To Bathe or Not to Bathe

The Effect of Acute, Passive Heating on Glucose Tolerance in Individuals With Type 2 Diabetes Mellitus: a Randomised, Balanced Crossover, Control Trial

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03798717

Enrollment

Registered

2019-01-10

Start date

2019-02-20

Completion date

2020-03-09

Last updated

2021-07-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diabetes Mellitus, Type 2

Brief summary

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).

Detailed description

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).

Interventions

DIAGNOSTIC_TESTHeating

Warm water immersion

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

35 Years to No maximum

Healthy volunteers

Inclusion 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

Design outcomes

Primary

Measure	Time frame	Description
Mean AUC (Area Under the Curve) Plasma [Glucose]	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does an acute bout of passive, warm water therapy reduce plasma \[glucose\]? Units for AUC are AU (arbitrary units) which have been derived from the trapezoidal method and have been published as such. Trapezoidal method: AUC = Δx ((y0/2)+y1+y2+y3+...+(yn/2)).

Secondary

Measure	Time frame	Description
Mean Insulin Sensitivity	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does insulin sensitivity increase following an acute bout of warm water therapy? Calculation of insulin sensitivity is measured in AU which have been derived from the Gutt method and have been published as such. Gutt insulin sensitivity = \[75,000 + (G0-G120) × 0.19 × BW\]/(120 × log \[(I0 + I120)/2\] × \[(G0 + G120)/2\]). Where G = plasma \[glucose\], I = plasma \[insulin\] and BW = body weight.
Change in Fuel Utilisation	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does carbohydrate and fat (RER) utilisation alter during and following an acute bout of warm water therapy?
Change in Plasma [Insulin]	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does plasma \[insulin\] reduce more if the passive, warm water therapy is conducted before or after the OGTT?
Change in eHSP70 (Extracellular Heat Shock Protein 70)	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does eHSP increases during and following an acute bout of warm water therapy?
Change in Inflammatory Status	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does inflammatory status (IL-6 & IL-10) change during or after an acute bout of warm water therapy?
Change in Cardiovascular Status	Visit 2, 3 and 4. 3 times in total, until study completion, approximately 8 weeks	Does heart rate (variability) change during or after an acute bout of warm water therapy?

Countries

United Kingdom

Participant flow

Recruitment details

440 individuals were screened for eligibility (200 clinical letters, 40 from day events and 200 from local diabetes education group). 420 declined and 0 were excluded. Once participants were randomly allocated to arm sequence 5 withdrew before starting. Three in-between experimental visits. Twelve completed the study and data analysed.

Pre-assignment details

Participants were excluded from the study before assignment to groups if they did not pass screening criteria. Balanced randomisation of order in which individuals completed each arm (cross-over) was carried out. Therefore there was an equal number of individuals completing all combinations of arms.

Participants by arm

Arm	Count
Control - Pre OGTT - Post OGTT Participants first underwent a 3 h OGTT with no passive heating. Then approximately a week later underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT.	4
Control - Post OGTT - Pre OGTT Participants first underwent a 3 h OGTT with no passive heating. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then approximately a week later underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT.	3
Pre OGTT - Control - Post OGTT Participants first underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT.	3
Pre OGTT - Post OGTT - Control Participants first underwent a 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating.	4
Post OGTT - Control - Pre OGTT Participants first underwent underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating. Then, approximately a week later underwent 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT.	3
Post OGTT - Pre OGTT - Control Participants first underwent underwent a 1 h bout of passive heating 30 min into a 3 h OGTT. Then, approximately a week later underwent 1 h bout of passive heating ending 30 min before undertaking a 3 h OGTT. Then, approximately a week later underwent a 3 h OGTT with no passive heating.	3
Total	20

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Adverse Event	0	1	0	0	0	0
Overall Study	COVID-19 (coronavirus disease) Lockdown	0	0	0	0	1	0
Overall Study	Failed Screening	0	0	0	0	0	1
Overall Study	Lost to Follow-up	1	0	0	1	0	0
Overall Study	Physician Decision	1	0	1	0	0	0
Overall Study	Withdrawal by Subject	0	0	0	1	0	0

Baseline characteristics

Characteristic	Control - Pre OGTT - Post OGTT	Control - Post OGTT - Pre OGTT	Pre OGTT - Control - Post OGTT	Pre OGTT - Post OGTT - Control	Post OGTT - Control - Pre OGTT	Post OGTT - Pre OGTT - Control	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	2 Participants	2 Participants	2 Participants	2 Participants	1 Participants	11 Participants
Age, Categorical Between 18 and 65 years	2 Participants	1 Participants	1 Participants	2 Participants	1 Participants	2 Participants	9 Participants
Race and Ethnicity Not Collected	—	—	—	—	—	—	0 Participants
Sex: Female, Male Female	1 Participants	1 Participants	1 Participants	1 Participants	0 Participants	1 Participants	5 Participants
Sex: Female, Male Male	3 Participants	2 Participants	2 Participants	3 Participants	3 Participants	2 Participants	15 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 12	0 / 12
other Total, other adverse events	0 / 12	1 / 12	2 / 12
serious Total, serious adverse events	0 / 12	0 / 12	0 / 12

Outcome results

Primary

Mean AUC (Area Under the Curve) Plasma [Glucose]

Does an acute bout of passive, warm water therapy reduce plasma \[glucose\]? Units for AUC are AU (arbitrary units) which have been derived from the trapezoidal method and have been published as such. Trapezoidal method: AUC = Δx ((y0/2)+y1+y2+y3+...+(yn/2)).