The Effect of a Very Low Calorie Diet (VLCD) With and Without Concomitant High Intensity Interval Training (HIIT) on Muscle Protein Synthesis (MPS) in Middle-aged Overweight Diabetic Men

Very low calorie diet (VLCD) is increasingly being utilized to improve cardio-metabolic outcomes in overweight/obese individuals with type 2 diabetes mellitus (T2DM), but concerns regarding its association with skeletal muscle mass losses persist, especially in middle-aged/older individuals, who are already at risk of accelerated sarcopenia. This is particularly relevant in people at risk of developing diabetes due to the rising incidence and prevalence of diabetes among older patients as well as accelerated sarcopenia in diabetes compared with non-diabetes. Given that low skeletal muscle mass and function is linked to mortality, frailty, and adverse cardio-metabolic outcomes, increased understanding of the mechanisms of VLCD-induced muscle atrophy, and novel strategies to overcome this is crucial to optimize healthy ageing. Alongside nutrition, physical activity is another key driver of muscle protein synthesis, with habitual physical activity required to maintain muscle mass. A number of studies have shown that even short-term muscle disuse (or reduced use in the form of reduced ambulation (e.g. 2 weeks of <1500 steps/day) or limb immobilization causes muscle wasting. Exercise has also been shown to improve metabolic control by increasing muscle glucose uptake during muscle contractions via insulin-independent mechanisms, and also by increasing skeletal muscle insulin sensitivity following physical activity. HIT has been shown in a number of studies to improve both cardiovascular and metabolic function in a variety of cohorts. Therefore, this study aims to quantitatively determine whether HIT helps prevent a major physiological detrimental effect of VLCD.

This study will randomise volunteers to:

1. VLCD ("Lighter Life" meal replacement product, total 600 calories (kcal)) alone (200kcal free allowance) (N=10)
2. VLCD and HIT (200kcal free allowance) (N=10) This will be undertaken in overweight and obese patients (BMI=27-50kg/m2) of male gender and between the ages of 35-65 years. Based on a power calculation derived from recently-published trial data utilising VLCDs and with MPS as the primary outcome, a minimum of 8 participants per group would be sufficient, with a further N=2 per arm (an increase in 25%) implemented to account for drop-outs.

The study will aim to recruit (to allow for potential non-completion) 10 subjects per group. Volunteers would undergo detailed physiological and metabolic investigations before and after interventions

1. Skeletal muscle mass, function and protein metabolism
2. Vascular function (microvascular perfusion, macrovascular blood flow and endothelial function)
3. Cardio-metabolic status (glucose handling, cardiorespiratory function, central blood flow parameters)
4. mechanisms regulating changes in glucose handling and muscle protein turnover It is anticipated that HIT may ameliorate VLCD-induced reductions in skeletal muscle mass and function, by boosting the molecular signals which involve the retention of muscle mass. This adjuvant exercise interventions may also elicit improvements in cardio-metabolic health (vs. VLCD alone) via improvements in blood vessel function.