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

Longitudinal Study of the GLUcagon REsponse to Hypoglycemia in Children and Adolescents With New-onset Type 1 DIAbetes (GLUREDIA Study): Characteristics and Predictive Biomarkers.

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.

Study Overview

• Status: Recruiting
• Conditions: Type1diabetes; Severe Hypoglycemia
• Intervention / Treatment: Diagnostic test: Insulin-induced hypoglycemia test; Other: Observation-questionnaire; Other: Biological sample once; Diagnostic test: Glucagon profile

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Philippe Lysy, Pr; Phone Number: +32 027641370; Email: antoine.harvengt@saintluc.uclouvain.be
• Study Contact Backup: Name: Antoine Harvengt, Dr; Phone Number: +32 027641370; Email: antoine.harvengt@saintluc.uclouvain.be

Study Locations

• Belgium
  • Woluwe-saint-lambert
    • Bruxelles, Woluwe-saint-lambert, Belgium, 1200
      • Recruiting
      • Clinique Universitaires Saint Luc
      • Contact: Philippe Lysy, Pr; Phone Number: +32 027641370; Email: philippe.lysy@saintluc.uclouvain.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

WP1 :

• 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.

  • 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 :

• 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 years and 18 years (<18 years).
  • Male - female patients
  • Free, written and oral consent.

• Exclusion criteria:

  • 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 :

• Inclusion Criteria:

  • 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

• Exclusion criteria:

  • 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 :

• Inclusion Criteria:

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

  • Exclusion criteria:
• 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 :

• Inclusion Criteria:

  • 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.

• Exclusion criteria:

  • 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 :

• Inclusion Criteria:

  • 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.

• 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).
  • 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 :

• 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 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Diagnostic test: 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.
Active Comparator: 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.	Other: Observation-questionnaire; only the answer to a questionnaire
Experimental: 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.	Diagnostic test: 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.
Experimental: 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.	Diagnostic test: 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.
Active Comparator: 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.	Diagnostic test: 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.
Experimental: 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.	Other: Biological sample once; The exome of each patient will then be analyzed from the blood sample taken beforehand.
Experimental: 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.	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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To investigate the evolution of pancreatic α-cell function. (WP1)	Regular clinical and biological monitoring will be performed during this period as well as four insulin-induced hypoglycemia (IIH) tests.	18 months per patient
To evaluate the presence of blood biomarkers that correlate with the evolution of α-cell function. (WP1)	Regular clinical and biological monitoring will be performed during this period as well as four insulin-induced hypoglycemia (IIH) tests. Hormones and other blood parameters will be measured and genome, proteome and microRNA (miRs) analysis will be performed during the IIH tests and during the biological follow-up. The expected results are the description and prediction of CRR in the first months after T1DM.	18 months per patient

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conduct an assessment of the management of severe hypoglycemia. (WP2)	Use of a questionnaire which is sent out once per patient during a routine consultation. The analysis does not take the form of a score, but is based on the analysis of the answers to the question according to the patient's profile. (WP2)	Baseline
Evaluate the α-cell function in first-degree relatives of patients with type 1 diabetes. (WP3)	In the remaining parents, those without biological signs of (pre-)diabetes, an IIH test will be performed during which blood samples identical to those performed in patients with type 1 diabetes will be taken. (WP3)	Baseline
Characterize the glycemic profile and α-cell function. (WP4)	IIH tests will be performed in these patients during which blood samples will be taken as in patients with type 1 diabetes. This group of patients will also be a control group for the study of our diabetic patients. (WP4)	Baseline
Evaluate the phenomenon of counter-regulation in patients with proven growth hormone. (WP5)	Patients suspected of adrenal or pituitary hormone deficiency, will perform as part of their diagnosis a hypoglycemic test. Here the difference is that the investigators will add two additional tubes to each sample, to those already collected as part of the hypoglycemic test. These tubes will be used, as in the other parts, to measure hormones and other blood parameters, as well as to perform an analysis of the genome, proteome and micro-RNAs (miRs). (WP5)	Baseline
Study the link between the clinical characteristics of diabetic patients and their genome (WP6)	For each participant, the investigators will study their clinical history, the evolution of their glycemic parameters from diagnosis to the date they agree 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 inestigators hope to gain a better understanding of the clinical course of our diabetic patients and their risk of severe hypoglycemia. (WP6)	Baseline
Evaluation of the circadian rhythm of glucagon (WP7)	Each participant will complete a questionnaire assessing his or her susceptibility to hypoglycemia. A glucagonemic profile will then be established for each participant. This step, carried out during quarterly consultations, will involve blood sampling. (WP7)	Baseline

Collaborators and Investigators

• Sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Collaborators: The Leona M. and Harry B. Helmsley Charitable Trust
• Investigators: Principal Investigator: Philippe Lysy, Pr, Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2022
• Primary Completion (Estimated): October 25, 2025
• Study Completion (Estimated): October 25, 2025

Study Registration Dates

• First Submitted: July 25, 2024
• First Submitted That Met QC Criteria: January 7, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 7, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Diabetes; Hypoglycemia; Pediatric
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Hypoglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: 2022/02FEV/043

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No