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Type 1 DiabetesNCT04614168

Maximising Time With a Normal Blood Glucose to Restore the Glucagon Response in Type 1 Diabetes

A study testing Stepped hyperinsulinaemic-hypoglycaemic clamp study, Insulin pump and Continuous glucose monitor in people with Type 1 Diabetes and Type 1 Diabetes Mellitus With Hypoglycemia, run by University of Edinburgh at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Almost all people who have had type 1 diabetes for 5 years have a defect in secretion of the hormone Glucagon. This hormone is involved in the body's response to low blood glucose (hypoglycaemia). It works by releasing glucose stores from the liver to bring the blood glucose back to normal. Read more about this study

Who is it for?
Ages 21 to 65 years
What is being tested?
Stepped hyperinsulinaemic-hypoglycaemic clamp study, Insulin pump and Continuous glucose monitor
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
1 siteUnited Kingdom
Study dates
26 Jul 2021to 26 Dec 2025
Phase
Interventional

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 21 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Participants with Type 1 diabetes with C-peptide levels less than 200pmol/L.
  • Type 1 diabetes for 5 years or more.
  • HbA1c greater than or equal to 53 mol/mol.
  • Normal renal function.
  • Normal thyroid function.
  • Gold Score 4-7 (indicating impaired awareness of hypoglycaemia)
  • Willingness to monitor blood ketones daily.
  • Use of freestyle libre device is permitted at study entry and may be continued in participants in group 1

Who cannot join

  • Current use of a non-approved closed loop / AID system or those on a predictive low glucose suspend insulin pump.
  • Proliferative retinopathy
  • Regular use of real time CGM in the preceding 3 months.
  • History of Diabetic ketoacidosis in the preceding 6 months.
  • Severe hypoglycaemic episode requiring external assistance in the preceding 6 months.
  • Inability to safely use technology used in this study (e.g. impaired vision, memory or dexterity that prevents safe operation of CGM or insulin pump.)
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  • Inability to support the technology requirements for the study (e.g. unable to upload study device at home)
  • History of Haemophilia, Cystic Fibrosis, pancreatic disease or complete pancreatectomy, ischaemic heart disease, epilepsy or hypoglycaemia induced seizure
  • History of severe reaction or allergy to adhesive necessary to this study.
  • Unable to adhere to study timetable.
  • Unable to give informed consent.
  • Pregnancy. We will perform a pregnancy test on all eligible participants at baseline.
  • Concurrent use of any non-insulin glucose-lowering agent (including GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas. These may lower insulin requirements and predispose to diabetic ketoacidosis.
  • Concurrent use of medication that may affect blood glucose such as SSRIs
  • A condition, which in the opinion of the investigator, would put the patient or study at risk
  • HbA1c greater than or equal to 75 mmol/mol

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • Edinburgh Royal Infirmary/University of Edinburgh

    Edinburgh

Other trials in United Kingdom

About this study

Official title: Can Maximising Time in Range Using Automated Insulin Delivery and a Low Carbohydrate Diet Restore the Glucagon Response to Hypoglycaemic in Type 1 Diabetes?

Almost all people who have had type 1 diabetes for 5 years have a defect in secretion of the hormone Glucagon. This hormone is involved in the body's response to low blood glucose (hypoglycaemia). It works by releasing glucose stores from the liver to bring the blood glucose back to normal. This defect therefore increases the risk of severe hypoglycaemia. The reason for this Glucagon defect in people with Type 1 diabetes is currently unknown.

This study aims to look at the Glucagon response to hypoglycaemia in 24 people with type 1 diabetes to ascertain whether tight blood glucose control over a period of time improves this response. The investigators aim to achieve good blood glucose control using new generation Automated Insulin Delivery systems (AIDs). This system is made of: an insulin pump, a continuous glucose monitor (CGM) and an algorithm that allows adjustment of insulin delivery based on the blood glucose readings from the CGM. This is the most up to date technology that there is in the management of type 1 diabetes. However, people using this technology often still have problems with high blood glucose after eating. To ensure a very good blood glucose control participants will also follow a low carbohydrate diet to prevent this blood glucose rise after meals.

The Glucagon response to low blood glucose will be measured at zero and eight months using the hyperinsulinaemic hypoglycaemic clamp technique.

Read the detailed description

This is a feasibility pilot study involving 24 participants with type 1 diabetes. Participants will be recruited from the local type 1 diabetes clinic and insulin pump waiting list. Each participant will enter the trial for a period of 8 months. The investigators aim to test if maximising time in glycaemic range (blood glucose 3.9-10 mmol/L) will restore the glucagon response to insulin-induced hypoglycaemia.

After signing informed consent participants will be screened for eligibility against the inclusion and exclusion criteria.

Those who are eligible will have an initial 20-day period of baseline blood glucose data collection. This will be achieved using a blinded continuous glucose monitoring (CGM) device. Participants will continue on their pre-trial diabetes care during this period and will be required to monitor their own blood glucose as normal.

The participants will be split into two groups using stratified sampling to match for: age, gender and BMI.

Group 1 will be the control group. Participants in this group will continue on standard diabetes care for the duration of the trial. Participants will be required to undertake two further periods of blinded CGM monitoring at 4 and 8 months.

Group 2 will be the intervention group. Participants in this group will be placed on the automated insulin delivery (AID) system and asked to follow a low carbohydrate diet of 30-40g of carbohydrate per main meal portion. The AID system will consist of: a Tandem t:slim X2 insulin pump with control IQ technology and a Dexcom G6 continuous glucose monitor. After receiving training on the use of the devices these participants will enter a 2 week study run-in period to become accustomed to the devices and so that device settings can be optimised. As a safety measure these participants will be asked to measure blood ketones at least once daily throughout the trial. Study staff will monitor the data from the participants study devices throughout the trial and adjust settings as required to maximise time in glycaemic range.

At the beginning and end of the trial all participants will undergo a hyperinsulinaemic hypoglycaemic clamp study to measure their counterregulatory hormone response to hypoglycaemic. Participants will also undergo cognitive tests and assessment of hypoglycaemic awareness during each clamp study.

Being tested
Stepped hyperinsulinaemic-hypoglycaemic clamp study, Insulin pump, Continuous glucose monitor, Low carbohydrate diet, Blinded continuous glucose monitor
Keywords
Type 1 diabetes, Hypoglycaemia, Hypoglycemia, Glucagon, Insulin, Low carbohydrate diet, Stable isotope
Medical subject headings
Diabetes Mellitus, Type 1, Hypoglycemia, Insulin Resistance

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Stepped hyperinsulinaemic-hypoglycaemic clamp studyProcedure or surgery

    Participants will commence on a primed insulin infusion at a constant rate of 60mU/m2/min along with a variable rate 20% glucose infusion. Participants will have their blood glucose monitored every 5 minutes. The glucose infusion will be altered to achieve the desired blood glucose plateaus of: 5mmol/l, 3mmol/l and 2.5mmol/l. Each plateau will be held for 40 minutes. During each plateau blood samples will be taken on three occasions for: glucagon, cortisol, adrenaline, noradrenaline, D2 glucose and D5 glycerol. On two occasions during each plateau participants will complete the Edinburgh hypoglycaemia scale and the following cognitive tests: trail making test, digit span test, digit symbol substitution test and four choice reaction time test. At the end of the clamp study the insulin infusion will be discontinued and the blood glucose will be allowed to rise to the normal range. Participants will consume lunch before leaving the clinical research facility.

  • Insulin pumpDevice

    Also called Tandem t:slim x2 with Control IQ technology

    Insulin pump with a built-in algorithm that allows it to work with a CGM device to adjust insulin delivery based on CGM readings.

  • Continuous glucose monitorDevice

    Also called Dexcom G6

    Continuous glucose monitoring device that sends data to the insulin pump to allow the algorithm to adjust insulin delivery. Participants are able to see the glucose data from the device when it is used in open mode.

  • Low carbohydrate dietOther

    30-40g of carbohydrate per main meal portion.

  • Blinded continuous glucose monitorDevice

    Also called Dexcom G6

    Allows data on blood glucose to be collected without values altering the behaviour of the participant. Participants have to continue to monitor their own blood glucose while wearing the device in the blinded mode.

  • Stable isotope studies- D2 Glucose and D5 GlycerolProcedure or surgery

    These studies will take place at the same time as the hyperinsulinaemic hypoglycaemic clamp studies. Participants will receive a priming dose of each stable isotope followed by a continuous infusion for the remainder of the clamp study.

Study groups in NCT04614168
Study groupRoleWhat they receive
Group 1 - Standard CareActive comparatorThis group will continue on their standard diabetes care. They will be required to undergo three periods of blinded continuous glucose monitoring each lasting 20-days at: baseline, 4 months and 8 months. Participants in this group will undergo a hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months. They will also complete quality of life and diabetes treatment questionnaires at baseline and 8 months.
Receives: Procedure: Stepped hyperinsulinaemic-hypoglycaemic clamp study; Device: Blinded continuous glucose monitor; Procedure: Stable isotope studies- D2 Glucose and D5 Glycerol
Group 2- Automated insulin delivery and low carbohydrate dietExperimentalThis group will be placed on an automated insulin delivery system: Tandem t:slim x2 insulin pump with Control IQ technology and Dexcom G6 continuous glucose monitor. They will also be asked to follow a low-carbohydrate diet of 30-40g of carbohydrate per main meal. At baseline they will have a 20-day period of blinded continuous glucose monitoring. Participants in this group will undergo a stepped hyperinsulinaemic hypoglycaemic clamp study at baseline and 8 months. They will also complete quality of life and diabetes treatment questionnaires at baseline and 8 months.
Receives: Procedure: Stepped hyperinsulinaemic-hypoglycaemic clamp study; Device: Insulin pump; Device: Continuous glucose monitor; Other: Low carbohydrate diet; Device: Blinded continuous glucose monitor; Procedure: Stable isotope studies- D2 Glucose and D5 Glycerol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The Change in Plasma Glucagon Levels (Pmol/L) Measured During Normoglycaemic and Hypoglycaemia

    The delta glucagon concentration (pmol/L) from plateau 1 (normoglycaemia- 5.0 mmol/L) to plateau 3 (hypoglycaemia- 2.5 mmol/L). The physiological response in health would be for an increase in glucagon secretion from normo- to hypoglycaemia.

    Measured: Clamp 1 at baseline and clamp 2 at 8 months

Secondary outcomes (17)

  1. Time in Glycaemic Range (3.9-10mmol/L)

    Percentage time spent in target glycaemic range.

    Measured: Baseline (study entry), midpoint at 4 months and endpoint at 8 months

  2. Time Spent Below the Target Glycaemic Range (<3.9mmol/L)

    Percentage of time spent below the target glycaemic range

    Measured: Baseline (study entry), midpoint at 4 months and endpoint at 8 months

  3. Time Spent Above the Target Glycaemic Range (>10mmol/L)

    Percentage of time spent above the target glycaemic range

    Measured: Baseline (study entry), midpoint at 4 months and endpoint at 8 months

  4. The Change in Plasma Cortisol (ng/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

    Delta cortisol from P1 (5.0 mmol/L) to P3 (2.5 mmol/L)

    Measured: Clamp 1 at baseline and clamp 2 at 8 months

  5. The Change in Plasma Adrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

    Delta adrenaline from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L)

    Measured: Clamp 1 at baseline and clamp 2 at 8 months

  6. The Change in Plasma Noradrenaline (pg/mL) Levels Measured During Normoglycaemic and Hypoglycaemia

    The change in noradrenaline concentration from plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L).

    Measured: Clamp 1 at baseline and clamp 2 at 8 months

  7. Endogenous Glucose Production

    The change in the glucose rate of appearance from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L)

    Measured: Clamp 1 at baseline and clamp 2 at 8 months

  8. HbA1c

    Delta HbA1c from baseline to study endpoint.

    Measured: Baseline (study entry) endpoint (8 months)

  9. Change in Quality of Life at Trial Entry and End.

    Measured using the EQ5D-5L- -VAS. Number on scale of 0-100 to assess wellbeing on that day. 100 being the most well.

    Measured: Baseline (study entry) endpoint (8 months)

  10. Change in Emotional Distress Related to Diabetes at Trial Entry and End.

    Diabetes Distress Scale (DDS-1)- a 28-item self-reporting scale. Each item can be scored from 1 (not a problem) to 6 (a very serious problem). This questionnaire will be completed at study entry and study end. Data presented is the DDS total score.

    Measured: Baseline (study entry) endpoint (8 months)

  11. Change in Fear of Hypoglycaemic

    Measured using the Hypoglycaemia Fear Survey (HFS)- this survey consists of two subscales- Baseline (study entry) endpoint (8 months) Behaviour and Worry. There are 28 items in the survey that the participant ranks from Never (0) to Almost Always (4). Higher scores indicate fear of hypoglycaemia. In the Behaviour subscale the lowest possible score in 0 and the highest possible score is 60. In the Worry subscale the lowest possible score is 0 and the highest is 72.

    Participants will complete this questionnaire at study entry and study end.

    Measured: Baseline (study entry) endpoint (8 months)

  12. Change in Confidence of Managing Hypoglycaemia

    Measured using the Hypoglycaemic Confidence Scale- this is a 9 item scale. The participant rates each item from Not Confident at All to Very Confident. Participants will complete this questionnaire at study entry and study end. Higher scores mean more confidence. 'Not confident' at lower end of scale scored as 1 and 'very confident' at top of the scale scored as 4. Min score is 9 and max score is 36.

    Measured: Baseline (study entry) endpoint (8 months)

  13. Hypoglycaemia Awareness

    Measured during each clamp study using the Edinburgh Hypoglycaemic Scale- this is a 17 item scale of symptoms of hypoglycaemia. The participant ranks on a scale from Not at all (1) to A Great Deal (7) whether they are experiencing each symptom at the time of the questionnaire being completed. Higher scores mean more hypoglycaemia symptoms. The lowest possible score is 0 and the highest possible score is 119.

    Measured: Clamp 1 - study entry, clamp 2 - 8 months

  14. Trial Making Test

    Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Delta score plateau 1 (5 mmol/L) to plateau 3 (2.5 mmol/L) compared between clamp studies. Participants are timed completing the test. Higher scores indicate a longer time to complete the test.

    Measured: Clamp 1- study entry, clamp 2 - 8 months

  15. Digit Span Test

    Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in change in score from plateau 1 (5mmol/L) to plateau 3 (2.5 mmol/L) compared between clamp studies. Lower scores mean more errors. Forwards- participant repeats the numbers as read. Backwards- the participant repeats the numbers backwards.

    Measured: Clamp 1- study entry, clamp 2 - 8 months

  16. Digit Symbol Substitution Test

    Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateau 1 (5.0 mmol/L) and plateau 3 (2.5 mmol/L) compared between clamp studies. Given 90 seconds to complete as many items as possible. Higher scores mean more items completed in the allotted time.

    Measured: Clamp 1- study entry, clamp 2 - 8 months

  17. Four Choice Reaction Time Test

    Measured during each plateau in a stepped hypoglycaemic clamp study at study entry and study end. Difference in score between plateau 1 (5.0mmol/L) and plateau 3 (2.5 mmol/L) compared between clamp studies. Higher scores mean more time taken to complete the task.

    Measured: Clamp 1- study entry, clamp 2 - 8 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Nov 2020
  2. Study start26 Jul 2021
  3. Primary completion22 Sep 2023
  4. Study completion26 Dec 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Basic science
Allocation
Randomised
Intervention model
Parallel groups
Model description
Participants will be divided into two groups using stratified sampling to match for age, sex and BMI.
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04614168
Sponsor's protocol ID
AC19163
Status last verified
Jan 2026
First submitted
7 Oct 2020
Last updated
28 Jan 2026
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
Yes
Individual data sharing
No

Publications

  • Baxter F, Baillie N, Forbes S. Study protocol: a randomised controlled proof-of-concept real-world study - does maximising time in range using hybrid closed loop insulin delivery and a low carbohydrate diet restore the glucagon response to hypoglycaemia in adults with type 1 diabetes? BMJ Open. 2022 Dec 20;12(12):e054958. doi: 10.1136/bmjopen-2021-054958.

    PubMed 36600427

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