A. Crinò

No effect of oral insulin on residual beta-cell function in recent-onset Type I diabetes (the IMDIAB VII)

Aims/hypothesis. Induction of tolerance to insulin is achievable in animal models of Type I (insulin-dependent) Diabetes mellitus by oral treatment with this hormone, which can lead to prevention of the disease. In the Diabetes Prevention Trial of Type I diabetes (DPT-1), oral insulin is given with the aim of preventing disease insurgence. We investigated whether if given at diagnosis of Type I diabetes in humans, oral insulin can still act as a tolerogen and therefore preserve residual beta-cell function, which is known to be substantial at diagnosis. Methods. A double-blind trial was carried out in patients (mean age ± SD: 14 ± 8 years) with recent-onset Type I diabetes to whom oral insulin (5 mg daily) or placebo was given for 12 months in addition to intensive subcutaneous insulin therapy. A total of 82 patients with clinical Type I diabetes ( < 4 weeks duration) were studied. Basal C peptide and glycated haemoglobin were measured and the insulin requirement monitored every 3 months up to 1 year. Insulin antibodies were also measured in 27 patients treated with oral insulin and in 18 patients receiving placebo at the beginning of the trial and after 3, 6 and 12 months of treatment. Results. The trial was completed by 80 patients. Overall and without distinction between age at diagnosis, at 3, 6, 9 and 12 months baseline mean C-peptide secretion in patients treated with oral insulin did not differ from that of those patients treated with placebo. In patients younger than 15 years a tendency for lower C-peptide values at 9 and 12 months was observed in the oral insulin group. Insulin requirement at 1 year was similar between the two groups as well as the percentage of glycated haemoglobin. Finally, IgG insulin antibodies were similar in the two groups at each time point. Conclusion/interpretation. The results of this study indicate that the addition of 5 mg of oral insulin does not modify the course of the disease in the first year after diagnosis and probably does not statistically affect the humoral immune response against insulin. [Diabetologia (2000) 43: 1000–1004]

The Continuous Glucose Monitoring System (CGMS) in type 1 diabetic children is the way to reduce hypoglycemic risk

Diabetic children treated with intensive insulin therapy are showing a dangerous increase in severe hypoglycemic episodes. The Continuous Glucose Monitoring System (CGMS) allows glycemic profiles to be monitored over a 72‐h period. The aim of the present study was to evaluate whether this system is sufficiently sensitive to detect asymptomatic hypoglycemia, and to determine if its periodic application would help to minimize the hypoglycemic risk in children with type 1 diabetes mellitus (T1DM).

Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study)

SummaryNicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels (6.7±1.8 % nicotinamide vs 7.1±0.6 % placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty. We conclude that in these patients nicotinamide can be added to insulin at the time of disease diagnosis to maintain and possibly improve residual beta-cell function. However, further studies on patients diagnosed after puberty are needed to confirm whether nicotinamide can be considered an additional tool to insulin in early-onset IDDM.

A multi-centre randomized trial of two different doses of nicotinamide in patients with recent-onset Type 1 diabetes (the IMDIAB VI)

Intensive insulin therapy is the gold standard by which Type 1 diabetes is treated. In addition to this therapy, administration of nicotinamide (NA) can be beneficial. This concept is reinforced by the results of a recent meta‐analysis of the use of NA in patients with recent‐onset Type 1 diabetes.

Blood ketone bodies in patients with recent‐onset type 1 diabetes (a multicenter study)

Background:  Insulin deficiency with glucagon excess leads to the release of ketone bodies (KBs) by the liver and excretion in the urine. So far, only KB monitoring in urine has been used during assessment of children with diabetes. Currently used nitroprusside strips for urine KB detection react only with acetoacetate (AcAc) and not with the most prevalent KB moiety – 3β‐hydroxybutyrate (3HB) – that is in equilibrium with AcAc (up to 10:1 ratio).

Combination of nicotinamide and steroid versus nicotinamide in recent-onset IDDM. The IMDIAB II Study.

OBJECTIVE The aim of this study was to compare the effect of nicotinamide (NCT) alone or in combination with a cortisone-like substance, deflazacort (DFL), on the integrated parameters of metabolic control in patients with the recent-onset of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS Thirty-six patients who were diagnosed with diabetes between 5 and 35 years of age entered a randomized, double-blind, 1-year prospective study. Group A (n = 18) received NCT for 1 year (25 mg· kg–1 · day–1) plus DFL for 3 months (0.6 mg · kg–1 · day–1 in the first month, 0.3 mg · kg–1 · day–1 in the other 2 months). Group B (n = 18) received NCT for 1 year (25 mg · kg–1 · day–1) plus placebo forthe first 3 months. All patients were treated with intensified insulin therapy. RESULTS At 3 months after diagnosis, the insulin dose was significantly higher in group A compared with group B (P < 0.03) with similar HbA1 levels. Basal and stimulated C-peptide levels in group A of both adults and children were significantly higher compared with patients of group B (P < 0.05 and P <0.03, respectively). At the end of a 1-year follow-up, basal C-peptide did not differ between the two groups, although stimulated C-peptide was still significantly higher in patients of group A compared with group B (P < 0.05). Finally, insulin requirement did not differ between the two groups. CONCLUSIONS A short-term course of DFL therapy at diagnosis in addition to NCT slightly increases glucagon-stimulated but not basal β-cell function after 1 year.

Computer use, free time activities and metabolic control in patients with type 1 diabetes.

We investigated the influence of computers use on metabolic control in 115 patients with type 1 diabetes (DM1). Multiple linear regression showed that HbA1c% was not related to age, DM1 duration, TV watching or computer use but was independently and negatively related to the weekly hours spent on physical exercise.

Intradermal skin test with diabetes specific antigens in patients with type 1 diabetes

Cell mediated immune response in vitro to a number of antigens has been reported in patients with Type 1 diabetes. The aim of the present study was to develop an in vivo intradermal (delayed type hypersensitivity) skin test using antigens known to be recognized by lymphocytes of patients with Type 1 diabetes and to compare, where possible, the in vivo response to the in vitro T cell proliferation to the same antigens.

Do mutations of RAG genes have a role in human autoimmunity? The Notarangelo's hypothesis revisited

Received: 4 February 2005 Revised: 4 July 2005 Accepted: 13 July 2005 In vertebrates, the diversity of immunoglobulins and T-cell receptors (TCRs) is mediated by the recombination of genes encoding variable (V), diversity (D) and joining (J) segments through a mechanism known as V(D)J recombination [1]. This process is initiated by the lymphoid specific recombinases, RAG1 and RAG2. The biological and crucial importance of this recombination process in the development of lymphoid cells has been extensively proven. Mutations that abrogate the expression of either the RAG1 and RAG2 proteins produce an early block in lymphoid development and, as a consequence, a complete lack of circulating T and B lymphocytes occurs, resulting in severe combined immunodeficiency (SCID) [2], a disorder documented both in humans and animal models. In humans, it has been recently shown that certain mutations of RAG genes may impair, but not completely abolish, the function of recombinases. As a consequence, B cell generation and partially that of T cells is disturbed, resulting in an enigmatic type of immunodeficiency, the so-called Omenn syndrome [3]. This disorder, usually based on missense RAG genes mutations, is characterized by the production of oligoclonal, activated T lymphocytes, with a skewed Th2 profile [4]. The highly restricted heterogeneity of the T-cell repertoire of these patients implies a potential autoantigen-driven peripheral expansion of T-cell clones, as the result of the underlining defect in the lymphocyte development. The skewed profiles of TCR Vβ usage and the overexpression of certain TCR Vβ families has also been interpreted as the consequence of a superantigenic stimulation [5], a phenomenon that may also occur in Omenn syndrome. Although attractive, this pathophysiological mechanism has not been proven as yet. On the basis of these basic and clinical observations, some authors [2,4] have formulated the hypothesis that distinct, but ‘milder’ RAG mutations may exist and, if demonstrated, they could be either responsible for less severe forms of immunodeficiency or associated with human autoimmune diseases, thus enhancing the genetic predisposition to autoimmunity. It is generally believed that pathogenic autoreactive T cells are responsible for organ-specific autoimmune destruction [6]. Similar to the highly restricted TCR profile observed in Omenn syndrome, with different predominant specificities for distinct tissues, high frequencies of T cells with the TCR family Vβ7 were detected among the lymphocytes infiltrating the pancreatic islets of children, who died at the onset of type 1 diabetes (T1D) [7]. A preferential expression of certain TCR Vβ gene families was also detected in the peripheral blood lymphocytes from other patients with T1D [7]. On the basis of this background, the aim of our study was to analyse RAG genes by direct sequencing in patients affected by autoimmunity and in particular T1D [6]. We extracted genomic DNA from peripheral blood lymphocytes of 10 patients with T1D and 10 normal control individuals and amplified the coding region of RAG1 and RAG2 genes by PCR. Primers were