Identification of New Biomarkers of Insulin Resistance

NCT03362554 | Active Not Recruiting

• 1 other identifier: RC-FH1158
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Insulin Resistance; Diabetes Mellitus, Type 2; Inflammation; Gastrointestinal Microbiome

Keywords

Insulin; Glucose; Rab3

Outcome Measures

Primary Outcomes (1)

• Change in insulin sensitivity

  Response to oral glucose tolerance test

  120 min (change after 3 weeks)

Secondary Outcomes (8)

• Rab3 protein expression

  Change after 3 weeks

• GLUT4 pathway protein expression

  Change after 3 weeks

• Metabolic markers

  Change after 3 weeks

• Inflammatory markers

  Change after 3 weeks

• Gut microbiome

  Change after 3 weeks

Study Arms (2)

Intervention

EXPERIMENTAL

Behavioral: Controlled diet and exercise.

Control

NO INTERVENTION

Interventions

Controlled diet and exercise. BEHAVIORAL

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.

Intervention

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Bath: lead
• Teagasc: collaborator

Study Sites (1)

Department for Health, University of Bath

Bath, BA2 7AY, United Kingdom

Location

Related Publications (7)

• DiabetesUK, Facts and Stats. 2016: https://diabetes-resources-production.s3-eu-west-1.amazonaws.com/diabetes-storage/migration/pdf/DiabetesUK_Facts_Stats_Oct16.pdf.

  BACKGROUND

• Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000 Aug;106(4):473-81. doi: 10.1172/JCI10842. No abstract available.

  PMID: 10953022 BACKGROUND

• Koumanov 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.

  PMID: 26024738 BACKGROUND

• Walhin 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.

  PMID: 28039399 BACKGROUND

• Utzschneider 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.

  PMID: 26938201 BACKGROUND

• Vrieze 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.

  PMID: 22728514 BACKGROUND

• Campbell 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.

  PMID: 27782912 BACKGROUND

MeSH Terms

Conditions

Insulin Resistance; Diabetes Mellitus, Type 2; Inflammation

Interventions

Exercise

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Francoise Koumanov, PhD

  University of Bath

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Lecturer

Study Record Dates

• First Submitted: November 29, 2017
• First Posted: December 5, 2017
• Study Start: February 1, 2018
• Primary Completion: January 31, 2024
• Study Completion (Estimated): January 1, 2028
• Last Updated: November 28, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)