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

Pozzilli, Paolo; Pitocco, Dario; Visalli, N; Cavallo, Maria Gisella; Buzzetti, Raffaella; Crinò, Antonino; Spera, S.; Suraci, C; Multari, G; Cervoni, M.; Bitti, Maria Luisa Manca; Matteoli, M. C.; Marietti, G.; Ferrazzoli, Federica; Faldetta, Maria R. Cassone; Giordano, Carla; Sbriglia, M S; Sarugeri, Elena; Ghirlanda, Giovanni

doi:10.1007/s001250051482

Cited by 199 publications

(127 citation statements)

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“…It was therefore not possible to track modifications induced in these pathogenic T-cell populations. In more recent years, insulin B [15][16][17][18][19][20][21][22][23] and isletspecific glucose-6-phophatase catalytic subunit-related protein (IGRP) 206-214 have emerged as major epitopes targeted by autoreactive CD8 + T cells [9]. Diabetes is induced when T-cell clones recognizing these sequences are transferred into healthy mice [10,11] or when transgenic T cells are primed by these epitopes in vivo [12,13].…”

Section: Introductionmentioning

confidence: 99%

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

2012

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Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-weekold NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8 + T cells recognizing the immunodominant epitopes insulin B 15-23 and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) [206][207][208][209][210][211][212][213][214] . Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high-but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials.Keywords: Insulin r NOD mouse r Prevention r T cells r Type 1 diabetes IntroductionType 1 diabetes (T1D) is an autoimmune disease in which failures in central and peripheral tolerance mechanisms lead to T-cellmediated destruction of insulin-producing β cells. Several β-cell Ags have been identified, among which insulin and its precursor (pre)proinsulin ((pre)PI) are major targets of islet-reactive T cells, both in humans [1] and in NOD mice [2]. This led to the Correspondence: Dr. Roberto Mallone e-mail: roberto.mallone@inserm.fr hypothesis that subcutaneous insulin administration could prevent disease, the rationale of which is twofold. First, insulin administration could induce a state of "β-cell rest" that would make β cells less vulnerable to metabolic stress, apoptosis [3], and possibly to immune-mediated destruction [4]. Second, repeated subcutaneous insulin injections could act as a vaccination protocol potentially restoring immune tolerance [5]. The relative role of these two putative mechanisms remains unsettled.Studies in the NOD mouse showed that subcutaneously administered insulin, started prior to disease development, is capable of preventing insulitis and diabetes [6]. This observation prompted the Diabetes Prevention Trial-Type 1 (DPT-1) [7] Eur. J. Immunol. 2012. 42: 1553-1561 developing disease [8]. However, both trials were unsuccessful, as no difference in T1D incidence was observed between insulinand placebo-treated individuals [7,8].It is still not clear why this translation from animal studies to human clinical trials fail...

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Section: Introductionmentioning

confidence: 99%

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

2012

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“…In our own trial [14], as well as in the French trial of Chaillous et al [15], the administration of oral insulin in addition to standard treatment with subcutaneous insulin failed to demonstrate a beneficial effect on residual beta cell function as assessed by C-peptide secretion.…”

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confidence: 54%

“…The data presented show that after 1 year of treatment with oral insulin, relevant immunological changes are observed in terms of a Th2/Th3 polarisation of the cytokine pattern and a Th2-like antibody response. However, previously reported metabolic data from the IMDIAB VII trial showed that this treatment has no effect on residual beta cell function, since C-peptide levels, insulin requirements and glycated haemoglobin levels were comparable during follow-up in patients receiving oral insulin or placebo in addition to intensive insulin therapy [14]. A different study also found no differences between treatment groups in terms of C-peptide levels and antibody responses to different antigens, including insulin, islet cell cytoplasmic antigen, GAD and islet antigen 2 [15].…”

Section: Discussionmentioning

confidence: 92%

“…Cytokine and/or insulin antibody measurements were studied in a total of 36 patients with Type 1 diabetes who were participating in the Immunotherapy Diabetes (IMDIAB) VII trial [14]. Venous blood samples were collected for assessment of cytokines from 20 of these patients at entry and after 12 months of treatment with either oral insulin (n=9, mean age 13.5±6.1 years) or placebo (n=9, mean age 16.2±10.4 years) [11].…”

Section: Methodsmentioning

confidence: 99%

“…Based on these observations, two double-blind trials were designed to assess the effect of oral insulin administration on the induction of immune tolerance in patients with recent onset Type 1 diabetes [14,15]. In our own trial [14], as well as in the French trial of Chaillous et al [15], the administration of oral insulin in addition to standard treatment with subcutaneous insulin failed to demonstrate a beneficial effect on residual beta cell function as assessed by C-peptide secretion.…”

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confidence: 93%

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Cytokine profile and insulin antibody IgG subclasses in patients with recent onset Type 1 diabetes treated with oral insulin

et al. 2004

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Aims/hypothesis. Tolerance to orally administered antigens may be generated through the induction of T helper cell type 2 and 3 (Th2/Th3) regulatory cells. We previously reported that treatment of recent onset Type 1 diabetes with oral insulin had no effect on residual beta cell function. The aim of this study was to evaluate whether this treatment produces a deviation in the immune response, with polarisation of the cytokine pattern and the induction of a Th2-like antibody response. Methods. Mononuclear cells were collected from a total of 20 patients with Type 1 diabetes before and after 12 months of treatment with oral insulin (n=11) or placebo (n=9). Following stimulation of the cells with insulin or phytohaemagglutinin, levels of Th2 and Th3 cytokines (including TGF-β, IFN-γ, IL-4 and IL-5) in the culture supernatants were assessed by ELISA. In addition, levels of total and specific insulin antibody IgG subclasses were measured by radioimmunoassay in serum samples drawn from 33 patients with Type 1 diabetes before and after 3, 6 and 12 months of therapy with oral insulin (n=18) or placebo (n=15). Results. After 12 months of treatment, the release of TGF-β was significantly higher in patients who received oral insulin compared with those who received placebo (p=0.025 and p=0.006 for lymphocytes challenged with insulin and phytohaemagglutinin respectively). The two groups had similar levels of IL-4 and IL-5 both at baseline and after 12 months of treatment. The release of IFN-γ was markedly reduced in patients treated with oral insulin compared with those who received placebo at the 12-month follow-up. Circulating levels of IgG1 and IgG3 subclasses directed against insulin were significantly lower in the oral insulin group than in the placebo group after 12 months of treatment (p=0.05 for IgG1 and p=0.014 for IgG3). Conclusions/interpretation. The increased TGF-β release observed in patients treated with oral insulin suggests that a regulatory response can be induced in vivo by this treatment. The lower levels of insulin antibody IgG1 and IgG3 subclasses present in patients exposed to oral insulin are consistent with a Th2 deviation of the immune response. The failure of oral insulin treatment to provide any measurable clinical benefit may be due to the timing of treatment initiation.

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Toward Primary Prevention of Type 1 Diabetes

Skyler

2015

JAMA

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

Cited by 199 publications

References 11 publications

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

Cytokine profile and insulin antibody IgG subclasses in patients with recent onset Type 1 diabetes treated with oral insulin

Toward Primary Prevention of Type 1 Diabetes

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