therefore, by taking the same measurements before and after this three week intervention we can observe any improvements in Rab3 expression and insulin sensitivity at a cellular level.
There is also evidence for an effect of the gut microbiome on insulin sensitivity so we will measure any changes that take place in the gut microbiome following this intervention, which can be determined from faecal samples taken before and after the three weeks.
Detailed description
Diabetes is a chronic metabolic disease affecting 415 million people worldwide and 3.5 million people in the UK, with ninety percent suffering from type 2 diabetes. Type 2 diabetes is characterised by the inability of muscle and fat tissues to adequately respond to physiological levels of insulin (peripheral tissue insulin resistance), and to restore the normal levels of sugars in the bloodstream. Insulin resistance may occur prior to the development of type 2 diabetes and has been shown to be strongly linked to lifestyle and to obesity, although the underlying mechanisms are incompletely resolved. A defining characteristic of insulin resistance is abnormal glucose transport as a result of decreased cell surface expression of the glucose receptor GLUT4. In healthy adipose and skeletal muscle this receptor is trafficked to the cell surface in response to an insulin stimulus. We have shown that this translocation to the cell membrane requires the protein Rab3, and expression levels of this protein are reduced in cell models of insulin resistance.
We hypothesise that this downregulation of Rab3 is associated with the development of insulin resistance and its activity would increase following the restoration of insulin sensitivity. The primary aim of this study is to examine the effect on Rab3 levels and GLUT4 trafficking of a diet and exercise intervention that has been previously shown to increase insulin sensitivity. Additionally, the gut microbiome will be studied before and after the intervention to determine any relationship to insulin sensitivity. Recent evidence suggests the microbiome has a significant role in the development of insulin resistance through a number of potential mechanisms. Infusion of microbiota from lean donors has been shown to result in improved insulin sensitivity in male recipients with metabolic syndrome, with concomitant increases in the prevalence of butyrate-producing intestinal microbiota. Exercise is associated with greater microbial diversity, including increases in butyrate-producing microbes. No study to date has monitored insulin sensitivity and microbiota composition before and after an exercise and diet intervention, and so this will lead to a better understanding of the mechanisms that lead to insulin resistance and subsequently type 2 diabetes.
The study participants will include males and females aged between 40-65 years who fit the criteria for inclusion. After monitoring of normal daily activities for 7 days, volunteers will reduce their calorie intake by 5000 kcal/week and take part in 5 weekly exercise sessions for 3 weeks. Participants will attend one session of laboratory testing before and one after this period which will take place at the University of Bath. This intervention should be sufficient to improve insulin sensitivity and allow us to study the cellular changes that will have taken place during this time.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intervention | Experimental | Behavioral: Controlled diet and exercise. |
| Control | No intervention | – |
Who may qualify
- Ages
- 40 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male or female
- Age 40-65
- BMI ≥25 to ≤ 40 kg/m2
- Physical activity level <1.75 (daily average)
- Waist size >80 cm (female) or >94 cm (male)
Key exclusion criteria (12 listed)
- Inability to undertake exercise as determined by PAR-Q
- Diagnosed diabetes
- Ongoing or planned lifestyle changes (diet/exercise)
- Recent large shift in bodyweight (>2.5%) within the last 3 months?
- Smoker (or having ceased <6mo ago)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Controlled diet and exercise.The intervention will involve 3 weeks of a diet and exercise program designed to cause a net energy decrease of 7000 kcal/week compared to habitual behaviour. This will be achieved through: * Five exercise sessions per week at 70% VO2 max, using 400 kcal per session. * Reduction of their standard diet by 5000 kcal per week Before and after this intervention period participants will take part in a trial day which includes measurement of body composition (using DEXA) and blood sugar control (oral glucose tolerance test). Samples of blood, adipose, skeletal muscle and faeces will also be taken. | Behavioural | Intervention |
Primary outcome
Change in insulin sensitivity
Time frame: 120 min (change after 3 weeks)
Response to oral glucose tolerance test
8 secondary outcomes
Rab3 protein expression
Time frame: Change after 3 weeks
GLUT4 pathway protein expression
Time frame: Change after 3 weeks
Metabolic markers
Time frame: Change after 3 weeks
Inflammatory markers
Time frame: Change after 3 weeks
Gut microbiome
Time frame: Change after 3 weeks
Body composition
Time frame: Change after 3 weeks
Waist circumference
Time frame: Change after 3 weeks
Body mass
Time frame: Change after 3 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2023.
- BackgroundDiabetesUK, Facts and Stats. 2016: https://diabetes-resources-production.s3-eu-west-1.amazonaws.com/diabetes-storage/migration/pdf/DiabetesUK_Facts_Stats_Oct16.pdf.
- Background: PubMed 10953022Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000 Aug;106(4):473-81. doi: 10.1172/JCI10842. No abstract available.
- Background: PubMed 26024738Koumanov F, Pereira VJ, Richardson JD, Sargent SL, Fazakerley DJ, Holman GD. Insulin regulates Rab3-Noc2 complex dissociation to promote GLUT4 translocation in rat adipocytes. Diabetologia. 2015 Aug;58(8):1877-86. doi: 10.1007/s00125-015-3627-3. Epub 2015 May 30.
- Background: PubMed 28039399Walhin JP, Dixon NC, Betts JA, Thompson D. The impact of exercise intensity on whole body and adipose tissue metabolism during energy restriction in sedentary overweight men and postmenopausal women. Physiol Rep. 2016 Dec;4(24):e13026. doi: 10.14814/phy2.13026.
- Background: PubMed 26938201Utzschneider KM, Kratz M, Damman CJ, Hullar M. Mechanisms Linking the Gut Microbiome and Glucose Metabolism. J Clin Endocrinol Metab. 2016 Apr;101(4):1445-54. doi: 10.1210/jc.2015-4251. Epub 2016 Mar 3.
- Background: PubMed 22728514Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7. doi: 10.1053/j.gastro.2012.06.031. Epub 2012 Jun 20.
- Background: PubMed 27782912Campbell SC, Wisniewski PJ 2nd. Exercise is a Novel Promoter of Intestinal Health and Microbial Diversity. Exerc Sport Sci Rev. 2017 Jan;45(1):41-47. doi: 10.1249/JES.0000000000000096.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Francoise Koumanov, PhD principal investigator
University of Bath
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study of Insulin Resistance and Diabetes Mellitus, Type 2, run by University of Bath at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 28 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in insulin sensitivity (time frame: 120 min (change after 3 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03362554, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2023; AzTrials last refreshed its copy on 8 Nov 2026.