Skip to main content
OpenTrials
Completed

NCT Number: NCT04614168

Maximising Time With a Normal Blood Glucose to Restore the Glucagon Response 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.

Completed

Looking for future studies?

Notify Me

Key information

Conditions

Type 1 Diabetes Autoimmune Diseases Diabetes Mellitus Diabetes Mellitus, Type 1 Endocrine System Diseases Glucagon Deficiency Glucose Metabolism Disorders Hyperinsulinism Hypoglycemia Hypoglycemia Unawareness Immune System Diseases Insulin Hypoglycemia Insulin Resistance Metabolic Diseases Nutritional and Metabolic Diseases Type 1 Diabetes Mellitus With Hypoglycemia

Age range

21 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Edinburgh Royal Infirmary/University of Edinburgh

Edinburgh, United Kingdom

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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.)
  • 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

Treatment and study plan

Stepped hyperinsulinaemic-hypoglycaemic clamp study

Procedure

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 pump

Device

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

Other names: Tandem t:slim x2 with Control IQ technology

Continuous Glucose Monitor

Device

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.

Other names: Dexcom G6

Low carbohydrate diet

Other

30-40g of carbohydrate per main meal portion.

Blinded continuous glucose monitor

Device

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.

Other names: Dexcom G6

Stable isotope studies- D2 Glucose and D5 Glycerol

Procedure

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.

Primary outcomes

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

    Time frame: Clamp 1 at baseline and clamp 2 at 8 months

    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.

Secondary outcomes

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

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

    Percentage time spent in target glycaemic range.

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

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

    Percentage of time spent below the target glycaemic range

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

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

    Percentage of time spent above the target glycaemic range

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

    Time frame: Clamp 1 at baseline and clamp 2 at 8 months

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

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

    Time frame: Clamp 1 at baseline and clamp 2 at 8 months

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

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

    Time frame: Clamp 1 at baseline and clamp 2 at 8 months

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

  7. Endogenous Glucose Production

    Time frame: Clamp 1 at baseline and clamp 2 at 8 months

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

  8. HbA1c

    Time frame: Baseline (study entry) endpoint (8 months)

    Delta HbA1c from baseline to study endpoint.

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

    Time frame: Baseline (study entry) endpoint (8 months)

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

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

    Time frame: Baseline (study entry) endpoint (8 months)

    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.

  11. Change in Fear of Hypoglycaemic

    Time frame: Baseline (study entry) endpoint (8 months)

    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.

  12. Change in Confidence of Managing Hypoglycaemia

    Time frame: Baseline (study entry) endpoint (8 months)

    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.

  13. Hypoglycaemia Awareness

    Time frame: Clamp 1 - study entry, clamp 2 - 8 months

    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.

  14. Trial Making Test

    Time frame: Clamp 1- study entry, clamp 2 - 8 months

    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.

  15. Digit Span Test

    Time frame: Clamp 1- study entry, clamp 2 - 8 months

    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.

  16. Digit Symbol Substitution Test

    Time frame: Clamp 1- study entry, clamp 2 - 8 months

    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.

  17. Four Choice Reaction Time Test

    Time frame: Clamp 1- study entry, clamp 2 - 8 months

    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.

Sponsors and collaborators

Lead sponsor

University of Edinburgh

Other

Collaborators

  • DexCom, Inc.
  • NHS Lothian
  • Tandem Diabetes Care, Inc.
  • The Leona M. and Harry B. Helmsley Charitable Trust

Registry information

Official study 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?

Important dates

Study start
2021
Primary completion
2023
Study completion
2025
First posted
Nov 3, 2020
Registry last updated
Jan 28, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.