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

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.


Eligibility Criteria:
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.