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

Not Applicable

Recruiting

• Conditions: Severe Hypoglycemia; Type1diabetes

• Registration Number: NCT06770621
• Lead Sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2022-05-25
• Study First Submitted: 2024-07-25
• Status Verified: 2025-01
• Study First Submitted QC: 2025-01-07
• Last Update Submitted: 2025-01-07
• Study First Posted: 2025-01-13
• Last Update Posted: 2025-01-13
• Primary Completion: 2025-10-25
• Study Completion: 2025-10-25

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1000

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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
To investigate the evolution of pancreatic α-cell function. (WP1)	18 months per patient	Regular clinical and biological monitoring will be performed during this period as well as four insulin-induced hypoglycemia (IIH) tests.
To evaluate the presence of blood biomarkers that correlate with the evolution of α-cell function. (WP1)	18 months per patient	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.

Secondary Outcome Measures

Name	Time	Method
Conduct an assessment of the management of severe hypoglycemia. (WP2)	Baseline	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)
Evaluate the α-cell function in first-degree relatives of patients with type 1 diabetes. (WP3)	Baseline	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)
Characterize the glycemic profile and α-cell function. (WP4)	Baseline	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)
Evaluate the phenomenon of counter-regulation in patients with proven growth hormone. (WP5)	Baseline	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)
Study the link between the clinical characteristics of diabetic patients and their genome (WP6)	Baseline	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)
Evaluation of the circadian rhythm of glucagon (WP7)	Baseline	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)

Trial Locations

Locations (1)

Clinique Universitaires Saint Luc; 🇧🇪 Bruxelles, Woluwe-saint-lambert, Belgium