Stimulated Glucagon as a Biomarker of Hypoglycemic Risk in Type 1 Diabetes

NCT05616273 | Completed DMC

• 4 other identifiers: 2021-22-5931958122/LO/0719Grant # 2012-04188
• Study Type: observational
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

Type 1 diabetes (T1D) results from destruction of insulin producing beta cells by the body's own immune system (autoimmunity) causing an individual to lose the ability to make enough insulin to control their blood sugar levels and need to have insulin injections to lower blood glucose levels. Whilst high blood sugar level is a problem for people with Type 1 diabetes, taking insulin medication to lower sugar levels, delayed meals and exercise can all result in dangerously low blood sugar levels (hypoglycaemia). The biological causes of hypoglycaemia, and ways to prevent it are poorly understood. In non-diabetic individuals, a hormone called glucagon is secreted naturally to raise blood glucose levels but it is unclear why glucagon secretion is impaired during hypoglycaemia in individuals with T1D. The aim of this prospective observational study is to test the relationship between a glucagon stimulation test and risk of hypoglycaemia in T1D. It is hoped this research will establish whether this relationship could be used as a blood test and be a clinically useful biomarker of hypoglycaemia risk and, therefore, directly inform clinical care of people with T1D, particularly those with highest risk of hypoglycaemia. Assessment of beta cell decline has traditionally relied on timed C-peptide measures following a standardised liquid meal known as the mixed meal tolerance test (MMTT). Home finger prick blood spot C-peptide measurement might be a practical, cheap, and non-invasive alternative to a MMTT and would allow regular assessment of beta cell function over time. If proven that this sample type is a robust alternative to the gold standard MMTT venous C-peptide, it would dramatically decrease the cost and participant burden of T1D research into beta cell function.

Conditions

Type 1 Diabetes; Hypoglycemia

Keywords

type 1 diabetes; autoimmune diabetes; beta cell destruction; hypoglycaemia; hyperglycaemia; glucagon; type 1 diabetes genetic risk; alpha cell

Outcome Measures

Primary Outcomes (1)

• A description of the strength and reproducibility of the relationship of post-Mixed Meal and Arginine stimulated glucagon with hypoglycaemia.

  The longitudinal stability of stimulated glucagon will be described, including its relationship with variation in hypoglycaemia frequency, and the potential to predict future hypoglycaemia. This will be be determined from post-MM \& Arginine-induced plasma glucagon levels, continuous glucose monitoring (CGM) time spent in hypoglycaemia, and self-reported hypoglycaemia episodes, hypoglycaemia fear/awareness, and fear of hypoglycaemia.

  22 months

Secondary Outcomes (3)

• Longitudinal variability of glucagon levels and its relationship to episodes of hypoglycaemia in long-duration T1D.

  22 months

• The relationship between plasma glucagon levels under basal conditions, following a stimulation (by mixed meal or arginine)

  22 months

• Home finger prick blood spot C-peptide measurement is a practical alternative to MMTT

  22 months

Study Arms (2)

MMTT Visit 1, AST Visit 2

Mixed Meal Tolerance Test (MMTT) Visit 1 and Arginine Stimulated Test (AST) Visit 2

Other: Mixed Meal Tolerance Test (MMTT); Other: Arginine Stimulation Test (AST); Other: Home Finger Prick Sample

AST Visit 1, MMTT Visit 2

Arginine Stimulated Test (AST) Visit 1 and Mixed Meal Tolerance Test (MMTT) Visit 2

Other: Mixed Meal Tolerance Test (MMTT); Other: Arginine Stimulation Test (AST); Other: Home Finger Prick Sample

Interventions

Mixed Meal Tolerance Test (MMTT) OTHER

At either Visit 1 or Visit 2, participants will be given Ensure HP or Fortisip (a drink containing the same amounts of carbohydrates, protein and fats as there would be in a meal; 6ml/kg to a max of 360mls), and have blood samples collected, to measure insulin (C-peptide), glucose, and glucagon, at specific intervals: -10, 0, 30, 60, 90, 120 minutes post meal. This test is used to measure how a participant's beta cells are working to produce insulin after a meal and to check for reactive hypoglycaemia.

AST Visit 1, MMTT Visit 2; MMTT Visit 1, AST Visit 2

Arginine Stimulation Test (AST) OTHER

At either Visit 1 or Visit 2, and Visit 3, participants will be given a dose of Arginine Hydrochloride (5 g Arginine during 1 min) by intravenous injection, and have blood samples collected to measure insulin (C-peptide), glucose, and glucagon, at specific intervals: -10, 0, 2, 5, 10, 15 and 30 minutes following the Arginine bolus injection. This test is designed primarily to test the maximum insulin secretion capacity of a participant's beta cells.

AST Visit 1, MMTT Visit 2; MMTT Visit 1, AST Visit 2

Home Finger Prick Sample OTHER

Participants will be provided with a kit to collect an optional home finger prick sample the day after each visit, and return the sample using the prepaid addressed padded envelope provided.

AST Visit 1, MMTT Visit 2; MMTT Visit 1, AST Visit 2

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

75 individuals with long duration T1D, identified from participation in the TIGI study (UK IRAS ID: 141756, REC Number: 13/SW/0312), with consent to be contacted for future research. The TIGI participants have a clinical diagnosis of T1D, were on insulin from diagnosis and, if BMI was \>30, were autoantibody positive. We will aim to recruit 50 people with undetectable C-peptide and 25 with detectable C-peptide. The selection of people with absent C-peptide allows a secondary analysis focussed on stimulated glucagon without any potential interaction with endogenous insulin secretion. It also focusses on a group of people known to be at high hypoglycaemia risk due to lack of endogenous insulin.

You may qualify if:

• Clinical diagnosis of Type 1 diabetes
• Insulin treated
• Known urine C-peptide status (using Urinary C-Peptide Creatinine Ratio \[UCPCR\], positive/negative defined by UCPCR 0.2nmol/mmol cut-off)
• Age 16-65 years inclusive
• Able and willing to provide informed consent/assent.

You may not qualify if:

• Age less than 16 year or over 65 years
• Pregnant or lactating (as this may limit blood sampling and affect T cell function)
• Any medical condition that, in the opinion of the investigator, would affect the safety of the subject's participation, or validity of results.

Sponsors & Collaborators

• University of Exeter: lead
• Royal Devon and Exeter NHS Foundation Trust: collaborator

Study Sites (1)

Royal Devon University Healthcare NHS Foundation Trust

Exeter, Devon, EX2 5DW, United Kingdom

Location

Related Publications (36)

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Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum, plasma, RNA, PBMCs at serial timepoints after a meal or intravenous stimulus.

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia; Hyperglycemia

Condition Hierarchy (Ancestors)

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

Study Officials

• Richard A Oram, MRCP (neph)

  University of Exeter

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 7, 2022
• First Posted: November 15, 2022
• Study Start: May 3, 2023
• Primary Completion: January 28, 2025
• Study Completion: September 30, 2025
• Last Updated: December 19, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data will become available 12 months after the study end.
• Access Criteria: Applications submitted via the approved data repository would be considered.

Locations

GB (1)