To Bathe or Not to Bathe

Type 2 diabetes mellitus (T2DM) is characterised by chronic high blood sugar concentration (hyperglycaemia) and insulin resistance leading to a reduction in insulin sensitivity. These hyperglycaemic excursions can seriously impact metabolic, micro and macrovascular health. The total cost of the direct and indirect care of individuals with diabetes (\~90% T2DM) in the UK (United Kingdom) is £23.7 billion, equating to \~20% of the annual national health service (NHS) budget, with this projected to become unsustainable. Low-cost interventions to improve glycaemic control in these individuals are therefore warranted. Current interventions include pharmaceuticals, exercise and calorie restrictive diets. Pharmaceutical interventions carry a high financial cost, while exercise and diet programmes have a low adherence rate in individuals with T2DM.

Heat therapy offers one potential low cost therapy. Immersion in a hot tub for 30 mins.day-1 for 10 days has been shown to reduce fasting plasma \[glucose\] and HbA1c in individuals with T2DM, which may be explained by acute (e.g. muscle) and chronic (e.g. reduced inflammatory status and increased heat shock proteins (HSP)) adaptations, although experimental evidence for these hypothesis are sparse. Other potential benefits include improved glycaemic control, insulin sensitivity, elevated resting metabolic rate and improved micro- and macrovascular function.

The aim of the present study is to determine whether acute hot water immersion can improve glucose tolerance in individuals with T2DM and whether it is more beneficial to undertake this before or after a OGTT (oral glucose tolerance test).

Visit 1 (consent, screening and familiarisation) During visit 1, participants will give their informed consent, followed by a health screening questionnaire. In addition to the health screening questionnaire, medical history and a blood sample will be collected and analysed for a full blood count, glycated haemoglobin (HbA1c), liver and kidney function. Finally, a resting electrocardiogram (ECG) will also be recorded and then examined for irregularities, where a clinical decision will be made on further participation to the study by consultants at QA (Queen Alexandra) hospital. Participants will then be shown the rest of the equipment and taken through the procedure for the next 3 visits and, if the participant is happy to continue the study, the next visit will be organised.

Visit 2, 3 and 4 Participants will arrive at the laboratory at \~9 am for conditions 1 and 2 and 8 am for condition 3. Prior to a 15 min resting period (supine) before any measures are taken participants will be asked to insert a rectal thermistor (participants will be given clear instructions using the investigator's SoPs (standard operating procedure)). Condition 1, 2 and 3 will be balanced and participants randomly allocated to begin the study in either visit 2, 3 or 4 using a blinded member of the team.

For all visits (see figure 2), participants will lie in a semi recumbent position in minimal clothing (bathing shorts and a t-shirt) for the entirety of the visit. Initially, participants will be cannulated (Versatus winged and ported IV cannula, Terumo, Japan) and blood samples drawn for analysis of osmolality (Lithium Heparin (LH) tubes BD (Becton, Dickinson and Company), USA) plasma \[glucose\] (Fluoride/Oxalate tubes, BD, USA), \[insulin\] (Ethylenediaminetetraacetic acid (EDTA) K2, BD, USA), and \[eHSP70 (extracellular heat shock protein 70)\] (EDTA K2, BD, USA) at baseline and every 30 min of each experimental visit. Following cannulation an 180 min OGTT (75g) (Rapilose OGTT solution, Penlan healthcare, Japan) will commence in a thermoneutral room (\~ 23oC). A maximum of 18 mL of blood being drawn at each time point (max 126 mL per visit). To maintain the patency of the cannula and to reduce the risk of infection, after every sample is taken, 5 mL of saline will be flushed through the cannula. Then before every sample is taken, 2.5 mL of blood will be drawn out of the cannula to ensure any remaining saline will not interfere with the samples and data interpretation (additional 17.5mL per visit). During the OGTT, HR (heart rate) (via electrocardiogram) will be measured continuously, whilst blood pressure (M5-1, Omron, Japan), deep body temperature (rectal probe) and resting metabolic rate (indirect calorimetry) (Quark CPET (cardiopulmonary exercise test), Cosmed, Italy) will be assessed every 30 min.

Condition 2 will employ identical procedures to condition 1, except thirty minutes into the OGTT, the participant will be immersed into an immersion tank (\~39oC) for 60 min. Water temperature will be manipulated as required to achieve and maintain a target Trec at 38.5 oC using water between 37.5 and 39oC, and then participants will be removed horizontally back into the thermoneutral room for the reminder of the OGTT. Participants will be towel dried and given a towelled robe to wear. Condition 3 will employ identical procedures to condition 2, with the exception that the heating via immersion will start as soon as the participant is instrumented (and following a 15 min rest period) and the OGTT will commence 30 min after the 60 min immersion time for a further 180 min (see figure 2 for a schematic).

Eligibility Criteria:
The participants must meet all of the following criteria to be considered eligible for the study:

* Male or female (either post-menopausal or in the early-follicular phase (3-5 days after the onset of menstruation) of the menstrual cycle), aged 35 years or above.
* Diagnosed with T2DM as defined by the WHO (World Health Organisation).
* Participant is willing and able to give informed consent for participation in the study.
* Participant is able to understand and fully cooperate with the study protocol.

Exclusion Criteria

The participant may not enter / be withdrawn from the study if any of the following apply:

* Severe peripheral neuropathy (to the point to which they cannot sense temperature)
* Uncontrolled hypertension (≥180 systolic / 100 diastolic mmHg)
* Taking any medication which may interfere with data interpretation or safety
* Who have had a myocardial infarction or cerebro-vascular event
* Any cardiac abnormalities which restrict hard exercise
* Current smokers or who have stopped within 3 months
* Participant is unable to understand and/or fully cooperate with the study protocol
* Any other serious medical condition which would interfere with data interpretation or safety will be excluded from participation.
* Any skin conditions including ulcerations