The very-low calorie diet (VLCD) is a highly effective and safe way to rapidly lose significant amounts of weight and dramatically improve blood sugar control in a short period of time (typically 8-12 weeks). It has recently become recommended by the UK National Health Service as a treatment for selected patients with type 2 diabetes. One drawback of VLCD however is the associated loss of skeletal muscle which affects some patients.

Semaglutide is a well-known medication for type 2 diabetes that also improves blood sugar control and facilitates weight loss. Recent research has shown that it may also stimulate muscle growth, meaning it could help to preserve muscle mass during weight loss. Therefore, this research study aims to see whether taking Semaglutide alongside the VLCD reduces the amount of muscle lost, and could improve the long-term outcomes of VLCD.

The study will take place in the Medical School building in the Royal Derby Hospital. Up to 45 participants will be recruited and allocated into one of 3 groups:

1. Semaglutide only
2. VLCD only
3. Combined Semaglutide plus VLCD The study is 12 weeks in duration and consists of four visits including two 6-hour visits, one 4-hour visit and one 30-minute visit. The first visit is a short Preliminary Visit where participants are asked to ingest stable isotope drinks for measurement of muscle growth rates and muscle mass. Food intake and physical activity monitoring will also be commenced.

Visits 1 & 3 are identical and occur at the beginning and end of the 12-week intervention period, respectively. During these visits participants will undergo a Dual-energy X-ray absorptiometry (DXA) scan, a right vastus lateralis muscle ultrasound scan & muscle biopsy, an intravenous glucose tolerance test, electromyography, tests of muscular function, gait & balance, and questionnaires regarding quality of life & physical activity. These visits are expected to last up to 6 hours.

Visit 2 is a shorter visit mid-way through the 12 weeks, lasting approximately 4.5 hours. Participants will undergo another DXA scan and muscle biopsy in addition to having multiple blood tests taken over a 4-hour period to determine muscle protein breakdown rates.

During the 12 weeks, those in the VLCD group will be asked to stick strictly to an 800 kilocalorie very-low calorie diet, whilst those in the Semaglutide group will be required to inject themselves with Semaglutide once a week. Those in the combined group will be asked to do both. All participants will be monitored closely throughout the 12-week period, with regular phone calls and/or emails.

Inclusion Criteria:

• Confirmed Type 2 Diabetes Mellitus
• Body mass index > 27kg·m-2
• Eligible for VLCD, Semaglutide (or both), within routine practice
• Ability to provide informed consent

Exclusion Criteria:

• BMI > 50kg·m-2
• Current pregnancy or breastfeeding, or intention to fall pregnant within the next 3 months
• Uncontrolled hypertension (blood pressure >200/120mmHg)
• Current treatment with insulin
• Current or recent use of GLP-1 agonists
• Previous adverse reaction to a GLP-1 agonist
• Current or recent involvement in a VLCD programme (within the last 12 months)
• History of >5% weight loss within the preceding 12 months
• Ingestion of exogenous D2O within the preceding 12 months
• Background of clinically significant cardiovascular, cerebrovascular or respiratory disease, neurological disorders or musculoskeletal problems
• History of malignancy undergoing current treatment or palliation
• History of any medical condition contraindicating the use of GLP-1 agonist medication
• Any other medical condition deemed by the investigators to preclude inclusion into the study