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

NCT04614168 | Completed Results DMC FDA Device

• 1 other identifier: AC19163
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Type 1 Diabetes; Hypoglycemia; Hypoglycemia Unawareness; Glucagon Deficiency; Insulin Hypoglycemia; Type 1 Diabetes Mellitus With Hypoglycemia

Keywords

Type 1 diabetes; Hypoglycaemia; Hypoglycemia; Glucagon; Insulin; Low carbohydrate diet; Stable isotope

Outcome Measures

Primary Outcomes (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.

  Clamp 1 at baseline and clamp 2 at 8 months

Secondary Outcomes (17)

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

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

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

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

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

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

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

  Clamp 1 at baseline and clamp 2 at 8 months

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

  Clamp 1 at baseline and clamp 2 at 8 months

Study Arms (2)

Group 1 - Standard Care

ACTIVE COMPARATOR

This 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.

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 diet

EXPERIMENTAL

This 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.

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

Interventions

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.

Group 1 - Standard Care; Group 2- Automated insulin delivery and low carbohydrate diet

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.

Also known as: Tandem t:slim x2 with Control IQ technology

Group 2- Automated insulin delivery and low carbohydrate diet

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.

Also known as: Dexcom G6

Group 2- Automated insulin delivery and low carbohydrate diet

Low carbohydrate diet OTHER

30-40g of carbohydrate per main meal portion.

Group 2- Automated insulin delivery and low carbohydrate diet

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.

Also known as: Dexcom G6

Group 1 - Standard Care; Group 2- Automated insulin delivery and low carbohydrate diet

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.

Group 1 - Standard Care; Group 2- Automated insulin delivery and low carbohydrate diet

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The Leona M. and Harry B. Helmsley Charitable Trust: collaborator
• Tandem Diabetes Care, Inc.: collaborator
• DexCom, Inc.: collaborator
• University of Edinburgh: lead
• NHS Lothian: collaborator

Study Sites (1)

Edinburgh Royal Infirmary/University of Edinburgh

Edinburgh, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 36600427 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia; Insulin Resistance

Interventions

Insulin Infusion Systems; Diet, Carbohydrate-Restricted

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Drug Delivery Systems; Drug Therapy; Therapeutics; Infusion Pumps; Equipment and Supplies; Artificial Organs; Surgical Equipment; Diet Therapy; Nutrition Therapy; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Results Point of Contact

• Title: Prof. Shareen Forbes
• Organization: University of Edinburgh

shareen.forbes@ed.ac.uk

0131 242 6740

Study Officials

• Shareen Forbes, MBChB, PhD

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be divided into two groups using stratified sampling to match for age, sex and BMI.

Study Record Dates

• First Submitted: October 7, 2020
• First Posted: November 3, 2020
• Study Start: July 26, 2021
• Primary Completion: September 22, 2023
• Study Completion: December 26, 2025
• Last Updated: January 28, 2026
• Results First Posted: December 17, 2025

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)