[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
In this study we compared two different doses of NA in 74 patients with duration of Type 1 diabetes <4 weeks (mean age 13 years). Patients were randomly allocated in blind to two treatment groups: 38 patients received a dose of 25 mg/kg (b.w.) of NA and 36 patients received a dose of 50 mg/kg (b.w.) of NA. Intensive insulin therapy was carried out in order to optimize metabolic control as soon as possible after diagnosis and to maintain blood glucose level as near to normal as possible. Response to therapy was monitored throughout the study by investigating the occurrence of clinical (complete) remission defined, according to the recommendations of the International Diabetes Immunotherapy Group, as restoration of normal fasting and post-prandial blood glucose without any insulin administration for more than 2 weeks. Moreover, the integrated measures of metabolic control (C-peptide, HbA(1c) and insulin dose) were analysed at 3- month intervals up to 1 year after diagnosis.
There were no significant differences in the integrated measures of metabolic control between the two NA treated groups either at onset of the disease or at each 3-month interval up to 1 year after diagnosis, although there was a tendency toward higher insulin dosages in the 50 mg NA group. No significant differences were observed in the rate of clinical remission between the two groups.
We conclude that patients with recent-onset Type 1 diabetes treated with two different doses of NA, in addition to intensive insulin therapy, show similar residual beta-cell function 1 year later. Since both doses of NA are likely to be effective in reducing beta-cell dysfunction, the smaller dose of 25 mg/kg NA would be sufficient as a higher dose may induce insulin resistance.
Diabetes/Metabolism Research and Reviews 05/1999; 15(3):181-5. DOI:10.1002/(SICI)1520-7560(199905/06)15:33.3.CO;2-8 · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Protection of residual beta cell function at the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) by intensive insulin therapy and the addition of nicotinamide (NA) has been established. The objective of this study was to evaluate the effect of a free oxygen radical scavenger such as vitamin E (Vit E) on residual beta cell function and parameters of metabolic control in patients with recent onset IDDM undergoing intensive insulin therapy.
The effect of Vit E was compared with that of NA (control group) in a randomized multicentre trial.
Eighty-four IDDM patients between 5 and 35 years of age (mean age 15.8 +/- 8.4 (s.d.) years) entered a one year prospective study. One group of patients (n = 42) was treated with Vit E (15 mg/kg body weight/day) for one year; the other group (n = 42) received NA for one year (25 mg/kg body weight/day). All patients were under intensive insulin therapy with three to four injections a day. Basal and stimulated (1 mg i.v. glucagon) C-peptide secretion, glycosylated haemoglobin and insulin dose were evaluated at diagnosis and at three-monthly intervals up to one year.
Preservation and slight increase of C-peptide levels at one year compared with diagnosis were obtained in the two treated patient groups. No statistically significant differences were observed in basal or stimulated C-peptide levels between the two groups of patients for up to one year after diagnosis. Glycosylated haemoglobin and insulin dose were also similar between the two groups; however patients receiving Vit E under the age of 15 years required significantly more insulin than NA-treated patients one year after diagnosis (P < 0.04).
Our data indicate that Vit E and NA possess similar effects in protecting residual beta cell function in patients with recent onset IDDM. Since their putative mechanism of protection on beta cell cytotoxicity is different, combination of these two vitamins may be envisaged for future trials of intervention at IDDM onset.
European Journal of Endocrinology 09/1997; 137(3):234-9. DOI:10.1530/eje.0.1370234 · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nicotinamide 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.
[Show abstract][Hide abstract] ABSTRACT: A 1-year open randomized controlled multicentre trial was carried out on 90 patients with recent onset (< 4 weeks) insulin-dependent diabetes (IDDM) to compare the effect of nicotinamide (NCT) with the combination NCT and low dose cyclosporin (CyA) on clinical remission and optimization of metabolic control during the first year from diagnosis. Three groups of patients were randomly assigned to receive for 12 months either NCT 25 mg kg−1 day−1 (n = 30) or NCT 25 mg kg−1 day−1 + CyA 5 mg kg−1 day−1 (n = 30), the latter adjusted to maintain 12 whole blood trough levels of 83 nmol l−1; a third group of patients (n = 30) receiving insulin only acted as a control group for spontaneous remission and metabolic control. Clinical remission (i.e. suspension of insulin therapy with normal metabolic parameters for more than 2 weeks according to the International Diabetes Immunotherapy Group) was achieved at 3 months in 6/30 NCT treated patients and in 1/30 NCT + CyA treated patient (p = 0.05); no remission was observed in control patients. At 6 months the number of patients achieving remission in each group was 4/29, 3/27, and 1/29, respectively (p = NS). One year after diagnosis 4/27 NCT treated, 2/25 NCT+ CyA treated but 0/28 of the control patients were in remission (NCT vs control p = 0.05). Clinical remission lasted longer (7 ± 3 SD months) in NCT treated patients than in NCT+ CyA treated or control patients (p < 0.02). In patients who did not show clinical remission, there were no significant differences in the integrated measures of metabolic control (HbA1 and C peptide) between the two groups; however, NCT+ CyA treated patients only required significantly less insulin at 12 months compared to control patients (p < 0.02). Side-effects were not observed in patients receiving NCT and were minimal in those treated with the combination of NCT+ CyA. We conclude that nicotinamide alone is a safe and effective adjunct to insulin in the early phase of IDDM to increase the rate of clinical remission and to improve integrated parameters of metabolic control.
Diabetic Medicine 01/1994; 11(1). DOI:10.1111/j.1464-5491.1994.tb00237.x · 3.06 Impact Factor