G. Multari

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]

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.

Genetic prediction of type 1 diabetes in a population with low frequency of HLA risk genotypes and low incidence of the disease (the DIABFIN study)

To develop a sensitive, specific screening strategy for predicting genetic risk for type 1 diabetes mellitus (T1DM) in the low‐incidence continental Italian population, and to define with this tool, a cohort of high‐to‐moderate risk infants for an immunological follow‐up study aimed at identifying environmental risk factors for T1DM.

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.

Autoantibody negative new onset type 1 diabetic patients lacking high risk HLA alleles in a caucasian population: are these type 1b diabetes cases?

In Caucasians, a small number of Type 1 diabetic patients do not show evidence of humoral islet autoimmunity at disease onset, at least with common screening procedures. In African– and Hispanic–American diabetic children at time of diagnosis, many show no evidence of autoimmunity but have an atypical clinical form of the disease. According to the recent American Diabetes Association classification, this subgroup of autoantibody negative patients is referred to as Type 1b diabetic subjects. In the present study, a homogeneous Caucasian Type 1 diabetic clinic‐based cohort has been evaluated at diagnosis using a large panel of diabetes‐related antibodies and then characterized for various genetic features in order to identify newly diagnosed Type 1 diabetics who are potentially autoantibody negative, i.e. possibly referrable to as idiopathic Type 1b diabetes.

123I-Interleukin-2 Scintigraphy: A New Approach to Assess Disease Activity in Autoimmunity

Several human chronic inflammatory diseases, such as organ specific autoimmune diseases, are characterized by a chronic, slowly progressing, mononuclear cell infiltration of the target organ with little increase of vascular permeability. This infiltration can precede the onset of clinical symptoms by several months or years. Tissue biopsies may not be easily applicable to every organ and may poorly represent the condition of the whole organ particularly in inflammatory bowel diseases and in type 1 diabetes (IDDM). Thus, the possibility to detect the presence and extent of mononuclear cell infiltration in vivo by simple scintigraphy may be of considerable clinical utility for diagnosis and followup of several chronic inflammatory diseases. Immunohistochemical studies of tissue biopsies in several chronic inflammatory diseases have revealed that the target tissue is infiltrated by mononuclear cells (mainly T-lymphocytes) and that 10-50% of these cells express interleukin-2 receptors (IL2R) as a sign of cell activation /1-5Λ We previously described the labeling of IL2 with I and its specificity for the in vivo detection of pancreatic mononuclear cell infiltration in two animal models of autoimmune type 1 diabetes, the Bio Breeding/Worcester (BB/W) rat 161 and the non-obese diabetic (NOD) mouse 111. In this study we describe for the first time the use of I-IL2 scintigraphy for the non-invasive evaluation of disease activity and extent in patients with several different chronic inflammatory diseases.

Anti-Ganglioside Antibodies in New Onset Type 1 Diabetic Patients and High Risk Subjects

Insulin dependent (type 1) diabetes mellitus appears to be a genetically determined autoimmune disease. Gangliosides have been implicated in type 1 diabetes as antigenic determinants recognized by islet cell antibodies (ICA) and shown to be able to modulate autoimmune phenomena in experimental diabetes. In order to explore in type 1 diabetes the humoral immune reactivity against gangliosides, taking into account their pancreatic localization and molecular characteristics, antibodies to gangliosides GM3, GM2, GM1, GD3, GD1a, GD1b, and GT1b have been investigated in sera from new onset type 1 diabetics and relatives of type 1 diabetic patients with or without insulin (CIAA) and/or islet cell autoantibodies. Using a purposefully designed sensitive ELISA method we found that presence of antibodies directed against the pacreatic disialo-ganglioside GD3 in a significant percentage of newly diagnosed type 1 diabetics (p < 0.001 vs normal controls) but not in CIAA and/or ICA positive relatives of type 1 diabetics. These findings confirm the involvement of gangliosides in autoimmune phenomena related to type 1 diabetes and suggest disialo-ganglioside GD3 as target of a humoral immune response associated with the onset of insulin-dependent diabetes.

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.