Impact of continuous glucose monitoring on quality of life, treatment satisfaction, and use of medical care resources: analyses from the SWITCH study.

To investigate the impact of continuous glucose monitoring (CGM) on health-related quality of life (HRQOL), treatment satisfaction (TS) medical resource use, and indirect costs in the SWITCH study. SWITCH was a multicentre, randomized, crossover study. Patients with type 1 diabetes (n = 153) using continuous subcutaneous insulin infusion (CSII) were randomized to a 12 month sensor-On/Off or sensor-Off/On sequence (6 months each treatment), with a 4-month washout between periods. HRQOL in children and TS in adults were measured using validated questionnaires. Medical resource utilization data were collected. In adults, TS was significantly higher in the sensor-On arm, and there were significant improvements in ratings for treatment convenience and flexibility. There were no clinically significant differences in children's HRQOL or parents' proxy ratings. The incidence of severe hypoglycaemia, unscheduled visits, or diabetes-related hospitalizations did not differ significantly between the two arms. Adult patients made fewer telephone consultations during the sensor-On arm; children's caregivers made similar numbers of telephone consultations during both arms, and calls were on average only 3 min longer during the sensor-On arm. Regarding indirect costs, children with >70 % sensor usage missed fewer school days, compared with the sensor-Off arm (P = 0.0046) but there was no significant difference in the adults days of work off. The addition of CGM to CSII resulted in better metabolic control without imposing an additional burden on the patient or increased medical resource use, and offered the potential for cost offsets.

Health-related quality of life and treatment preferences in adolescents with type 1 diabetes. The VIPKIDS study.

A multi-centre, observational, cross-sectional study was carried out to determine whether the health-related quality of life (HRQOL) of adolescents with type 1 diabetes is affected by different insulin treatment systems, and which features of HRQOL are impacted by the respective insulin treatment. The study regarded 577 adolescents, aged 10-17 years, with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) (n = 306) or multiple daily injections (MDI) (n = 271). The Insulin Delivery System Rating Questionnaire was validated in Italian and was self-completed by the subjects during a routine visit to the centres. Subjects were compared following the domains of the questionnaire. Good HRQOL was seen in subjects treated with either MDI or CSII. Significant differences were not found in the domains for general diabetes, including diabetes worries, social burden and psychological well-being. Multiple quantile regression analysis showed that CSII confers significant advantages in terms of HRQOL with improvements in treatment satisfaction, perceived clinical efficacy and reduction in treatment interference with daily activities. This favourable impact was more evident in subjects reporting lower HRQOL scores, suggesting that CSII may be especially useful for individuals perceiving a poor HRQOL. Analysis of the domains indicated that CSII was associated with a higher HRQOL than MDI. Life-course HRQOL evaluation using a standardised questionnaire can ensure better chronic disease management. This is particularly important when providing individualised care for adolescents, as they become increasingly responsible for managing their diabetes.

The use and efficacy of continuous glucose monitoring in type 1 diabetes treated with insulin pump therapy: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this multicentre, randomised, controlled crossover study was to determine the efficacy of adding continuous glucose monitoring (CGM) to insulin pump therapy (CSII) in type 1 diabetes. METHODS: Children and adults (n = 153) on CSII with HbA(1c) 7.5-9.5% (58.5-80.3 mmol/mol) were randomised to (CGM) a Sensor On or Sensor Off arm for 6 months. After 4 months' washout, participants crossed over to the other arm for 6 months. Paediatric and adult participants were separately electronically randomised through the case report form according to a predefined randomisation sequence in eight secondary and tertiary centres. The primary outcome was the difference in HbA(1c) levels between arms after 6 months. RESULTS: Seventy-seven participants were randomised to the On/Off sequence and 76 to the Off/On sequence; all were included in the primary analysis. The mean difference in HbA(1c) was -0.43% (-4.74 mmol/mol) in favour of the Sensor On arm (8.04% [64.34 mmol/mol] vs 8.47% [69.08 mmol/mol]; 95% CI -0.32%, -0.55% [-3.50, -6.01 mmol/mol]; p < 0.001). Following cessation of glucose sensing, HbA(1c) reverted to baseline levels. Less time was spent with sensor glucose <3.9 mmol/l during the Sensor On arm than in the Sensor Off arm (19 vs 31 min/day; p = 0.009). The mean number of daily boluses increased in the Sensor On arm (6.8 ± 2.5 vs 5.8 ± 1.9, p < 0.0001), together with the frequency of use of the temporary basal rate (0.75 ± 1.11 vs 0.26 ± 0.47, p < 0.0001) and manual insulin suspend (0.91 ± 1.25 vs 0.70 ± 0.75, p < 0.018) functions. Four vs two events of severe hypoglycaemia occurred in the Sensor On and Sensor Off arm, respectively (p = 0.40). CONCLUSIONS/INTERPRETATION: Continuous glucose monitoring was associated with decreased HbA(1c) levels and time spent in hypoglycaemia in individuals with type 1 diabetes using CSII. More frequent self-adjustments of insulin therapy may have contributed to these effects.

Difference in insulin usage patterns with pubertal development in children with type 1 diabetes during transition from multiple daily injections to continuous subcutaneous insulin infusion (CSII) and through the CSII treatment.

OBJECTIVE: This study analyzed the changes in insulin requirement in the transition from multiple daily injections (MDI) to continuous subcutaneous insulin infusion (CSII) and the differences through the CSII treatment in pediatric patients in different pubertal developmental stages. METHODS: We analyzed, through a longitudinal retrospective study, the insulin usage patterns and glycemic control of 40 patients with type 1 diabetes on CSII treatment for 12 months. The patients were subdivided in three groups: group A, 13 prepubertal subjects (Tanner stage I); group B, 15 pubertal subjects (Tanner stage II-IV); and group C, 12 postpubertal subjects (Tanner stage V). RESULTS: During the transition from MDI to CSII, the insulin requirements decreased significantly by 21 +/- 5% (0.89 +/- 0.26 U/kg/day vs. 0.70 +/- 0.11 U/kg/day). Through the CSII treatment the percentage of total daily insulin delivered as the basal rate in groups A, B, and C was 54-60%, 52-54%, and 52-54%, respectively. The number of basal rates per day was significantly higher in groups A and B. The overall profile of basal rate differed among the groups. During the night, prepubertal patients required more insulin from 12 p.m. to 2 a.m., whereas pubertal and postpubertal patients required more insulin between 2-3 a.m. to 7 a.m. Prepubertal patients had a maximum basal rate between 9 a.m. to 12 a.m. and 2 p.m. to 4 p.m., in contrast to pubertal and postpubertal patients between 2 p.m. to 3 p.m. and 5 p.m. to 6 p.m. The number of "extra" boluses per day was significantly higher in groups B and C compared to group A. CONCLUSIONS: Age-related differences exist in insulin usage patterns of pediatric patients on pump treatment. A greater knowledge of these variations may help to obtain optimum conditions in the CSII treatment in pediatric patients.

Benefits of a bolus calculator in pre- and postprandial glycaemic control and meal flexibility of paediatric patients using continuous subcutaneous insulin infusion (CSII).

AIMS: To assess the efficacy in pre- and postprandial glycaemic control and the impact on treatment satisfaction of a bolus calculator (Bolus Wizard) incorporated into the insulin pump in Type 1 diabetic (T1D) paediatric patients using continuous subcutaneous insulin infusion (CSII) treatment at various stages of pubertal development. METHODS: Thirty-six T1D patients on CSII treatment (19 males; mean age 13.9 +/- 3.5 years; range 4.9-17.8 years), were prospectively enrolled into this two-period crossover study. Eighteen patients were randomized to begin phase A using the Bolus Wizard, followed by phase B, using their current conventional insulin dosing method to determine pre-meal boluses. The remaining subjects were randomized to begin with phase B followed by phase A. Each study period lasted 2 weeks. A questionnaire assessing treatment satisfaction with the Bolus Wizard was compiled. RESULTS: There was a significant reduction in blood glucose levels before and 2 h after meals and in the number of correction boluses during phase A with respect to phase B of the study. The lower frequency of hypoglycaemic events during phase A did not reach statistical significance. There were no differences between the two phases: insulin requirement, daily bolus rate (%) and meal bolus quantity. CONCLUSIONS: When paediatric patients used CSII, the bolus insulin dose calculated using the Bolus Wizard was more effective in improving pre- and postprandial glycaemic control with fewer correction boluses, without differences in the prandial insulin requirements and without restriction in the carbohydrate content of meals. The use of the Bolus Wizard was easy and was associated with a high level of satisfaction in these patients.

Long-term benefits of continuous subcutaneous insulin infusion in children with Type 1 diabetes: a 4-year follow-up.

AIM: To determine the safety and effectiveness of continuous subcutaneous insulin infusion (CSII) in attaining long-term glycaemic control in paediatric patients with Type 1 diabetes and to compare the results with those previously recorded in the same patients taking multiple daily injections (MDI) (four injections a day). METHODS: Forty-two patients (mean age 12.2 +/- 3.4 years; range 4.5-17 years; 24 males; mean duration of Type 1 diabetes 5.1 +/- 3.0 years) were studied. The following parameters were assessed in the year before starting CSII treatment (during MDI treatment) and during the 4 years of insulin pump treatment: annual mean HbA1c, insulin requirements (U/kg per day), annual mean of body mass index (BMI) z scores, and adverse events (severe hypoglycaemia and diabetic ketoacidosis/patient per year). Two patients discontinued pump therapy (after 1-year and 2-year follow-up, respectively) because of non-compliance with CSII therapy. RESULTS: Compared with the annual mean HbA1c observed prior to CSII therapy (8.9 +/- 1.0%), the mean HbA1c levels were lower during the first (8.2 +/- 0.9%; P = 0.00), second (8.6 +/- 1.0%; P = 0.05), third (8.4 +/- 0.9%; P = 0.01) and fourth (8.2 +/- 1%; P = 0.00) year of CSII therapy. The insulin requirements (U/kg per day) decreased during CSII treatment compared with MDI treatment. Compared with the annual mean of BMI z scores prior to CSII therapy, BMI z scores were significantly lower during the third and fourth years of CSII therapy. Through the first, second, third and fourth years of follow-up the number of episodes of severe hypoglycaemia (20.0, 20.0, 20.0 and 0 episodes/1000 patient-years, respectively) and diabetic ketoacidosis (0.05, 0.00, 0.03 and 0.00 episodes/patient per year, respectively), events were similar to that in the year preceding CSII therapy (20.0 and 0.03, respectively). CONCLUSION: In this population of selected patients in our clinic, CSII appears to be a safe and effective therapeutic alternative to MDI treatment. This therapy may ensure a stable improvement in long-term glycaemic control in paediatric patients, with no increase in diabetic ketoacidosis and severe hypoglycaemic events and, on the other hand, with a trend of reduction in BMI z scores.

Continuous subcutaneous insulin infusion in children and adolescents with diabetes mellitus: decreased HbA1c with low risk of hypoglycemia.

AIM: To evaluate blood glucose and HbA1c levels, insulin dosage, hypoglycemia rate and body mass index (BMI) at baseline, and at 3 and 6 months after initiation of continuous subcutaneous insulin infusion (CSII) in children and youth with type 1 diabetes mellitus (DM). METHODS: A 6-month trial of pump therapy was carried out in 40 patients with type 1 DM and one with cystic fibrosis (CF) induced DM (25 males), aged 4-25 years (mean 13.5 +/- 4.2 [SD]; 4-8 years, n = 6; 8-10 years, n = 8; 10-12 years, n = 4; 12-15 years, n = 11; >15 years, n = 12). RESULTS: HbA1c was significantly reduced from 9.5 +/- 1.7% to 8.6 +/- 1.2% at 3 months (p < 0.03), and at 6 months 8.8 +/- 1.5% (p < 0.05). The mean daily values of blood glucose, as well as individual mean values of blood glucose at fasting and before lunch, also exhibited a significant reduction (p < 0.05) at 3 and 6 months. There was a significant reduction in the number of hypoglycemic events (level of plasma glucose <3.3 mmol/l, calculated as number of events per patient/30 days) at 3 months (6.5 +/- 5.5 vs 2.8 +/- 3.3; p = 0.02) and at 6 months (6.5 +/- 5.5 vs 3.5 +/- 3.0; p = 0.04). The insulin requirement dropped by 27.2% (1.03 +/- 0.30 U/kg/day before starting CSII; 0.75 +/- 020 U/kg/day on insulin pump therapy onset; 0.76 +/- 0.18 U/kg/day at 3 months; 0.75 +/- 0.21 U/kg/day at 6 months). During the follow-up 0.10 events of diabetic ketoacidosis/patient/year were recorded. The patients exhibited no increase in BMI during the 6 months of follow-up. CONCLUSION: CSII was safe and effective in improving short- and medium-term metabolic control in young adults, adolescents and younger children with DM.

High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI.

AIMS/HYPOTHESIS: The aim of this study was to assess the prevalence of glucokinase gene mutations in Italian children with MODY and to investigate genotype/phenotype correlations of the mutants. METHODS: Screening for sequence variants in the glucokinase gene was performed by denaturing gradient gel electrophoresis and direct sequencing in 132 children with maturity onset diabetes of the young (MODY) and in 9 children with chronic fasting hyperglycaemia but without laboratory evidence for Type I (insulin-dependent) diabetes mellitus and with normoglycaemic parents ("non-classical" MODY). RESULTS: Altogether 54 mutations were identified in the MODY group (54/132 or 41%) and 3 among the "non-classical" MODY individuals (3/9 or 33%). Paternity testing indicated that the latter mutations have arisen de novo. Mean fasting plasma glucose concentrations of the children with the mutant glucokinase was in the expected impaired fasting glucose range. In contrast, results of the oral glucose tolerance test showed a wide range from normal glucose tolerance (Group 1: 2-h OGTT = 6.7 +/- 1.1 mmol/l; 11 patients) to diabetes (Group 2: 2-h OGTT = 11.5 +/- 0.5 mmol/l; 9 patients), with the remaining in the impaired glucose tolerance range. Disruptive mutations (i.e. nonsense, frameshifts, splice-site) were equally represented in Groups 1 and 2 and were not clearly associated with an impaired first-phase insulin response. Surprisingly, 5 out of 11 children (or 45%) in Group 1 were found to be overweight but no children in Group 2 were overweight. Sensitivity index (SI), calculated by a recently described method, was found to be significantly lower in Group 2 than in Group 1 (SI Group 2 = 0.0013 +/- 0.0009 ml Kg(-1) min(-1)/muU/ml; SI Group 1 = 0.0068 +/- 0.0048, p < 0.0035). CONCLUSION/INTERPRETATION: Mutations in glucokinase are the first cause of MODY among Italian children selected through a low threshold limit of fasting plasma glucose (i. e. > 5.5 mmol). The lack of correlation between the molecular severity of glucokinase mutations, insulin secretion at intravenous glucose tolerance test and differences in glucose tolerance suggests that factors outside the beta cell are also involved in determining post-load glucose concentrations in these subjects. Our results seem to indicate that the differences observed in the 2-h responses at the OGTT among children with MODY 2 could be related to individual differences in insulin sensitivity.

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.

Interaction of HIV-1 with susceptible lymphoblastoid cells. 1H NMR studies.

Different strains of HIV susceptible lymphoblastoid cells have been infected by HIV-1 and examined by means of 1H NMR spectroscopy at different times after infection, taking advantage of the presence of high resolution lipid signals from the plasma membrane of tumor cells. A transient decrease in intensity of fatty acid signals, originated by changes in membrane structure, has been observed early after viral infection. Marked alterations in membrane-dependent steps of phospholipid synthesis can also be inferred by the observed transient depression in peaks from choline-based metabolites. Spectral modifications deriving from changes in lipid metabolism are also produced both in infected cells a few days after infection and in permanently infected cells. 1H NMR can, therefore, monitor structural and metabolic effects induced by HIV infection.

Metabolic and structural effects of HIV infection in human peripheral blood mononuclear cells can be monitored with 1H NMR spectroscopy.

Infection of human peripheral blood lymphocytes by human immunodeficiency virus type 1 (HIV-1) was investigated by means of 1H nuclear magnetic resonance spectroscopy, taking advantage of the presence of signals from fluid lipid domains in the membrane of stimulated lymphocytes. A transient decrease of the lipid methylene signal intensity was observed at the time of HIV internalization, monitoring a general rearrangement of membrane structure associated with virus entry. A similar effect was also observed a few days after infection, when HIV particles are released by infected cells as demonstrated by high reverse transcriptase activity in cell supernatant. Signals arising from choline-based metabolites were also affected by HIV infection, indicating a possible slowing down of phospholipid synthesis.

A male patient with 48,XXYY syndrome: importance of distinction from Klinefelter's syndrome.

The authors report a patient affected with mental retardation, dysarthria, bilateral testicular hypoplasia and extensive ulcers of the lower limbs. Clinical study and laboratory tests revealed 48,XXYY syndrome. The authors confirm the importance of differential diagnosis from Klinefelter syndrome, illustrating the parameters and the pathology of both syndromes. They discuss the hypotheses concerning the pathogenesis of the ulcerations, and stress the importance of clinical and genetic characterization, leading to a differentiated prognosis of social capacity and prospect of working.

Variable number of tandem repeats in zygosity diagnosis in twins.

The use of DNA restriction fragment length polymorphisms (RFLP) to analyze variable number of tandem repeat (VNTR) sequences dispersed in the human genome, has become a powerful tool for the study of population genetics due to the very substantial polymorphism involved. Because the markers usually employed for twin zygosity determination (such as sex combination, placentation, HLA typing, blood group antigens, etc) may not be uniformly informative, we propose the use of synthetic olygonucleotides, representing VNTR "core" sequences, for the determination of zygosity in twins.