The Genetics of Adipose Tissue Function and Its Link to Type 2 Diabetes and Heart Disease

NCT04040595 | Completed

• 4 other identifiers: IRAS: 25769310500919/SW/00121909872
• Study Type: interventional
• Target: 207
• Locations: 1 country
• Sites: 1

Brief Summary

Obesity is a major risk factor for Type 2 diabetes. However, two obese people of the same height and weight can have very different risks of the condition. As a greater proportion of the population is becoming obese, scientists need to understand more about why some people develop Type 2 diabetes at lower weight and why some people stay healthy despite being obese. The investigators and others provided evidence for genetic factors associated with higher weight for a given height but lower risk of diabetes, lower cholesterol and fat levels, lower blood pressure and lower risk of heart disease. The investigators showed that people who carry these genetic factors are able to store extra fat in a safe place, which is under the skin, as they gain weight. The proposed project aims to establish whether or not these genetic factors are associated with better development and function of fat tissue in storing extra fat. It is thought that a healthy and functional fat tissue in the human body has a key role in modifying the risk of diseases such as Type 2 diabetes, heart disease and hypertension. Volunteers from Exeter 10,000 who gave their permission to contact them about further research will be recruited to the study. In those that agree, detailed body size measures, including body composition assessments by the BodPodTM machine will be recorded, a blood sample will be collected, and a small subcutaneous abdominal fat biopsy will be collected to measure fat cell size and from which a sample will be stored for future analyses. The results between people with and without the particular genetic changes of interest will be compared. Knowing more about these genetic changes and how fat cells work could help to improve understanding of the factors that predispose, delay or protect obese individuals from Type 2 diabetes and other metabolic disturbances.

Conditions

Diabetes Mellitus

Keywords

Type 2 diabetes; adipocyte; adipocyte tissue dysfunction; adiposity; favourable adiposity; gene expression; adipose tissue

Outcome Measures

Primary Outcomes (1)

• Mean adipocyte size (µm2) assessed using Image J software.

  ImageJ is a cross-platform image analysis tool developed to measure particle/cell size and will be used here to measure adipocyte size to test whether or not individuals carrying a high genetic load of "favourable adiposity" alleles have smaller subcutaneous fat cells.

  Within 12 months of recruitment date of final participant

Secondary Outcomes (3)

• Adipose tissue expression of genes that are markers of adipogenesis (PPARy, CREBP).

  Within 12 months of recruitment date of final participant

• Adipose tissue expression of genes that are markers of fibrosis (SPARC, collagens, TGFbeta, LOX).

  Within 12 months of recruitment date of final participant

• Adipose tissue expression of genes that are determinants of adipose inflammation (IL-1beta, IL-6, and 8, TNFalpha, MCP-1/CCL2).

  Within 12 months of recruitment date of final participant

Study Arms (1)

Adipocyte measurement

EXPERIMENTAL

Abdominal fat biopsy

Procedure: Abdominal fat biopsy

Interventions

Abdominal fat biopsy PROCEDURE

A sample of abdominal fat will be obtained by firstly injecting some local anaesthetic into an accessible area of the abdomen. Using a scalpel, a small incision (approx 2-3 cm) will be made to a depth of approx 15mm and two small pea-sized samples of fat will be removed. The wound will be closed with simple sutures or steristrips.

Adipocyte measurement

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Demographics: Age 18-75 inclusive
• Ethnicity: Reflective of local demographic
• Mental capacity: Willing and able to provide informed consent

You may not qualify if:

• Medical history: History of bariatric surgery and recent significant weight loss/gain (+/- 3 kgs/ half a stone in the last 3 months); connective tissue disease, pregnancy and lactation (if women are recruited).
• Medications: Currently prescribed oral/IV corticosteroid treatment or loop diuretics (furosemide, bumetanide), antiplatelet and anticoagulation medication, methotrexate
• Mental capacity: Unable/unwilling to provide informed consent.

Sponsors & Collaborators

• Royal Devon and Exeter NHS Foundation Trust: lead
• University of Exeter: collaborator
• NIHR Exeter Clinical Research Facility: collaborator

Study Sites (1)

Royal Devon and Exeter NHS Foundation Trust / University of Exeter

Exeter, Devon, EX2 5DW, United Kingdom

Location

Related Publications (9)

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  PMID: 9588440 BACKGROUND

• Ruderman NB, Schneider SH, Berchtold P. The "metabolically-obese," normal-weight individual. Am J Clin Nutr. 1981 Aug;34(8):1617-21. doi: 10.1093/ajcn/34.8.1617.

  PMID: 7270486 BACKGROUND

• Ji Y, Yiorkas AM, Frau F, Mook-Kanamori D, Staiger H, Thomas EL, Atabaki-Pasdar N, Campbell A, Tyrrell J, Jones SE, Beaumont RN, Wood AR, Tuke MA, Ruth KS, Mahajan A, Murray A, Freathy RM, Weedon MN, Hattersley AT, Hayward C, Machann J, Haring HU, Franks P, de Mutsert R, Pearson E, Stefan N, Frayling TM, Allebrandt KV, Bell JD, Blakemore AI, Yaghootkar H. Genome-Wide and Abdominal MRI Data Provide Evidence That a Genetically Determined Favorable Adiposity Phenotype Is Characterized by Lower Ectopic Liver Fat and Lower Risk of Type 2 Diabetes, Heart Disease, and Hypertension. Diabetes. 2019 Jan;68(1):207-219. doi: 10.2337/db18-0708. Epub 2018 Oct 23.

  PMID: 30352878 BACKGROUND

• Yaghootkar H, Lotta LA, Tyrrell J, Smit RA, Jones SE, Donnelly L, Beaumont R, Campbell A, Tuke MA, Hayward C, Ruth KS, Padmanabhan S, Jukema JW, Palmer CC, Hattersley A, Freathy RM, Langenberg C, Wareham NJ, Wood AR, Murray A, Weedon MN, Sattar N, Pearson E, Scott RA, Frayling TM. Genetic Evidence for a Link Between Favorable Adiposity and Lower Risk of Type 2 Diabetes, Hypertension, and Heart Disease. Diabetes. 2016 Aug;65(8):2448-60. doi: 10.2337/db15-1671. Epub 2016 Apr 26.

  PMID: 27207519 BACKGROUND

• Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Walker M, Borecki IB, Knowles JW, Yerges-Armstrong L, Ohlsson C, Perry JR, Chambers JC, Kooner JS, Franceschini N, Langenberg C, Hivert MF, Dastani Z, Richards JB, Semple RK, Frayling TM. Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes. 2014 Dec;63(12):4369-77. doi: 10.2337/db14-0318. Epub 2014 Jul 21.

  PMID: 25048195 BACKGROUND

• Lotta LA, Gulati P, Day FR, Payne F, Ongen H, van de Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, De Lucia Rolfe E, Stewart ID, Wheeler E, Willems SM, Adams C, Yaghootkar H; EPIC-InterAct Consortium; Cambridge FPLD1 Consortium; Forouhi NG, Khaw KT, Johnson AD, Semple RK, Frayling T, Perry JR, Dermitzakis E, McCarthy MI, Barroso I, Wareham NJ, Savage DB, Langenberg C, O'Rahilly S, Scott RA. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nat Genet. 2017 Jan;49(1):17-26. doi: 10.1038/ng.3714. Epub 2016 Nov 14.

  PMID: 27841877 BACKGROUND

• Scott RA, Fall T, Pasko D, Barker A, Sharp SJ, Arriola L, Balkau B, Barricarte A, Barroso I, Boeing H, Clavel-Chapelon F, Crowe FL, Dekker JM, Fagherazzi G, Ferrannini E, Forouhi NG, Franks PW, Gavrila D, Giedraitis V, Grioni S, Groop LC, Kaaks R, Key TJ, Kuhn T, Lotta LA, Nilsson PM, Overvad K, Palli D, Panico S, Quiros JR, Rolandsson O, Roswall N, Sacerdote C, Sala N, Sanchez MJ, Schulze MB, Siddiq A, Slimani N, Sluijs I, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, Yaghootkar H; RISC study group; EPIC-InterAct consortium; McCarthy MI, Semple RK, Riboli E, Walker M, Ingelsson E, Frayling TM, Savage DB, Langenberg C, Wareham NJ. Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity. Diabetes. 2014 Dec;63(12):4378-4387. doi: 10.2337/db14-0319. Epub 2014 Jun 19.

  PMID: 24947364 BACKGROUND

• Alkhouli N, Mansfield J, Green E, Bell J, Knight B, Liversedge N, Tham JC, Welbourn R, Shore AC, Kos K, Winlove CP. The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix. Am J Physiol Endocrinol Metab. 2013 Dec;305(12):E1427-35. doi: 10.1152/ajpendo.00111.2013. Epub 2013 Oct 8.

  PMID: 24105412 BACKGROUND

• Acosta JR, Douagi I, Andersson DP, Backdahl J, Ryden M, Arner P, Laurencikiene J. Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes. Diabetologia. 2016 Mar;59(3):560-70. doi: 10.1007/s00125-015-3810-6. Epub 2015 Nov 25.

  PMID: 26607638 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus; Diabetes Mellitus, Type 2; Obesity

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Timothy Frayling, PhD

  University of Exeter

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Anthropometry: * Baseline data including Height (m), Weight (kg), Waist (cm) and Hip (cm) circumference will be recorded. * Skin fold measurements (mm) from biceps, triceps, subscapular, and suprailiac regions * Detailed body fat measures will be obtained from the BodPodTM. Medical history: • including current medications and lifestyle information (smoking/alcohol). Blood sample: • Up to 20 ml venous blood sample for HbA1c and storage for analysis of biomarkers of adiposity. Abdominal fat biopsy: for adipocyte measurements and store a sample for future analyses. A sample of abdominal fat will be obtained by firstly injecting some local anaesthetic into an accessible area of the abdomen. Using a scalpel, a small incision (approx 2-3 cm) will be made to a depth of approx15mm and two small pea-sized samples of fat will be removed. The wound will be closed with simple sutures or steristrips.

Study Record Dates

• First Submitted: June 12, 2019
• First Posted: July 31, 2019
• Study Start: March 7, 2019
• Primary Completion: May 20, 2021
• Study Completion: May 20, 2021
• Last Updated: June 8, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)