Natalia Visalli

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.

Metabolic and immune parameters at clinical onset of insulin-dependent diabetes: A population-based study☆

The age at diagnosis of insulin-dependent diabetes mellitus (type I DM) varies between childhood and adulthood. The aim of this study was to define the immunologic and metabolic characteristics of the disease according to the age at which it is diagnosed. We evaluated the residual beta-cell function (basal and stimulated C-peptide) and frequency of two major islet cell-related autoantibodies, glutamic acid decarboxylase (GAD) and tyrosine phosphatase-like molecule (IA-2ic), at the onset of type I DM. A population-based study was performed with 235 consecutive cases of recent-onset (<4 weeks) type I DM (ages 5 to 45 years) diagnosed in the Lazio region of central Italy. Five age groups were considered: patients diagnosed between ages 5 and 7 years (n = 10), 7 and 10 years (n = 38), 10 and 17 years (n = 94), 17 and 20 years (n = 17), and 20 and 45 years (n = 76). Patients diagnosed before puberty had significantly reduced C-peptide secretion compared with patients diagnosed at a later age (P < .02). Glycosylated hemoglobin (HbA1c) did not differ at diagnosis between the different age groups. Patients diagnosed at puberty or after required significantly less insulin compared with younger patients (P < .04). GAD antibodies were found in 65% and IA-2ic antibodies in 59% of patients. GAD antibodies tended to be more frequent in patients diagnosed after age 17 compared with younger patients (P = .05), while IA-2ic antibodies were not age-related. These data suggest that (1) the extent of beta-cell damage differs between patients diagnosed before and after puberty, the process being more destructive in children less than 7 years of age, when C-peptide levels are the lowest; and (2) residual beta-cell function at diagnosis is not influenced by the presence or absence of islet cell-related antibodies. These findings have implications for trials in type I DM diagnosis aimed at protecting beta cells from end-stage destruction and in attempts to prevent the disease in susceptible individuals.

Environmental risk factors for type 1 diabetes in Rome and province

Background: In subjects genetically susceptible to type 1 diabetes, exposure to environmental factors during the gestational period, the neonatal period, and the first years of life is thought to play an important role in triggering the immune process leading to β cell destruction. Aims: To investigate risk factors for inhabitants of continental Italy. Methods: A case-control study of 150 type 1 diabetes cases and 750 control subjects (age range 6–18 years) was carried out in Rome and its province, measuring the exposure to environmental risk factors. Results: Three environmental factors were found to occur significantly more in the diabetic group than in the controls. During the mothers’ pregnancies, the one risk factor which proved to be higher in diabetics than in controls was maternal infectious disease. During the neonatal period, no risk factors associated with the disease were detected. During early life, eczema and a short duration of breast feeding (less than three months), occurred significantly more in diabetic cases than controls. Conclusion: Eczema and breast feeding for less than three months are risk factors for type 1 diabetes in a southern European population. The type, duration, and mode of treatment for infectious diseases during pregnancy need additional investigation as risk factors for type 1 diabetes.

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.

A 2-Year Pilot Trial of Continuous Subcutaneous Insulin Infusion Versus Intensive Insulin Therapy in Patients with Newly Diagnosed Type 1 Diabetes (IMDIAB 8)

In a pilot study, the metabolic effects of continuous subcutaneous insulin infusion (CSII) versus intensive subcutaneous insulin therapy (ISIT) started at diagnosis in patients with Type 1 diabetes and continued for a 2-year period were evaluated and compared. Twenty-three patients (between 12 and 35 years old, mean +/- SD 18.4 +/- 9 years) were randomized into two treatment groups (CSII vs. ISIT), and both received supplemental nicotinamide (NA), 25 mg/kg of body weight. CSII was started immediately after admission to the hospital. Parameters of metabolic control [insulin dose, hemoglobin A1c (HbA1c), and C-peptide] were evaluated for a 2-year follow-up period. Data are presented for a total of 19 patients who remained in the study for its duration. Two years after diagnosis, mean +/- SD HbA1c was 6.3 +/- 0.5% and 6.2 +/- 0.3% for the CSII and ISIT groups, respectively (p=not significant). Compared with baseline values, an increase of baseline C-peptide of 38% for the CSII group and 27% for the ISIT group was observed; however, the difference between the groups was not significant. The insulin requirement for the entire duration of the study, but not at entry and 3 months, was significantly higher in CSII compared with ISIT patients (0.62 +/- 0.4 IU/kg/day vs. 0.3 +/- 0.4 IU/kg/day, respectively; p<0.01). After trial completion patients on CSII continued with this mode of therapy. Implementation of CSII as well as ISIT at diagnosis of Type 1 diabetes and continuation for 2 years thereafter achieved similar and optimal metabolic control, but more insulin was required with the CSII group. Both types of intensive insulin therapy combined with NA are able to preserve C-peptide secretion or even increase baseline levels for up to 2 years after diagnosis.

A 5-year (1989–1993) Prospective Study of the Incidence of IDDM in Rome and the Lazio Region in the Age-Group 0–14 years

OBJECTIVE To provide data on the incidence of IDDM in Rome and the Lazio region evaluated prospectively from 1989 to 1993 for a total of > 5 million subjects younger than 15 years. RESEARCH DESIGN AND METHODS All patients with newly discovered IDDM diagnosed between 1 January 1989 and 31 December 1993 among residents in Rome and its region were recorded. Primary ascertainment was based in diabetes clinics and specialized hospitals in the region, whereas the secondary independent source was taken from the archives of the region where patients are registered to obtain exemption from paying for medications. RESULTS We identified 330 new patients with a degree of ascertainment of 85%. Overall the incidence rate of the disease was 7.9 per 100,000 per year (95% CI 7.1–8.8). The incidence was higher in the 5- to 9-year-old age-group (10.4 per 100,000) and in winter (36.2%). The cumulative risk for the disease is on the order of 1.18 per 1,000 subjects < 15 years of age. No significant differences in incidence were observed between boys and girls. There were 14 instances of coma at diagnosis (4.3%), but hyperglycemia without ketonuria was diagnosed in 35% of patients, suggesting an early diagnosis. DISCUSSION Compared with the other continental Italian regions for which data are available for a single year, the IDDM incidence rate in Rome is similar. We conclude that the IDDM incidence rate in Rome and its region is comparable to that in other Southern European countries and remained stable over the 5-year observation period.

Pancreatic scintigraphy with 99mTc-interleukin-2 at diagnosis of type 1 diabetes and after 1 year of nicotinamide therapy

To evaluate the clinical utility of pancreatic scintigraphy with 99mTc‐interleukin‐2 to identify Type 1 diabetic patients with pancreatic inflammation at diagnosis.

Experiences of Continuous Subcutaneous Insulin Infusion in Pregnant Women with Type 1 Diabetes During Delivery from Four Italian Centers: A Retrospective Observational Study

OBJECTIVES An optimized metabolic control during delivery is mandatory to prevent maternal-neonatal complications. The primary aim of this study was to evaluate the efficacy and safety of continuous subcutaneous insulin infusion (CSII) during delivery in pregnant women with type 1 diabetes. The secondary aim was to assess the impact of real-time continuous glucose monitoring (RT-CGM) added to CSII versus CSII alone. RESEARCH DESIGN AND METHODS This was a multicenter observational retrospective study. A standardized protocol, to use CSII throughout pregnancy and delivery, foresaw three different insulin basal rates according to blood glucose level: profile A, the last basal rate in use; profile B, preventive 50% reduction of the last basal rate in use; and profile C, 0.1-0.2 U/h for blood glucose level <70 mg/dL, activated just before anesthesia or at the beginning of active labor. An alternative intravenous protocol (IVP) was given in case of complications and relevant metabolic deterioration. Blood glucose in the target range (70-140 mg/dL) throughout delivery and percentage of activation of the IVP were primary outcomes. RESULTS Sixty-five pregnant women with diabetes included in the study (56-86% cesarean section; 9-14% spontaneous/stimulated vaginal delivery). Mean blood glucose level was 102 ± 31 mg/dL at 0 min, 109 ± 42 mg/dL at 30 min, 120 ± 48 mg/dL at 60 min, and 99 ± 34 mg/dL at 24 h. Mean basal rate during delivery was 0.6 ± 0.4 U/h (profile B). Mean capillary blood glucose (CBG) level was lower in the RT-CGM group relative to the CSII-alone group: 80 ± 14 mg/dL versus 111 ± 32 mg/dL at 0 min (P<0.01), 79 ± 11 mg/dL versus 109 ± 42 mg/dL at 30 min (P<0.02), and 98 ± 20 mg/dL versus 125 ± 51 mg/dL at 60 min (difference not significant). Eleven newborns experienced transient neonatal hypoglycemia. None of the women switched to IVP. No major differences were observed according to delivery procedure. CONCLUSIONS CSII is possible and safe in different types of delivery in selected and educated women. RT-CGM helps to obtain better outcomes in terms of maternal peripartum CBG level.

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.