Immune Biomarkers of Residual Beta-cell Mass in Type 1 Diabetes (IMMADIAB)

July 31, 2017 updated by: Assistance Publique - Hôpitaux de Paris

There is currently no imaging technique allowing to directly visualize and measure pancreatic beta-cell mass. Consequently, the best parameter to estimate this mass is the insulin (and its C-peptide byproduct) that residual beta cells are able to produce. This insulin secretion is measured during a meal test, before and at different times after drinking a standardized quantity of nutrients. However, this test is cumbersome (lasting 3 h, with blood samples taken every 30 minutes) and it holds poor sensitivity, probably insufficient to detect very few residual beta cells. Nevertheless, these few residual cells can improve glycemic control and can be instrumental for the clinical efficacy of immune and/or regenerative therapies.

We hypothesize that residual beta cells may not only represent the remaining insulin secretory capacity, but also the antigenic load capable of stimulating beta-cell-reactive T lymphocytes. The disappearance of these T lymphocytes from circulating blood over time may thus be correlated with beta-cell loss. Measuring beta-cell-reactive T-cell responses may therefore provide simple and sensitive immune surrogate markers of residual insulin secretion. Other surrogate markers may be obtained by measuring urinary C peptide or residual secretion of the counter-regulatory hormone glucagon.

The main objectives of this study are:

  1. To evaluate the correlation between beta-cell-reactive T-cell responses and residual insulin secretion.
  2. To evaluate the correlation between the residual insulin secretion measured by serum C peptide and by urinary C peptide.
  3. To evaluate the correlation between the residual insulin and glucagon secretion.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Type 1 Diabetes (T1D) displays an average 4% annual increase in incidence in most Western countries, particularly in children and young adults. As it requires life-long treatments and it carries significant risks of hypoglycemic and long-term micro- and macrovascular complications, it is a leading cause of disability and public health expenditure.

T1D is an autoimmune disease which comprises humoral responses (antibody-producing B lymphocytes) and cellular responses (T lymphocytes). However, antibodies are merely disease markers and do not play any major pathogenic role. Rather, T1D is caused by an abnormal recognition of beta-cell epitopes by T lymphocytes. This recognition leads to destruction of pancreatic insulin-secreting beta cells, hence the need for lifelong insulin treatment. However, beta-cell destruction is rarely complete at the time of T1D onset.

The hypothesis under testing is that the residual beta-cell mass may represent not only the endogenous insulin secretory capacity, but also the antigenic load capable of maintaining activation of autoreactive T lymphocytes. In other words, the disappearance of beta-cell-reactive T-cell responses over time may be correlated with beta-cell loss. Measurement of these T-cell responses may thus provide surrogate immune markers of residual beta cells.

The primary objective is to evaluate the correlation between residual insulin secretion and T-cell responses directed against beta-cell antigens.

The secondary objectives are to evaluate the correlation between residual insulin secretion estimated by serum and urine C-peptide measurement; and to evaluate the correlation between residual insulin and glucagon secretion.

The ImMaDiab study is a cohort-based investigation with blood sample collection. Both new-onset T1D children and adults will be recruited. Insulin secretion will be stimulated by a standardized meal test. Following T1D diagnosis, blood and urine samples will be collected every 6 months during 30 months in order to measure serum and urine C peptide, glucagon and T-lymphocyte responses against selected beta-cell antigens.

Study Type

Interventional

Enrollment (Actual)

156

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75014
        • INSERM U1016 - DeAR Lab Avenir, Hôpital Cochin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 60 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Pre-inclusion criteria :

  • children 6-18 years old;
  • adults 19-60 years old;
  • patients with a likely diagnosis of T1D, defined by an hyperglycaemia with ketonuria and/or weight loss ≥5% in the last 6 months, requiring insulin therapy.

Inclusion criteria:

  • presence of serum anti-GAD antibodies; and/or
  • presence of serum anti-IA-2 antibodies; and/or
  • for children, presence of serum IAA antibodies; and/or
  • presence of T-cell autoimmune responses;
  • meal test feasible within 10 weeks of diagnosis.

Exclusion Criteria:

  • recipients of solid organ or hematopoietic tissue transplantations ;
  • immunosuppressive therapies (anti-histamine agents are not included);
  • thyroid disease treated by methimazole;
  • known HIV, HBV or HCV infection;
  • known progressive cancer disease;
  • known primary immune deficiency

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Meal test
Both new-onset T1D children and adults will be recruited and followed up through 4 meal tests at 0, 6, 12 , 18, 24 and 30 months.
Other: Meal Test
Insulin secretion is stimulated by a standardized meal test. Blood and urine samples are collected in order to measure serum and urinary C peptide, glucagon and T-lymphocyte responses against selected beta-cell antigens. The meal test is performed at 0, 6, 12, 18, 24 and 30 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation between residual insulin secretion and T-cell responses against beta-cell antigens.
Time Frame: up to 18 months
To evaluate the correlation between residual insulin secretion and T-cell responses against beta-cell antigens.
up to 18 months
Correlation between residual insulin secretion and T-cell responses against beta-cell antigens.
Time Frame: up to 30 months
To evaluate the correlation between residual insulin secretion and T-cell responses against beta-cell antigens.
up to 30 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation between residual insulin secretion estimated by serum and urine C-peptide measurement.
Time Frame: at Day 1 and at 18 months
To evaluate the correlation between residual insulin secretion estimated by serum and urine C-peptide measurement.
at Day 1 and at 18 months
Correlation between residual insulin and glucagon secretion.
Time Frame: at Day 1 and at 18 months
To evaluate the correlation between residual insulin and glucagon secretion.
at Day 1 and at 18 months
Correlation between residual insulin secretion estimated by serum and urine C-peptide measurement.
Time Frame: at Day 1 and at 30 months
To evaluate the correlation between residual insulin secretion estimated by serum and urine C-peptide measurement.
at Day 1 and at 30 months
Correlation between residual insulin and glucagon secretion.
Time Frame: at Day 1 and at 30 months
To evaluate the correlation between residual insulin and glucagon secretion.
at Day 1 and at 30 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

Institut National de la Santé Et de la Recherche Médicale, France
Recherche Clinique Paris Descartes Necker Cochin Sainte Anne

Investigators

  • Study Director: Etienne LARGER, MD, PhD, Service de Diabétologie, Hôtel Dieu, AP-HP, Paris
  • Principal Investigator: Roberto MALLONE, MD, PhD, INSERM , AP-HP

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2011

Primary Completion (Actual)

May 30, 2017

Study Completion (Actual)

May 30, 2017

Study Registration Dates

First Submitted

December 10, 2012

First Submitted That Met QC Criteria

December 11, 2012

First Posted (Estimate)

December 12, 2012

Study Record Updates

Last Update Posted (Actual)

August 1, 2017

Last Update Submitted That Met QC Criteria

July 31, 2017

Last Verified

July 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • K 091101

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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