The Genetics of Adipose Tissue Function and Its Link to Type 2 Diabetes and Heart Disease
Condition: Diabetes Mellitus
MeSH terms: Heart Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional

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.
    

Detailed description: 
      Introduction:

      Diabetes is the most common chronic metabolic disease and is a major source of morbidity and
      mortality. It is one of the biggest healthcare challenges facing the United Kingdom's (UK)
      National Health Service (NHS) with more than 2.6 million adults diagnosed in the UK, with the
      vast majority (90%) having Type 2 diabetes (T2D). It is anticipated that the numbers will
      continue to rise, in part due to the increasing levels of obesity in the population.

      Type 2 diabetes is characterised by high blood glucose levels in the context of increasing
      insulin resistance and reduced beta cell function, and this can develop over several years
      with individuals unaware of the problem.

      Research groups in Exeter are leading efforts to identify the genetic factors that influence
      why some people develop Type 2 diabetes despite relative leanness, whilst many obese people
      do not get the disease. The investigators have identified many such factors but now wish to
      study them in more detail to understand the role of a healthy and functioning adipose tissue
      in the disease mechanism. This study builds on a previous 'recruit by genotype' study to
      explore the size of fat cells in people carrying the most genetic factors for being fatter
      but healthier (fATDIVA (for Adipose Tissue DIabetes VAriants) NCT02505321). The investigators
      will expand on the range of genetic variations to be undertaken in the research volunteers.
      The preliminary data from fATDIVA helped to secure prestigious funding from Diabetes UK to
      expand this work to improve understanding of the complex processes that lead to Type 2
      diabetes.

      The investigators are trying to understand how genetic variations cause differences in the
      human ability to store fat. The hypothesis to be tested is that individuals carrying
      different genetic variations have different abilities to store fat under the skin as
      subcutaneous fat tissue. This could lead to an improved understanding of subcutaneous fat
      storage. It is very unlikely that scientists will be able to reverse substantially the rising
      numbers of people becoming overweight or obese as they age, therefore this study's findings
      could be important in identifying how to reduce the risk of disease caused by obesity.

      Study Design:

      This is a prospective observational study that will take place over a 30 month period (March
      2019 to August 2021).

      Study participants:

      All participants will be identified from existing research cohorts managed by the National
      Institute for Health Research (NIHR) Exeter Clinical Research Facility (Exeter CRF) and
      recruitment will be facilitated within the Exeter CRF.

      Under over-arching ethical approval 09/H0106/75, approximately 8900 anonymised DNA samples
      have whole genome genotype data.

      Subject Selection:

      The researchers will provide the Exeter Clinical Research Facility (Exeter CRF) with a list
      of the sample numbers that fulfil the inclusion criteria. The Exeter CRF will approach these
      individuals on the researcher's behalf to ask if they would be willing to provide body fat
      measures, a blood sample and an abdominal fat biopsy. Participants would be invited to a
      single visit lasting up to 2 hours at the Exeter CRF for data and sample collection.

      Interested participants will then be contacted directly by a member of the study team who
      will be responsible for the recruitment process, providing more detailed verbal and written
      project-specific information.

      The investigators will aim to target men only to increase power for two reasons. First, men
      and women have different body shape and different fat distribution. Men tend to store the
      extra fat in abdominal subcutaneous adipose tissue while women tend to store it in the lower
      body. Second, the study of fat biopsy samples in women could be affected by menopause which
      could cause bias in the data.

      However, as the target sample size is 500 and the number of men who fulfil the inclusion
      criteria is approximately 3000, this will be reviewed after a year. If projections indicate
      that the target sample size will not be met, women will also be recruited in the second year.
    

Intervention name(s): Abdominal fat biopsy
Intervention type(s): Procedure
Intervention description(s): 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.
Intervention model: Single Group Assignment
Intervention model description: 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.
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Type 2 diabetes; adipocyte; adipocyte tissue dysfunction; adiposity; favourable adiposity; gene expression; adipose tissue