Individualised Postprandial Glucose Responses in Type 1 Diabetes
Condition: Type 1 Diabetes; Diabetes Complications; Postprandial Hyperglycemia
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Hyperglycemia; Diabetes Complications
Study type: Interventional

Summary: 
      Type 1 diabetes (T1D) is a lifelong disease which stops the body from producing insulin - an
      important hormone that controls blood sugar (glucose) levels. People with T1D use insulin
      replacement therapy, usually in the form of injections, to help control blood glucose levels,
      however keeping glucose levels within normal ranges is usually a challenge. Mealtime glucose
      control is fundamental to good diabetes management and are an important contributor to
      long-term diabetes complications. However, many individuals experience variability in glucose
      levels around mealtimes. The objective of this study is to establish whether and which
      parameters are important predictors of mealtime glucose levels in people with T1D.

      The investigators will monitor glucose levels using the latest glucose monitoring technology
      and collect blood samples to:

        1. Characterise changes in glucose levels in individuals with T1D in response to different
           meals

        2. Determine whether and what food characteristics and personal factors are linked to
           individual glucose responses to different meals.

      The investigators will recruit 150 individuals with type 1 diabetes. Firstly participants
      will attend a preliminary visit, where a blood sample will be donated to study laboratory
      blood markers of vascular and metabolic health accompanied by a full medical examination in
      which body composition will be established. During this visit participants will also complete
      questionnaires about their lifestyle, and be fitted with two wearable devices to monitor
      glucose levels and physical activity levels under free-living conditions.

      After 4-weeks of wearing the devices, participants will attend two experimental laboratory
      visits where breakfast and lunch will be served and blood samples taken. This will enable us
      to observe glucose and metabolic responses to feeding under controlled conditions.
    

Detailed description: 
      Recruitment: Participants will be recruited using advertisements through university channels.
      The investigators will also approach local and national diabetes charities (Diabetes UK,
      JDRF) who the investigators work with closely to advertise through written publications
      (patient magazines), websites, social media, and patient support groups. In addition, the
      investigators will contact patients who have previously participated in our research who have
      consented to being contacted about future research. Contact information for the research team
      will be provided in advertisements; an initial telephone call will be available to interested
      participants to discuss the study, answer any questions, and obtain contact information to
      send a study information pack including a participant information sheet. Participants will be
      given 6-weeks to decide whether to participate in the study.

      Preliminary visit: Patients will attend a preliminary visit to our dedicated laboratories at
      the University of Sunderland to assess eligibility and obtain written informed consent by a
      GCP trained member of the research team. At this visit, consented participants will be fitted
      with a blinded real-time CGM and an accelerometer and provided with a food diary. During this
      visit, patients will complete a questionnaire to assess their medical history and physical
      activity. Both CGM and accelerometer devices will be worn by participants for the duration of
      their study involvement; both devices complete with data capture will be returned by
      participants to the research team either in person or via post (using a prepaid envelope).

      CGM measurement: A small CGM device (CGM; Freestyle Libre Pro; Abbott Diabetes Care) will be
      inserted during the preliminary visit to the laboratory. It is a small discreet,
      water-resistant sensor, with a thin filament (<0.4m thick) that is inserted (painlessly) 5mm
      beneath the skin surface on the upper arm. The sensor will be inserted into the subcutaneous
      tissue on the anterior of the upper arm. The insertion site will be taken as equidistant
      between the most medial portion of the upper arm and marked with indelible ink so that
      initial placement can be replicated on subsequent insertions in the unlikely event that a
      sensor should fail. The sensor is factory calibrated making it far more convenient and
      removing the risk for sensor inaccuracies from calibration user error (capillary meter
      inaccuracy, not washing hands etc) seen with other CGM devices. Glucose data generated by the
      CGM is masked (i.e., participants cannot see their glucose data and thus cannot change their
      treatment regimen based on this information). A single reader device is used to activate and
      retrieve the data. The accuracy and safety of this device has been established in T1D across
      the full range of glucose levels likely to be observed in this study, including those in the
      normal range; the latest generation of the CGM sensor has a MARD of <9% as of 2018. Moreover,
      as an un-blinded version of this device is now made available to people with T1D with
      treatment indications through the NHS, the use of this technology is deemed acceptable to
      people with T1D. Study participants who are using Freestyle Libre to monitor their glucose
      patterns can continue to use the device as usual but will be asked to wear an additional
      blinded sensor. In total, patients will be requested to wear the CGM device for 6 continuous
      weeks, consisting of 4-weeks observation followed by 2-weeks observation during which
      laboratory experimental testing will occur.

      Accelerometer: Participants will be issued and fitted with an accelerometer (GeneActiv, worn
      on the arm) which will provide a comprehensive assessment of sitting/standing patterns (i.e.
      posture allocated) and physical activity levels. The data collected from this device will be
      used to estimate daily energy expenditure (using a priori cut points) and calculate physical
      activity levels including time spent in different postures and activities during discrete
      parts of the day both before and after each laboratory visit. This will allow for
      quantification, standardisation and replication of physical activity patterns during
      free-living episodes. In total, patients will be requested to wear the accelerometer device
      for 2 continuous weeks.

      Medical history: To include: age, gender, duration of diabetes, insulin therapy (average
      total daily dose and basal insulin dose), associated medical conditions, family history of
      T2D and cardiovascular disease, hypoglycaemia unawareness (assessed through a combination of
      the Clarke and Gold methods).

      Physical activity assessment: Patients will complete the IPAQ (International Physical
      Activity Questionnaire), the Exercise Benefits/Barriers Scale Questionnaire, and The Barriers
      to Physical Activity in Type 1 Diabetes Scale. These will assess current levels of physical
      activity participation, as well as general and diabetes-specific enablers and barriers to
      physical activity.

      Anthropometrics: Anthropometric data will include: weight, height, waist circumference and
      waist-hip-ratio. Body composition will be determined using the bioelectrical impedance method
      [Seca mBCA 525] as detailed above. Blood pressure will be taken alongside ankle brachial
      index measurements. Estimated glucose disposal rate (eGDR; a measure of insulin resistance)
      will be calculated for all patients.

      Dietary assessment: Patients will complete a food frequency questionnaire (Dietary Instrument
      for Nutrition Education) and will be provided with a food scale and a food diary to perform a
      weighed food log. In total, participants will complete the weighed food diary for 1-week.

      Blood donation: A single 50mL blood donation will be made which will be retrospectively
      analysed for parameters of vascular and metabolic health. Blood will be obtained using
      venepuncture technique by a trained phlebotomist.

      Experimental laboratory visits Pre-laboratory phase: Prior to the first experimental visit,
      the investigators will assess glycaemic control (CGM) and physical activity patterns
      (accelerometer) for 4- and 1-weeks, respectively. Patients will be required to use their
      dietary recording sheets to replicate their dietary patterns in the 48-hours prior to each
      experimental laboratory visit. For standardisation of glycaemic control, as well as
      biochemical parameters, participants will be provided with a standardised meal to be consumed
      on the evening before each experimental laboratory visit based upon their weight (~635kcal;
      vegetarian lasagne; Tesco). Since an acute exercise session may enhance insulin action for up
      to 48-hours, participants will be asked to reframe from moderate-to-vigorous physical
      activity/exercise during the 48-hours preceding each laboratory visit to avoid the potential
      impact of this on glycaemia and hypoglycaemia risk. Additionally, during the 24-hour prior to
      each laboratory visit, participants will be asked to reframe from caffeine and alcohol which
      are known to influence glucose levels.

      To avoid any confounding influence of hyper/hypoglycaemia or illness, a researcher will call
      the morning of each testing day - if blood glucose is outside the range of 4-12 mmol/L or if
      the participant is unwell with blood ketones >0.6 mmol/L, the experimental visit will be
      postponed. The dosage and timing of insulin administrations as well as any
      supplements/vitamins being taken will be standardised for the duration of each trial period.
      To control for the potential confounding effect of insulin regimen (CSII vs MDI) and
      medication, insulin regimen and medication will be included as a covariate in the statistical
      model. Participants using CSII will be advised to avoid making changes to their insulin pump
      delivery settings and insulin regimen between study visits. Participants treated with MDI
      will be advised not to change their insulin regimen between study visits. Due to the
      likelihood of changes in glycaemic control and/or insulin requirements over longer periods of
      time, pre-menopausal women will complete each condition with a 1-week washout, as for all
      other participants. Menstrual phase will be recorded for each condition and controlled for as
      a covariate in statistical models.

      Main experimental visits: In a randomised crossover design, patients will attend two separate
      morning-time (~08:00am) laboratory-based visits (lasting ~4.5-hours in duration) within the
      dedicated clinical testing facility at the Univeristy of Sunderland, each interspersed by one
      week. Each experimental condition will be conducted in a controlled laboratory setting to
      maximise internal validity and minimise the inherent variability of less-controlled
      'real-world' settings. Except for toilet breaks, participants will be seated in a comfortable
      lounge-chair and instructed to minimise excessive movement.

      On each occasion and upon arrival to the laboratory following an overnight fast, participants
      will assume a seated and rested position while a 20-gauge cannula (Vasofix, B. Braun,
      Melsungen AG, Melsungen, Germany) is inserted into the antecubital vein of their non-dominant
      arm; resting, fasted venous blood samples will be collected prior to experimental testing.
      Following the initial blood sample, patients will be given a standardised mixed-macronutrient
      breakfast-based meal on each occasion. At 4-hours post-breakfast, participants will be
      provided with a standardised mixed-macronutrient lunch meal before being discharged home.
      Each meal will be matched for carbohydrate (equating 1g.carbohydrate.kg.BM-1 ), fat, protein,
      and fibre content but differing in glycaemic index through manipulation of carbohydrate
      composition to represent either a low or high glycaemic index meal. Insulin administration
      will be standardised across visits based on the carbohydrate counting method. Meals will be
      preceded by an insulin bolus, calculated from each participant's usual
      insulin-to-carbohydrate ratio (with no correction dose), administered 10-minutes before
      eating, with those treated on MDI standardising insulin injection site. The timing and amount
      of water consumed with each meal, and ad libitum throughout the duration of the first visit
      will be recorded so that this can be replicated on subsequent visits.

      Blood sampling: Periodic blood samples will be drawn at 30-minute intervals across the 4-hour
      observation window and commencing immediately prior to the consumption of the breakfast
      meal). At each time point, 10mL of venous whole blood will be taken and dispensed into
      Vacutainers before centrifugation at 3000 rev/min for 15-minutes at 4ºC. Plasma will be
      separated and stored at -80 degrees centigrade for retrospective analysis, or immediate
      analysis for a panel of vascular inflammatory and thrombotic parameters, including plasma
      levels of C-reactive protein (CRP), complement C3, fibrinogen, plasminogen activator
      inhibitors (PAI)-1, interleukin 1b, will be assessed using standard ELISA techniques. An
      additional 5mL of venous blood will be taken at rest on one arm of the study for C-peptide
      and routine blood tests (including HbA1c, U&Es, LFTs, full lipid profile, urinary albumin
      creatinine ratio (unless these have been done within three months of enrolment). A total of 8
      blood samples will be taken with the total volume of blood equalling 85mL, which is
      approximately 1/5th of a full blood donation. The total volume of blood to be taken is safe
      and is similar to other studies that the investigators have performed previously in people
      with T1D. Further, the investigators have worked hard with our PPI representatives to
      minimise the participant burden of all study procedures; the volume and frequency of blood
      sampling has been deemed acceptable by our PPI representatives.

      Post-laboratory observation period:

      Following the last blood sample at 7-hours post-breakfast, participants will be discharged
      from the laboratory. Glycaemia will continue to be monitored under free-living conditions for
      a total of 48-hours post-intervention using CGM. As the investigators are interested in the
      48-hour glucose responses following our intervention (including the dawn phenomenon),
      participants will be given two standardised meals to consume as their evening meal and
      breakfast and be required to replicate their dietary intake across trials for the duration of
      the 48-hour post-intervention period, in order to control for the potentially confounding
      effects of diet on glycaemic control.
    

Intervention name(s): Nutritional Interventional
Intervention type(s): Other
Intervention description(s): Individualised postprandial glucose and vascular risk responses
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: A single centre, randomised and counter-balanced, two-arm cross-over study.
Masking: Double (Participant, Investigator)
Primary purpose: Prevention