VLCD & Adjuvant Exercise Effect in Overweight Diabetic Men
Condition: Diabetes Mellitus Type 2 in Obese
MeSH terms: Overweight; Diabetes Mellitus, Type 2
Study type: Interventional

Summary: 
      Sarcopenia is defined as the incremental age-related loss of skeletal muscle in humans which
      generally begins from forty years old. It is associated with an overall reduction in quality
      of life and increased morbidity and mortality. Patients with type two diabetes mellitus
      (T2DM) are particularly at risk of developing sarcopenia, partly due to the condition and
      also due to the common incidence after or during middle age. A promising
      recently-investigated and effective conservative approach to T2DM is through very low calorie
      diets (VLCD). Some studies have shown that the diabetic status of some patients can be
      reversed through VLCD. However, VLCD will theoretically result in an acceleration of
      sarcopenia. This presents as a limiting factor for the implementation of VLCD in this at-risk
      patient group. Skeletal muscle tissue is encouraged to grow in size or be maintained through
      two means - an increase in circulating protein breakdown products, or through resistance
      exercise (RE). Additionally, RE has been shown to increase the body's sensitivity to insulin,
      the main hormone which controls circulating glucose levels and is frequently impaired in
      T2DM, as well as temporarily decreasing glucose levels. The precise mechanism by which these
      happen is not fully understood yet. In this study, the effect of a VLCD is used, alongside
      one form of exercise (high intensity interval training, HIT), in overweight, middle-aged male
      patients with T2DM. 10 patients are to be recruited into each group (control/VLCD-only and
      VLCD with HIT) at our centre. Patient weight, markers of muscle protein synthesis, glucose
      levels and changes to blood vessels will be investigated before, during and after across a
      six week timeframe. Investigations will include muscle and fat biopsies, blood samples,
      ultrasound scans, strength testing and deuterium oxide (D2O) isotope ingestion for later
      non-invasive body fluid sample mass spectrometric analysis.
    

Detailed description: 
      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.

      The findings from this project could enhance our understanding on the role of VLCD in
      inducing improvement in cardio-metabolic health, provide rapid, practical low cost clinical
      interventions for people with T2DM and/or obesity, while unearthing potential new therapeutic
      targets for the future management of high blood sugar and obesity in people with T2DM.

      STUDY PROTOCOL After having passed screening and being formally enrolled, participants will
      be randomised and stratified (described previously), and then attend the department twice
      prior to their intervention commencement, with each day consisting of a full study day,
      whereby the various primary and secondary outcome measurements will be performed.

      On the first study day (D-5 from intervention), subjects will be asked to fast from midnight
      (except for water). This first 'study day' will consist of, in chronological order, repeat
      height and weight measurement, a baseline urine sample, DXA and oral glucose tolerance test
      (OGTT) with concurrent questionnaire completion, followed by lunch. This is followed by hand
      grip dynamometry, electromyogram, maximal voluntary isometric contraction (MVC), the Short
      Physical Performance Battery (SPPB), and 1 repetition-maximum (1RM) testing of three lower
      body (leg press, hamstring curl, quadriceps extension) and three upper body movements (chest
      press, machine row, machine pulldown). Thereafter, participants would be fitted with an
      Actiheart monitor, followed by a staggered dosing of a D2O bolus with a concurrent bolus dose
      of D3-creatine. Additionally, they would be provided with several collection vessels (24 hour
      jar, two collection pots for 48 hour and 72 hour spot samples for the D3-creatine; a saliva
      collection pot to be filled two hours following the D2O bolus). They would also be provided
      with a loading dose of 3-methylhistidine (3MH) to be taken one day prior to the second study
      day (D-1 from intervention). Finally, they would be provided with an updated itinerary of the
      available VLCD meals for selection.

      Between the two study days (D-4 to D-1 from intervention), the participant would collect
      their D3-creatine-containing urine at home (24 hour period, and 48 & 72 hour spot samples).
      Additionally, one day prior to the second study day (D-1 from intervention), participants
      would be asked to consume the 3MH bolus at precisely 13:00. During the interim period, the
      participant would also be contacted to receive their preferences for meal profiles, which
      would be organised by the department. Finally, if the participant had been randomised into
      the 'VLCD only' group, they will advise the research team of their preferred food items
      (vegetables and/or nuts) during this interval, in order for a calculation of the approximate
      breakdown of calories that may be required to achieve a 200kcal value.

      On the second study day (D0 from intervention), subjects would once again be asked to fast
      from midnight (except for water). Upon attendance, they would be asked to provide a fasting
      saliva sample, blood (a repeat of the screening panel, alongside the '0 hour' serum 3MH level
      and D2O baseline measurement). Additionally, they would have their estimated 50% 1RM
      calculated for the quadriceps leg extension of their dominant leg (for utilisation in the
      subsequent analyses that day). They will also be expected to return their Actiheart monitor
      and D3-creatine samples for subsequent analysis.

      Thereafter, the participants would undergo (in chronological order) abdominal adipose tissue
      biopsy, vastus lateralis muscle biopsy (non-dominant leg), vastus lateralis ultrasound
      assessment (dominant leg), contrast-enhanced ultrasound scan (using the Sonovue agent;
      dominant leg), leg blood flow (dominant leg), flow-mediated dilation (dominant arm), and
      cardiopulmonary exercise testing (CPET). Throughout, across a four hour period from 09:00 to
      13:00, serial measurement of the participant's serum 3MH levels are performed. At the end of
      the session, the participant would be provided with two to three weeks of VLCD meals (per
      their previously-agreed profile choices pending availability), alongside a diet and sleep
      diary. Further, they will be provided with the details of a registered dietician for support,
      and six once-weekly 'top up' doses of D2O, with the adjoining saliva sample vessels, to be
      filled immediately prior to 'top up' and two hours afterwards.

      The day after, the participant will commence their VLCD diet (D1), and will be expected to
      attend the department for a brief period several days afterwards (D4-5) for an inspection of
      their biopsy incision sites by a research clinician.

      Within weeks three to four of the intervention, a peri-intervention study day will be
      undertaken, whereby the participant would have repeat serial 3MH testing (as described in the
      second pre-intervention study day), alongside another set of repeat blood tests (as described
      in the first pre-intervention study day). All D2O saliva samples generated up to this
      juncture may be submitted to us at this time. The participant would also be refitted with an
      Actiheart monitor, to be worn for five full days.

      Following the completion of six full weeks of interventionIn the sixth and final week of
      their intervention period, the participants would be brought in for the post-intervention
      study days, which fully replicate the procedures described in the pre-intervention study
      days, with the exception of a D2O loading dose, and the returning of the Actiheart monitor
      worn following the peri-intervention study day. Thus, these final two post-intervention study
      days would occur on week six day two and week six day seven of the intervention period.

      After the post-intervention study days have been completed, the participant would once again
      attend the department after several days for a biopsy site incision inspection, in addition
      to the organisation of their reimbursement and guidance with respect to transitioning towards
      an increased calorie intake post-intervention All subjects will have 6-week intervention
      period of VLCD nutritional intervention with LighterLife VLCD meal replacement diets,
      600kcal/day with 100% recommended daily allowance (RDA) vitamins and minerals. Meal
      replacements, which will be acquired from LighterLife, comprise of four food packs a day in
      the forms of soups, porridge, bars and drink mixes.
    

Intervention name(s): Very Low Calorie Diet; High Intensity Interval Training
Intervention type(s): Dietary Supplement; Other
Intervention description(s): A dietary intervention consisting of four meals (provided by LighterLife®), totaling approximately 600kcal/day (each meal comprising approximately 150kcal/day). Participants are provided with a choice of one of six "meal protocols", which consist of a pre-set combination of meals that arrive at approximately 52g protein, more than 15g fibre and less than 20g sugar per day.; The HIIT training will consist of a five-exercise approach across three movements (star jumps, standing squats, on-the-spot-sprinting, standing squats and star jumps), which are collectively described as a cycle in this context. Each exercise is performed for 60 seconds with a 90 seconds recovery period. Each training session will begin with a two minute warm-up and cooldown (on-the-spot-jogging) followed by five minutes of static stretching. Volunteers would aim to exceed the initial number of star jumps and standing squats in the subsequent attempt per cycle. A total of three training sessions per week are to be completed, preferably non-consecutive but may be consecutive on no more than two training sessions per week. Progression is through a gradual increase in volume (repetitions of star jumps and standing squats) on a per-session basis.
Other intervention name(s): LighterLife®; Very Low Energy Diet; Calorie Restriction; Caloric Restriction; HIIT; Home HIIT
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a proof-of-concept, single centre, randomised, non-blinded control trial.
Masking: None (Open Label)
Primary purpose: Treatment