A two year observational study of nicotinamide and intensive insulin therapy in patients with recent onset type 1 diabetes mellitus.

BACKGROUND AND AIMS: A number of trials have evaluated residual beta-cell function in patients with recent onset type 1 diabetes mellitus (DM1) treated with nicotinamide in addition to intensive insulin therapy (IIT). In most studies, only a slight decline of C-peptide secretion was observed 12 months after diagnosis; however, no data is available on C-peptide secretion and metabolic control in patients continuing nicotinamide and IIT for up to 2 years after diagnosis. PATIENTS AND METHODS: We retrospectively analysed data from 25 patients (mean age 14.7 years +/- 5 SD) with DM1 in whom nicotinamide at a dose of 25 mg/kg b. wt. was added from diagnosis (< 4 weeks) to IIT (three injections of regular insulin at meals + one NPH at bed time) and continued for up to 2 years after diagnosis. Data were also analysed from patients (n = 27) in whom IIT was introduced at diagnosis and who were similarly followed for 2 years. Baseline C-peptide as well as insulin dose and HbA1c levels were evaluated at 12 and 24 months after diagnosis. RESULTS: In the course of the follow-up, patients on nicotinamide + IIT or IIT alone did not significantly differ in terms of C-peptide secretion (values at 24 months in the two groups were 0.19 +/- 0.24 nM vs 0.19 +/- 0.13 nM, respectively). Insulin requirement (0.6 +/- 0.3 U/kg/day vs 0.7 +/- 0.2 U/kg/day at 24 months, respectively) did not differ between the two groups. However, HbA1c was significantly lower 2 years after diagnosis in patients treated with nicotinamide + IIT (6.09 +/- 0.9% vs 6.98 +/- 0.9%, respectively, p < 0.01). No adverse effects were observed in patients receiving nicotinamide for 2 years. CONCLUSION: Implementation of IIT with the addition of nicotinamide at diagnosis continued for 2 years improves metabolic control as assessed by HbA1c. In both nicotinamide and control patients, no decline in C-peptide was detected 2 years after diagnosis, indicating that IIT preserves C-peptide secretion. We conclude that nicotinamide + IIT at diagnosis of DM1 prolonged for up to 2 years can be recommended, but longer follow-up is required to determine whether nicotinamide should be continued beyond this period.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes (the IMDIAB IV study)

OBJECTIVE: 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. DESIGN: The effect of Vit E was compared with that of NA (control group) in a randomized multicentre trial. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Adjuvant therapy in recent onset type 1 diabetes at diagnosis and insulin requirement after 2 years.

Partial recovery of beta-cell function in type 1 diabetes is common after diagnosis by intensive insulin therapy. Residual beta-cell function can be improved by other therapies. Cyclosporin (CyA) and nicotinamide (NA), alone or in combination, can preserve this function, as indicated by the parameters of metabolic control (insulin dose, HbA1C). After suspension of CyA, insulin requirement returns to control values, suggesting loss of residual beta-cell function. The effects induced by withdrawal of NA after 1 year are not known. For the first time, we studied 27 type 1 diabetes patients treated with NA for 12 months and then followed up for 1 year after discontinuance of NA. Another 25 patients treated with NA + CyA and 28 control patients were followed up similarly. Insulin requirement doubled 12 months after discontinuance of NA or NA + CyA, becoming identical to that of controls. As patients showed HbA1C values similar to control subjects, it is likely that beta-cell function deteriorated after discontinuance of therapy. As NA is safer than other agents and its effects are beneficial, longer studies are warranted to investigate NA in prolonged treatments since this compound is also being considered for prevention of type 1 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 for the 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 beta-cell function after 1 year.

Randomized trial comparing nicotinamide and nicotinamide plus cyclosporin in recent onset insulin-dependent diabetes (IMDIAB 1). The IMDIAB Study Group.

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).(ABSTRACT TRUNCATED AT 250 WORDS)