Longitudinal Study of the GLUcagon REsponse to Hypoglycemia in Children and Adolescents With New-onset Type 1 DIAbetes

NCT ID: NCT06770621

Last Updated: 2025-01-13

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 1000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-25
• Study Completion Date: 2025-10-25

Brief Summary

The GLUREDIA study investigates the counter-regulatory response (CRR) during hypoglycemia in children with type 1 diabetes (T1D). Hypoglycemia can lead to severe symptoms, but is normally counteracted by CRR, corresponding to the secretion of hormones to maintain normoglycemia. Hypoglycemia is common in T1DM but some patients develop severe hypoglycemia as a result of CRR dysfunction. Despite several studies in adults, the presence of CRR dysfunction remains unpredictable and not well understood. The objective of GLUREDIA is therefore to describe and predict the evolution of CRR in children with T1DM.

Conditions

Severe Hypoglycemia; Type1diabetes

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

To investigate the evolution of pancreatic α-cell function. (WP1)

Regular clinical and biological monitoring will be conducted during this period, as well as four insulin-induced hypoglycemia (IIH) tests. Hormones and other blood parameters will be measured, and an analysis of the genome, proteome, and micro-RNAs (miRs) will be performed during these IIH tests and throughout the biological monitoring. The primary goal of this study is to find a correlation between the patient's phenotype and the various biological results obtained, mainly blood biomarkers, in order to subsequently determine models to predict the state of pancreatic α-cell function in the first months post-diagnosis.

Group Type: EXPERIMENTAL

Insulin-induced hypoglycemia test

Intervention Type: DIAGNOSTIC_TEST

For these tests, multiple blood samples will be collected during insulin-induced hypoglycemia (stage 1 hypoglycemia is defined as a blood glucose level below 70 mg/dL, while stage 2 corresponds to values below 54 mg/dL). The tests will be conducted on patients who have fasted for at least 12 hours and will be supervised by a medical staff member trained to manage severe hypoglycemia.

Conduct an assessment of the management of severe hypoglycemia. (WP2)

Study of glycemic variations collected by the continuous glucose monitoring sensor in the days preceding a severe hypoglycemia. The aim of this analysis is to identify a specific glycemic profile in patients in the days leading up to severe hypoglycemia in order to better anticipate such events.

Group Type: ACTIVE_COMPARATOR

Observation-questionnaire

Intervention Type: OTHER

only the answer to a questionnaire

Evaluate the α-cell function in first-degree relatives of patients with type 1 diabetes. (WP3)

In this cohort of relatives, the investigators will evaluate the function of pancreatic α-islets and the counter-regulation mechanism. This evaluation will have two main objectives. The first objective will be to compare this counter-regulation mechanism between individuals without type 1 diabetes and patients with type 1 diabetes. The second objective is to determine whether the dysfunction of the counter-regulation mechanism in diabetic patients is solely due to type 1 diabetes or if there is a familial component to this dysfunction.

Group Type: EXPERIMENTAL

Insulin-induced hypoglycemia test

Intervention Type: DIAGNOSTIC_TEST

For these tests, multiple blood samples will be collected during insulin-induced hypoglycemia (stage 1 hypoglycemia is defined as a blood glucose level below 70 mg/dL, while stage 2 corresponds to values below 54 mg/dL). The tests will be conducted on patients who have fasted for at least 12 hours and will be supervised by a medical staff member trained to manage severe hypoglycemia.

Characterize the glycemic profile and α-cell function. (WP4)

The aim is to assess residual function in patients with pancreatic disease, the phenomenon of counter-regulation and its impact on carbohydrate metabolism. To this end, IIH tests will be carried out in these patients, during which blood samples will be taken as in patients with type 1 diabetes (see above). This group of patients will also serve as a control group for the study of our diabetic patients.

Patient with : exocrine dysfunction of the pancreas either as a consequence of cystic fibrosis or as a consequence of (sub)total pancreatectomy.

Group Type: EXPERIMENTAL

Insulin-induced hypoglycemia test

Intervention Type: DIAGNOSTIC_TEST

For these tests, multiple blood samples will be collected during insulin-induced hypoglycemia (stage 1 hypoglycemia is defined as a blood glucose level below 70 mg/dL, while stage 2 corresponds to values below 54 mg/dL). The tests will be conducted on patients who have fasted for at least 12 hours and will be supervised by a medical staff member trained to manage severe hypoglycemia.

Evaluate the phenomenon of counter-regulation in patients with proven growth hormone. (WP5)

These patients will serve as control groups for our GLUREDIA study to assess counter-regulation in our diabetic patients.

Patient with : groth hormone or adrenal hormone deficiency and in healthy patients with no proven hormone deficiency.

Group Type: ACTIVE_COMPARATOR

Insulin-induced hypoglycemia test

Intervention Type: DIAGNOSTIC_TEST

For these tests, multiple blood samples will be collected during insulin-induced hypoglycemia (stage 1 hypoglycemia is defined as a blood glucose level below 70 mg/dL, while stage 2 corresponds to values below 54 mg/dL). The tests will be conducted on patients who have fasted for at least 12 hours and will be supervised by a medical staff member trained to manage severe hypoglycemia.

Study the link between the clinical characteristics of diabetic patients and their genome (WP6)

For each participant, the investigators will study their clinical history and the evolution of their glycemic parameters from diagnosis to the date they agreed to take part in the study (retrospective analysis). Next, each patient's exome will be analyzed from a blood tube taken during a consultation following agreement to take part in the study. With these analyses, the investigators hope to gain a better understanding of the clinical course of our diabetic patients and their risk of severe hypoglycemia.

Group Type: EXPERIMENTAL

Biological sample once

Intervention Type: OTHER

The exome of each patient will then be analyzed from the blood sample taken beforehand.

Evaluation of the circadian rhythm of glucagon (WP7)

After recruitment, each participant will complete a questionnaire assessing their sensitivity to hypoglycemia. Based on their responses and phenotype, participants will be divided into two cohorts for analysis. Subsequently, a glucagon profile will be established for each participant through quarterly consultations involving blood samples taken by a pediatric nurse.

Group Type: EXPERIMENTAL

Glucagon profile

Intervention Type: DIAGNOSTIC_TEST

The subject must fast before the consultation and follow a specific diet the day before; after an initial blood draw (P1), the patient will have breakfast and take any required insulin, followed by two additional blood draws 1.5 hours after breakfast (P2) and 1.5 hours after P2 (P3)

Interventions

Insulin-induced hypoglycemia test

For these tests, multiple blood samples will be collected during insulin-induced hypoglycemia (stage 1 hypoglycemia is defined as a blood glucose level below 70 mg/dL, while stage 2 corresponds to values below 54 mg/dL). The tests will be conducted on patients who have fasted for at least 12 hours and will be supervised by a medical staff member trained to manage severe hypoglycemia.

Intervention Type: DIAGNOSTIC_TEST

Glucagon profile

The subject must fast before the consultation and follow a specific diet the day before; after an initial blood draw (P1), the patient will have breakfast and take any required insulin, followed by two additional blood draws 1.5 hours after breakfast (P2) and 1.5 hours after P2 (P3)

Intervention Type: DIAGNOSTIC_TEST

Biological sample once

The exome of each patient will then be analyzed from the blood sample taken beforehand.

Intervention Type: OTHER

Observation-questionnaire

only the answer to a questionnaire

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• De novo type 1 diabetic patient, as per ISPAD criteria;
• Symptoms of hyperglycemia: polyuria-polydipsia-amaigrin +/- Acido ketosis.
• Fasting blood glucose ≥126 mg/dL AND/OR blood glucose ≥200 mg/dL at 120 minutes of an OGTT AND/OR HbA1c ≥6.5% AND/OR a patient with symptoms of hyperglycemia/hyperglycemic crisis (see 8. a. 2.) with random blood glucose ≥200 mg/dL.

Presence in serum of one or more anti-islet autoantibodies (anti-insulin, anti-IA2, anti-GAD65, anti-ZnT8)

• Patients aged between 2 and 30 years
• Minimum weight: 17 kg (for blood samples)
• Male - female patients
• Free, written and oral consent.

• De novo type 1 diabetic patient, as per ISPAD criteria;
• Symptoms of hyperglycemia: polyuria-polydipsia-amaigrin +/- Acido ketosis.
• Fasting blood glucose ≥126 mg/dL AND/OR blood glucose ≥200 mg/dL at 120 minutes of an OGTT AND/OR HbA1c ≥6.5% AND/OR a patient with symptoms of hyperglycemia/hyperglycemic crisis (see 8. a. 2.) with random blood glucose ≥200 mg/dL.
• Presence in serum of one or more anti-islet autoantibodies (anti-insulin, anti-IA2, anti-GAD65, anti-ZnT8)
• Patients aged between 2 years and 18 years (<18 years).
• Male - female patients
• Free, written and oral consent.

• Adult older than 18 years.
• Absence of blood marker of diabetes (Absence of antibodies, HbA1C <6.5%, C-peptide > 0.18 nmol/L, Fasting blood glucose < 100 mg/dL, blood glucose at any time < 200 mg/dL).
• Be a first-degree relative with a patient being followed for diabetes (meeting ISPAD criteria).
• Male - Female
• Free written and oral consent

Cohort of patients followed for cystic fibrosis:

• Pediatric patient between 2 and 18 years of age.
• Diagnosed with cystic fibrosis with impaired pancreatic endocrine function.
• Presents glucose homeostasis disorders (regular hypo/hyper-glycemia).
• Male - female patient
• Free, written and oral consent

Cohort of patients with (sub)total pancreatectomy:

• Pediatric patients between 2 and 18 years of age.
• Follow-up for total pancreatectomy or caudal pancreatectomy
• Presents disorders of carbohydrate homeostasis (regular hypo-/hyper-glycemia)
• Male - female patient
• Free, written and oral consent

• Patient who has undergone insulin testing due to suspected growth hormone deficiency or adrenal insufficiency or hypopituitarism.
• Patients between the ages of 2 years and 18 years (<18 years).
• Male - female patient.
• Free written and oral consent.

• Type 1 diabetic patient, as per ISPAD criteria;
• Symptoms of hyperglycemia: polyuria-polydipsia-amaigrin +/- Acido ketosis.
• Fasting blood glucose ≥126 mg/dL AND/OR blood glucose ≥200 mg/dL at 120 minutes of an OGTT AND/OR HbA1c ≥6.5% AND/OR a patient with symptoms of hyperglycemia/hyperglycemic crisis (see 8. a. 2.) with random blood glucose ≥200 mg/dL.
• Presence in serum of one or more anti-islet autoantibodies (anti-insulin, anti-IA2, anti-GAD65, anti-ZnT8)
• Patients aged between 2 and 18 years (<18 years).
• Male - female patients
• Free, written and oral consent.

• De novo type 1 diabetic patient, as per ISPAD criteria;
• Symptoms of hyperglycemia: polyuria-polydipsia-amaigrin +/- Acido ketosis.
• Fasting blood glucose ≥126 mg/dL AND/OR blood glucose ≥200 mg/dL at 120 minutes of an OGTT AND/OR HbA1c ≥6.5% AND/OR a patient with symptoms of hyperglycemia/hyperglycemic crisis (see 8. a. 2.) with random blood glucose ≥200 mg/dL.
• Presence in serum of one or more anti-islet autoantibodies (anti-insulin, anti-IA2, anti-GAD65, anti-ZnT8)
• Patients aged between 2 and 18 years
• Minimum weight: 17 kg (for blood samples)
• Male - female patients
• Free, written and oral consent.

Exclusion Criteria

• Child under 2 years of age.
• Taking treatments interfering with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Presence of newly diagnosed (within 1 month) celiac disease (diagnosed on pathological duodenal biopsy) at inclusion.
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD.
• Hepatic, renal or adrenal insufficiency.
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Epileptic patient
• Absence of anti-islet autoantibodies.
• Dysmorphia with suspicion of underlying genetic syndrome.
• Participation in another study in the previous 3 months, with administration of blood derivatives or potentially immunomodulating treatments.

WP2 :

• Child under 2 years of age.
• Taking treatments that interfere with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Presence of newly diagnosed (within 1 month) celiac disease (diagnosed on pathological duodenal biopsy) at inclusion.
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD.
• Hepatic, renal or adrenal insufficiency.
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Absence of anti-islet autoantibodies.
• Dysmorphia with suspected underlying genetic syndrome.
• Participation in another study within the previous 3 months with administration of blood derivatives or potentially immunomodulatory treatments.

WP3 :

• Taking treatments that interfere with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Presence of newly diagnosed (within 1 month) celiac disease (diagnosed on pathological duodenal biopsy) at inclusion.
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD.
• Hepatic, renal or adrenal insufficiency.
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Ischemic cardiomyopathy
• Pregnant participant
• Epileptic patient

WP4 :

• Child under 2 years of age.
• Body weight less than 17 kg.
• Taking treatments that interfere with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Presence of newly diagnosed (within 1 month) celiac disease (diagnosed on pathological duodenal biopsy) at inclusion.
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD.
• Hepatic, renal or adrenal insufficiency.
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Dysmorphia with suspected underlying genetic syndrome.
• Participation in another study within the last 3 months, with administration of blood derivatives or potentially immunomodulatory treatments.

WP5 :

• Child under 2 years of age.
• Body weight less than 17 kg.
• Taking treatments that interfere with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Presence of newly diagnosed (within 1 month) celiac disease (diagnosed on pathological duodenal biopsy) at inclusion.
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD..
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Participation in another study within the last 3 months, with administration of blood derivatives or potentially immunomodulatory treatments.

WP6 :

• Child under 2 years of age.
• Taking treatments interfering with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD.
• Hepatic, renal or adrenal insufficiency.
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Epileptic patient
• Dysmorphia with suspicion of underlying genetic syndrome.
• Participation in another study in the previous 3 months, with administration of blood derivatives or potentially immunomodulating treatments.

WP7 :

• Child under 2 years of age.
• Taking treatments interfering with insulin secretion and sensitivity (e.g. sulfonylureas, diazoxide, somatostatin, methylxanthine derivatives, corticosteroids, biguanide, incretins).
• Presence of newly diagnosed (within 1 month) celiac disease (diagnosed on pathological duodenal biopsy) at inclusion.
• Autoimmune/autoinflammatory disease (other than type 1 diabetes) or active malignancy present at inclusion.
• Obesity defined as a BMI with a z-score >+3 SD.
• Hepatic, renal or adrenal insufficiency.
• History of bone marrow transplantation.
• History of diabetes after hemolytic-uremic syndrome.
• Epileptic patient
• Absence of anti-islet autoantibodies.
• Dysmorphia with suspicion of underlying genetic syndrome.
• Participation in another study in the previous 3 months, with administration of blood derivatives or potentially immunomodulating treatments.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The Leona M. and Harry B. Helmsley Charitable Trust

OTHER

Sponsor Role: collaborator

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Philippe Lysy, Pr

Role: PRINCIPAL_INVESTIGATOR

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Locations

Clinique Universitaires Saint Luc

Brussels, Woluwe-saint-lambert, Belgium

Site Status: RECRUITING

Countries

Belgium

Central Contacts

Philippe Lysy, Pr

Role: CONTACT

antoine.harvengt@saintluc.uclouvain.be

027641370 ext. +32

Antoine Harvengt, Dr

Role: CONTACT

antoine.harvengt@saintluc.uclouvain.be

027641370 ext. +32

Facility Contacts

Philippe Lysy, Pr

Role: primary

philippe.lysy@saintluc.uclouvain.be

027641370 ext. +32

Other Identifiers

2022/02FEV/043

Identifier Type: -

Identifier Source: org_study_id