Immune Biomarkers of Residual Beta-cell Mass in Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): Meal Test
Intervention type(s): Other
Intervention description(s): 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.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Antibodies; Beta cells; C-peptide; GAD; Glucose; Glycemia; Insulin; Meal test; Pancreas; Proinsulin,; T lymphocytes