Reversing type 2 diabetes through a low calorie diet and supervised exercise

INTERVENTION: This trial is a 24‐week randomised control trial with two arms. Randomisation (at the individual level, stratified by country) will occur once all baseline measures are completed and individuals are confirmed to be eligible. Individuals deemed ineligible following baseline evaluation will not be randomised. A permuted block randomisation will be performed and an independent statistician will develop a computer‐assisted random sequence within the block. When the investigator is not blinded, and the block size is fixed, the allocation is predictable. To preserve allocation concealment, the block size will be varied (e.g., 2, 4). 1. The control group ‐ participants randomly allocated to this group will continue to receive standard care. 2. The intervention group will be prescribed a low energy diet with total meal replacement for the first 2 weeks, followed by partial meal replacement from weeks 3‐12. This will be followed by individualised food reintroduction (weeks 13‐24). During weeks 3‐12, this will be combined with supervised aerobic and resistance exercise, and a transition to unsupervised home‐based exercise will be introduced in weeks 13‐24. Individuals randomly assigned to the intervention group will be taken off their glucose‐lowering medication and antihypertensive medication by a study physician at the onset of the intervention. However, ACE inhibitors or angiotensin receptor blockers will not be discontinued in the context of albuminuria. Following the 24‐week intervention period, participants enrolled into the control group will be offered the meal replacement component of the low energy diet complemented by a 4‐week food reintroduction period with support from the study dietitians and physi CONDITION: Type 2 diabetes mellitus (T2DM) ; Nutritional, Metabolic, Endocrine ; Type 2 diabetes mellitus PRIMARY OUTCOME: Diabetes remission defined as HbA1c <6.5% (48 mmol/mol) without prescribed glucose‐lowering medications between 12 and 24 weeks of the study period. HbA1c will be obtained through a venous blood sample SECONDARY OUTCOME: ; Measured at baseline, 12 weeks and 24 weeks (unless stated otherwise):; 1. Indices of cardiac function and structure, including the variables listed beneath, assessed using magnetic resonance imaging at baseline and 24 weeks only: left ventricular (LV) end diastolic volume; LV end systolic volume; LV ejection fraction; LV stroke; volume; LV cardiac output; LV diastolic myocardial mass; LV peak diastolic filling rate; LV systolic global longitudinal strain; LV systolic global circumferential strain; LV longitudinal peak early diastolic strain rate and LV circumferential peak early diastolic strain rate.; 2. Cardiometabolic risk factors, such as lipid profile (including total cholesterol, HDL, LDL and triglycerides) and systolic and diastolic blood pressure. Among those not requiring angiotensin‐converting enzyme inhibitors (ACE I) inhibitors or angiotensive receptor blockers (ARB) specifically for micro/macroalbuminuria, the researchers will examine hypertension remission. Urea and electrolytes [U&Es], creatinine (for estimated glomerular filtration rate [eGFR]) and liver function tests [LFTs]) will be obtained through venous blood sampling.; 3. Aerobic capacity (peak oxygen uptake; V?O2peak) (to include absolute V?O2peak (L•min‐1) and V?O2peak relative to lean body mass (LBM) (i.e., ml•kg LBM‐1•min‐1) and relative to overall body mass (ml•kg BW‐1•min‐1)), measured through gas analysis during maximal CardioPulmonary Exercise Testing (CPET); 4. Physical function measured using the Short Physical Performance Battery (SPPB) and handgrip dynamometry; 5. Anthropometry and body composition (to include total body weight, BMI, lean body mass, fat mass [FM]):; 5.1. Body composition measured through bioelectrical impedance testing and Dual Energy X‐Ray Absorptiometry (DEXA); 5.2. Anthropometrics such as height and waist circumference measured using standardised tape measure procedures; 6. Intra‐ and inter‐organ adiposity (to include subcutaneous abdominal adipose tissue (SAT), visceral adipose tissue (VAT), intrahepatic and pancreatic fat, liver fat, mid‐thigh fat and muscle area, assessed through magnetic resonance imaging at baseline and 24 weeks only); 7. Resting metabolic rate (RMR) assessed via indirect calorimetry; 8. Sleep, sedentary time and physical activity measured using a wrist‐worn device; 9. Urine albumin to creatinine ratio (ACR) measured with a urine sample; 10. Mental wellbeing (to include anxiety, depression and diabetes distress) assessed through the Hospital Anxiety and Depression scale (HADS); 11. Quality of life assessed through the EQ‐5D‐5L questionnaire; 12. Health resource usage assessed through medical notes and a health resource questionnaire; 13. Acceptability, feasibility, facilitators, barriers, adherence to the intervention as assessed through process evaluations; 14. Dietary micro‐macro nutrient compositions captured through validated nutritional analysis software; 15. Average glucose, glucose variability (standard deviation and coefficient of variation) and percent time in range (3.9 to 10 mmol/l) measured using continuous glucose monitoring starting at baseline and during weeks 2, 4, 11 and 23 within a sub‐sample of the intervention group; INCLUSION CRITERIA: 1. Age 18 to 40 years, inclusive 2. A clinically coded diagnosis of T2DM between 3 months and 6 years previously 3. HbA1c 6.5% (48 mmol/mol) to 10% (86 mmol/mol), inclusive, within the last 12 months 4. BMI =30 kg/m² and =45 kg/m² (= 27.0 kg/m² if BAME (self‐identified)), within the last 12 months 5. Self‐reported stable weight over the previous 6 months (<+/‐ 5 kg) 6. Treatment stable; no significant change to glucose‐lowering regimen in the preceding 3 months, as determined by a study investigator 7. Able to provide informed consent 8. Able to understand written and spoken English 9. Able to take part in structured exercise training requiring the lower limbs (e.g., able to walk without assists or impairment)