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Identification of New Biomarkers of Insulin Resistance

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03362554
Recruitment Status : Unknown
Verified May 2018 by Francoise Koumanov, University of Bath.
Recruitment status was:  Recruiting
First Posted : December 5, 2017
Last Update Posted : May 2, 2018
Teagasc Food Research Centre
Information provided by (Responsible Party):
Francoise Koumanov, University of Bath

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Insulin Resistance Diabetes Mellitus, Type 2 Inflammation Gastrointestinal Microbiome Behavioral: Controlled diet and exercise. Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Identification of New Biomarkers of Insulin Resistance
Actual Study Start Date : February 1, 2018
Estimated Primary Completion Date : January 2019
Estimated Study Completion Date : January 2019

Arm Intervention/treatment
Experimental: Intervention Behavioral: 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.

No Intervention: Control

Primary Outcome Measures :
  1. Change in insulin sensitivity [ Time Frame: 120 min (change after 3 weeks) ]
    Response to oral glucose tolerance test

Secondary Outcome Measures :
  1. Rab3 protein expression [ Time Frame: Change after 3 weeks ]
    Levels of Rab3 in adipose and muscle samples

  2. GLUT4 pathway protein expression [ Time Frame: Change after 3 weeks ]
    Expression levels of GLUT4 pathway proteins in adipose and muscle samples

  3. Metabolic markers [ Time Frame: Change after 3 weeks ]
    Levels of circulating metabolic markers implicated in insulin resistance

  4. Inflammatory markers [ Time Frame: Change after 3 weeks ]
    Levels of circulating inflammatory cytokines

  5. Gut microbiome [ Time Frame: Change after 3 weeks ]
    Species of microorganisms present in fecal samples

  6. Body composition [ Time Frame: Change after 3 weeks ]
    Assessed by whole body DEXA scan

  7. Waist circumference [ Time Frame: Change after 3 weeks ]
  8. Body mass [ Time Frame: Change after 3 weeks ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03362554

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Contact: Francoise Koumanov, PhD +441225 384775
Contact: Laura Wood, PhD

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United Kingdom
Department for Health, University of Bath Recruiting
Bath, United Kingdom, BA2 7AY
Contact: Francoise Koumanov, PhD    +441225 384649   
Contact: Laura Wood, PhD    +441225 384775   
Sponsors and Collaborators
University of Bath
Teagasc Food Research Centre
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Principal Investigator: Francoise Koumanov, PhD University of Bath
DiabetesUK, Facts and Stats. 2016:

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Responsible Party: Francoise Koumanov, Lecturer, University of Bath Identifier: NCT03362554    
Other Study ID Numbers: RC-FH1158
First Posted: December 5, 2017    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Francoise Koumanov, University of Bath:
Additional relevant MeSH terms:
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Insulin Resistance
Diabetes Mellitus, Type 2
Pathologic Processes
Glucose Metabolism Disorders
Metabolic Diseases
Diabetes Mellitus
Endocrine System Diseases