Identification of New Biomarkers of Insulin Resistance

November 27, 2023 updated by: Francoise Koumanov, University of Bath

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.

Study Overview

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 Type

Interventional

Enrollment (Actual)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Bath, United Kingdom, BA2 7AY
        • Department for Health, University of Bath

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

38 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in insulin sensitivity
Time Frame: 120 min (change after 3 weeks)
Response to oral glucose tolerance test
120 min (change after 3 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rab3 protein expression
Time Frame: Change after 3 weeks
Levels of Rab3 in adipose and muscle samples
Change after 3 weeks
GLUT4 pathway protein expression
Time Frame: Change after 3 weeks
Expression levels of GLUT4 pathway proteins in adipose and muscle samples
Change after 3 weeks
Metabolic markers
Time Frame: Change after 3 weeks
Levels of circulating metabolic markers implicated in insulin resistance
Change after 3 weeks
Inflammatory markers
Time Frame: Change after 3 weeks
Levels of circulating inflammatory cytokines
Change after 3 weeks
Gut microbiome
Time Frame: Change after 3 weeks
Species of microorganisms present in fecal samples
Change after 3 weeks
Body composition
Time Frame: Change after 3 weeks
Assessed by whole body DEXA scan
Change after 3 weeks
Waist circumference
Time Frame: Change after 3 weeks
Change after 3 weeks
Body mass
Time Frame: Change after 3 weeks
Change after 3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Francoise Koumanov, PhD, University of Bath

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2018

Primary Completion (Estimated)

January 31, 2024

Study Completion (Estimated)

January 1, 2028

Study Registration Dates

First Submitted

November 29, 2017

First Submitted That Met QC Criteria

November 29, 2017

First Posted (Actual)

December 5, 2017

Study Record Updates

Last Update Posted (Actual)

November 28, 2023

Last Update Submitted That Met QC Criteria

November 27, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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