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Background and Aim: To assess the incidence of Type 1 Diabetes Mellitus (T1DM) during the period 2012-2017, the frequency and severity of ketoacidosis (DKA) at diabetes onset, and the factors associated with DKA in children and adolescents younger than 18 years old in the Abruzzo region, Italy., Methods: All incident cases of T1DM (0-17 years old) diagnosed between January 2012 and December 2017 were included. Data about the patients were obtained from two independent sources; insulin prescriptions and medical records. Clinical data at diabetes onset, as well as demographic and non-demographic data, including center of first hospitalization, distance to regional reference center and number of pediatricians (per 1000 residents younger than 18 years) were collected and evaluated., Results: During 2012-2017 period, 177 patients were diagnosed with T1DM. In 2012, T1DM incidence was 15.6 per 100,000/year; in 2013, 16.4 per 100,000/year; in 2014, 11.6 per 100,000/year; in 2015, 14.2 per 100,000/year; in 2016, 16.2 per 100,000/year and in 2017, 12.2 per 100,000/year. DKA was present in 29.3% of patients, 6.9% with severe DKA. The DKA presence was correlated to age (p<0.02), ethnicity (p<0.04), being transferred to a specialist center instead of being directly admitted to one (p<0.002) and the number of pediatricians in the population (p<0.01). The DKA severity was associated with the delay of transfer (p<0.04)., Conclusions: Being admitted directly to a specialist center is very important and it could be expression of high alertness of pediatricians. Availability of well-trained pediatricians is necessary for the prevention of DKA. (www.actabiomedica.it).

Aim: To ascertain whether the prevalence of retinopathy has declined over the last 2 decades in individuals with childhood-onset type 1 diabetes and whether this might be explained by changes in lifetime HbA1c., Materials and Methods: A multicentre, retrospective, observational study, comparing 128 subjects with diabetes onset in 2000-2003 assessed for retinopathy in 2016-2019, with a previous cohort of 115 individuals diagnosed in 1990-1993 and assessed for retinopathy in 2007-2009, was conducted. The two cohorts had both a similar diabetes duration and age at diagnosis. Retinal photographs were centrally graded. Lifetime HbA1c and its variability, estimated as the ratio between intrapersonal mean and standard deviation of HbA1c, were evaluated., Results: The prevalence of any retinopathy in the new and old cohort was 24.2% and 43.5% (P < .003), respectively, and that of severe retinopathy was 1.7% and 9.6% (P = .018). Lifetime HbA1c was lower in the new cohort (7.8% ± 0.8% vs. 8.1% ± 0.8%; P = .002) during all periods following the first 5 years after diagnosis. Patients without retinopathy in the two cohorts had similar levels of HbA1c. Compared with patients without retinopathy, those with retinopathy had higher lifetime HbA1c and long-term HbA1c variability. However, on multiple regression analysis, only lifetime HbA1c was independently associated with retinopathy (P = .0018)., Conclusions: The risk of developing retinopathy was nearly halved in children who developed type 1 diabetes in the new millennium compared with previous cohorts. These results confirm that maintaining the lowest possible levels of HbA1c throughout lifetime protects from diabetic retinopathy., (© 2021 John Wiley & Sons Ltd.)

Diabetes is considered as a disease with a wide and continuous clinical spectrum, ranging from Type 1 (T1D) and Type 2 Diabetes (T2D) with complex multifactorial causes. In the last years, particular attention has been focused on the predictive value and therapeutic potential of single nucleotide polymorphisms (SNPs). SNPs can alter the seed-sequence in miRNA's loci and miRNA target sites causing changes in the structure and influencing the binding function. Only few studies have investigated the clinical influence of SNPs, in particular potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ) gene variants in T1D population. The aim of the study is to investigate the occurrence and the possible metabolic significance of KCNJ polymorphism in a group of pediatric patients with T1D. The study was performed in a cohort of 90 Caucasian children and adolescents with T1D and 93 healthy subjects. Rs5210 polymorphism has been analyzed with a prevalence of the GG genotype in the patient group suggesting its association with T1D. Therefore, a relationship was found between GG genotype and body mass index (BMI) at diagnosis and insulin requirement (IR) after 6 months. The study suggested an action for rs5210 in determining the metabolic features of T1D pediatric patients, by showing some clues of insulin resistance in patients carrying that polymorphism., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Objectives: To assess the optimal setting of the predictive low glucose management (PLGM) algorithm for preventing exercise-induced hypoglycemia in adolescents with type 1 diabetes., Methods: Thirty-four adolescents, 15 to 20 years, wearing PLGM system, were followed during 3 days exercise during a diabetes camp. PLGM threshold was set at 70 mg/dL between 8 am and 10 pm and 90 mg/dL during 10 pm and 8 am Adolescents were divided into group A and B, with PLGM threshold at 90 and 70 mg/dL, respectively, during exercise. Time spent in hypoglycemia and AUC for time slots 8 am to 1 pm, 1 to 4 pm, 4 to 11 pm, 11 pm to 3 am, 3 to 8 am, in 3 days were compared between groups by Wilcoxon rank sum test., Results: We analyzed 31 patients (median age 15.0 years, 58.1% males, median diabetes duration 7.0 years, hemoglobin A1c [HbA1c] 7.1%). No significant difference has been observed in time spent in hypoglycemia between groups using threshold 70 or 90. Time spent in target was similar in both groups, as well as time spent in hypo or hyperglycemia. The trends of blood glucose over the 3 days in the 2 groups over-lapped without significant differences., Conclusions: A PLGM threshold of 90 mg/dL during the night was associated with reduced time in hypoglycemia in adolescents doing frequent physical exercise, while maintaining 65.1% time in range during the day. However, a threshold of 70 mg/dL seems to be safe in the duration of the physical exercise. PLGM system in adolescents with type 1 diabetes was effective to prevent hypoglycemia during and after exercise, irrespective of the PLGM thresholds used., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The goal of insulin therapy in people affected by type 1 diabetes mellitus consists in achieving an optimal metabolic control and so HbA1c levels below 7.5%, according to the conclusions of relevant scientific studies. In any case it seems that this target is far from being achieved, mostly in the pediatric population. However, many important pharmacological, technological and cultural milestones have been placed both in therapy and management of insulin-dependent diabetes even if the gap between growing knowledge in these fields and its application in daily clinical practice appears still too wide. A fundamental component of these advancements concerns the design of new insulin basal analogues; molecules used to realize a basal-bolus model of therapy with MDI scheme. Degludec insulin has been recently approved for the pediatric utilization (aged 1 to 17 years). A registration trial for pediatric population (aged 6 to 17 years) is in progress for glargine U-300 insulin. These two insulin types have different biochemical and pharmacological properties and they represent two different ways to achieve the ideal basal analogue. Insulin degludec and insulin glargine U-300 are the newest basal analogues and each of them has proper pharmacokinetic and pharmacodynamic characteristics. Their characteristics represent an effort to create the ideal solution. The aim of this review is to summarize the pharmacokinetic and pharmacodynamic properties of these new insulins, to list the most significant scientific findings regarding their pharmacology as well as clinical uses, with particular reference to the pediatric population in order to declare them to clinical experience and to report data on an initial experience with these analogues, especially with degludec insulin. Once again, evolution goes through the specialized training of the staff involved in the care of the diabetic patient and the constant education of the latter.

Context: An etiologic diagnosis of diabetes can affect the therapeutic strategy and prognosis of chronic complications., Objective: The aim of the present study was to establish the relative percentage of different diabetes subtypes in patients attending Italian pediatric diabetes centers and the influence of an etiologic diagnosis on therapy., Design, Setting, and Patients: This was a retrospective study. The clinical records of 3781 consecutive patients (age, 0 to 18 years) referred to 15 pediatric diabetes clinics with a diagnosis of diabetes or impaired fasting glucose from January 1, 2007 to December 31, 2012 were examined. The clinical characteristics of the patients at their first referral to the centers, type 1 diabetes-related autoantibodies, molecular genetics records, and C-peptide measurements, if requested for the etiologic diagnosis, were acquired., Main Outcome Measures: The primary outcome was to assess the percentage of each diabetes subtype in our sample., Results: Type 1 diabetes represented the main cause (92.4%) of diabetes in this group of patients, followed by monogenic diabetes, which accounted for 6.3% of cases [maturity onset diabetes of the young (MODY), 5.5%; neonatal diabetes mellitus, 0.6%, genetic syndromes, 0.2%]. A genetic diagnosis prompted the transfer from insulin to sulphonylureas in 12 patients bearing mutations in the HNF1A or KCNJ11 genes. Type 2 diabetes was diagnosed in 1% of the patients., Conclusions: Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling., (Copyright © 2017 Endocrine Society)

Aims: Insulin pump failure and/or malfunction requiring replacement have not been thoroughly investigated. This study evaluated pump replacement in children and adolescents with Type 1 diabetes using insulin pump therapy., Methods: Data were collected for all participants younger than 19 years, starting insulin pump therapy before 31 December 2013. For each child, age, disease duration, date of insulin pump therapy initiation, insulin pump model, failure/malfunction/replacement yes/no and reason were considered for the year 2013., Results: Data were returned by 40 of 43 paediatric centres belonging to the Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. In total, 1574 of 11 311 (13.9%) children and adolescents with Type 1 diabetes were using an insulin pump: 29.2% Animas VIBE ™ , 9.4% Medtronic MiniMed 715/515 ™ , 34.3% Medtronic MiniMed VEO ™ , 24.3% Accu-Check Spirit Combo ™ and 2.8% other models. In 2013, 0.165 insulin pump replacements per patient-year (11.8% due to pump failure/malfunction and 4.7% due to accidental damage) were recorded. Animas VIBE ™ (22.1%) and Medtronic MiniMed VEO ™ (17.7%) were the most replaced., Conclusions: In a large cohort of Italian children and adolescents with Type 1 diabetes, insulin pump failure/malfunction and consequent replacement are aligned with rates previously reported and higher in more sophisticated pump models., (© 2016 Diabetes UK.)

In recent years, increasing interest has been devoted to the susceptibility gene polymorphisms in type 1 diabetes (T1D) as well as in other autoimmune diseases. Among these, a nucleotide polymorphism of the gene encoding for the protein tyrosine phosphatase non-receptor type 22 (PTPN22) has been associated with T1D in several studies. The aim of this study is to define the frequency of the C1858T polymorphism in the PTPN22 gene in a cohort of 113 Caucasian patients (58 males and 55 females) with T1D, and to assess a possible correlation with a group of clinically relevant variables: age at onset, gender, diabetes-related autoantibodies, residual β-cell function and daily insulin requirement (IR) 6 months after diagnosis. Using a PCR-RFLP approach, we evidenced a 17.7% frequency of the PTPN22 C1858T polymorphism in diabetic patients, higher than the frequency showed in the general population. A statistically significant correlation between this polymorphism and higher levels of C-peptide at diagnosis and lower IR at 6 months from diagnosis was observed (P=0.001 and P=0.04). Moreover, 1858T variant carriers were more frequently positive for glutamic acid decarboxylase (GAD) autoantibodies at diagnosis than wild-type subjects (P=0.19). On the other hand, no significant difference regarding age at onset, gender distribution, insulinoma-associated 2 molecule (IA2) and islet cell antibodies (ICA) positivity was found. These findings, if adequately confirmed in the future and extended to larger samples, may characterize a subset of T1D patients with a defined genetic pattern, who may be eligible for trials aimed to preserve residual β-cell function in the coming years.

This longitudinal population-based study analyses the frequency of diabetic ketoacidosis (DKA) at type 1 diabetes diagnosis in Italian children under 15 years of age, during 2004-2013. DKA was defined as absent (pH ≥ 7.30), mild/moderate (7.1 ≤ pH < 7.30) and severe (pH < 7.1). Two multiple logistic regression models were used to evaluate the time trend of DKA frequency considered as present versus absent and severe versus absent, adjusted for gender, age group and geographical area of residence at diagnosis. Overall, 9,040 cases were ascertained. DKA frequency was 40.3% (95%CI: 39.3-41.4%), with 29.1% and 11.2% for mild/moderate and severe DKA, respectively. Severe DKA increased significantly during the period (OR = 1.03, 95%CI: 1.003-1.05). Younger-age children and children living in Southern Italy compared to Central Italy were at significantly higher risk of DKA and severe DKA. Family history of type 1 diabetes and residence in Sardinia compared to Central Italy were significantly associated with a lower probability of DKA and severe DKA. The high frequency of ketoacidosis in Italy over time and high variability among age groups and geographical area of residence, strongly suggests a continuing need for nationwide healthcare strategies to increase awareness of early detection of diabetes.

We conducted a retrospective survey in pediatric centers belonging to the Italian Society for Pediatric Diabetology and Endocrinology. The following data were collected for all new-onset diabetes patients aged 0-18 years: DKA (pH < 7.30), severe DKA (pH < 7.1), DKA in preschool children, DKA treatment according to ISPAD protocol, type of rehydrating solution used, bicarbonates use, and amount of insulin infused. Records (n = 2453) of children with newly diagnosed diabetes were collected from 68/77 centers (87%), 39 of which are tertiary referral centers, the majority of whom (n = 1536, 89.4%) were diagnosed in the tertiary referral centers. DKA was observed in 38.5% and severe DKA in 10.3%. Considering preschool children, DKA was observed in 72%, and severe DKA in 16.7%. Cerebral edema following DKA treatment was observed in 5 (0.5%). DKA treatment according to ISPAD guidelines was adopted in 68% of the centers. In the first 2 hours, rehydration was started with normal saline in all centers, but with different amount. Bicarbonate was quite never been used. Insulin was infused starting from third hour at the rate of 0.05-0.1 U/kg/h in 72% of centers. Despite prevention campaign, DKA is still observed in Italian children at onset, with significant variability in DKA treatment, underlying the need to share guidelines among centers.

Aims: To investigate on the relationship between severity of ketoacidosis, an important risk factor for C-peptide preservation, and long-term microvascular complications in childhood-onset type 1 diabetes mellitus (T1DM)., Methods: 230 childhood-onset diabetic patients (177 pre-pubertal), aged 7.0±3.8years followed for at least 15years after their diagnosis, were enrolled. Clinical and laboratory data at diagnosis, and C-peptide levels in a subset of patients, were compared with the severity of retinopathy and nephropathy, after a mean of 19.6±3.8years of disease. Digital retinal photographs were taken in all patients, and centrally graded. Repeated measurements of HbA1c and microalbuminuria for the whole duration of diabetes were collected in over half of the cases., Results: Out of 230 patients, those with the lowest age at diagnosis had the most severe DKA and clinical conditions (p<0.05), and lower C-peptide levels (p<0.0001) at diagnosis. There was a significant relationship between pH and clinical severity (r=-0.783, p<0.0001), and between pH and C-peptide levels (r=0.278, p<0.05). The severity of ketoacidosis had no relationship with subsequent lifetime HbA1c values and long-term microvascular complications. In logistic regression analysis, the only variables that independently influenced severity of retinopathy were lifetime HbA1c (B=0.838, p<0.001), duration of disease (B=0.208, p<0.005) and age at diagnosis (B=0.116, p<0.05)., Conclusions: The degree of metabolic derangement at diagnosis is not associated with retinopathy and nephropathy in childhood-onset T1DM. Age at diagnosis seems to be an important variable to be considered when evaluating the long-term effects of residual beta-cell function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Early signs of renal complications can be common in youths with type 1 diabetes (T1D). Recently, there has been an increasing interest in potential renal complications associated with obesity, paralleling the epidemics of this condition, although there are limited data in children., Hypothesis: Obese children and adolescents present signs of early alterations in renal function similar to non-obese peers with T1D., Subjects: Eighty-three obese (age: 11.6 ± 3.0 yr), 164 non-obese T1D (age: 12.4 ± 3.2 yr), and 71 non-obese control (age: 12.3 ± 3.2 yr) children and adolescents were enrolled in the study., Methods: Anthropometric parameters and blood pressure were measured. Renal function was assessed by albumin excretion rate (AER), serum cystatin C, creatinine and estimated glomerular filtration rate (e-GFR), calculated using the Bouvet's formula., Results: Obese and non-obese T1D youths had similar AER [8.9(5.9-10.8) vs. 8.7(5.9-13.1) µg/min] and e-GFR levels (114.8 ± 19.6 vs. 113.4 ± 19.1 mL/min), which were higher than in controls [AER: 8.1(5.9-8.7) µg/min, e-GFR: 104.7 ± 18.9 mL/min]. Prevalence of microalbuminuria and hyperfiltration was similar between obese and T1D youths and higher than their control peers (6.0 vs. 8.0 vs. 0%, p = 0.02; 15.9 vs. 15.9 vs. 4.3%, p = 0.03, respectively). Body mass index (BMI) z-score was independently related to e-GFR (r = 0.328; p < 0.001), and AER (r = 0.138; p = 0.017). Hemoglobin A1c (HbA1c) correlated with AER (r = 0.148; p = 0.007) but not with eGFR (r = 0.041; p = 0.310)., Conclusions: Obese children and adolescents show early alterations in renal function, compared to normal weight peers, and they have similar renal profiles than age-matched peers with T1D., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Insulin degludec (IDeg) once-daily was compared with insulin detemir (IDet) once- or twice-daily, with prandial insulin aspart in a treat-to-target, randomized controlled trial in children 1-17 yr with type 1 diabetes, for 26 wk (n = 350), followed by a 26-wk extension (n = 280). Participants were randomized to receive either IDeg once daily at the same time each day or IDet given once or twice daily according to local labeling. Aspart was titrated according to a sliding scale or in accordance with an insulin:carbohydrate ratio and a plasma glucose correction factor. Randomization was age-stratified: 85 subjects 1-5 yr. (IDeg: 43), 138 6-11 yr (IDeg: 70) and 127 12-17 yr (IDeg: 61) were included. Baseline characteristics were generally similar between groups overall and within each stratification. Non-inferiority of IDeg vs. IDet was confirmed for HbA1c at 26 wk; estimated treatment difference (ETD) 0.15% [-0.03; 0.32]95% CI . At 52 wk, HbA1c was 7.9% (IDeg) vs. 7.8% (IDet), NS; change in mean FPG was -1.29 mmol/L (IDeg) vs. +1.10 mmol/L (IDet) (ETD -1.62 mmol/L [-2.84; -0.41]95% CI , p = 0.0090) and mean basal insulin dose was 0.38 U/kg (IDeg) vs. 0.55 U/kg (IDet). The majority of IDet treated patients (64%) required twice-daily administration to achieve glycemic targets. Hypoglycemia rates did not differ significantly between IDeg and IDet, but confirmed and severe hypoglycemia rates were numerically higher with IDeg (57.7 vs. 54.1 patient-years of exposure (PYE) [NS] and 0.51 vs. 0.33, PYE [NS], respectively) although nocturnal hypoglycemia rates were numerically lower (6.0 vs. 7.6 PYE, NS). Rates of hyperglycemia with ketosis were significantly lower for IDeg vs. IDet [0.7 vs. 1.1 PYE, treatment ratio 0.41 (0.22; 0.78)95% CI , p = 0.0066]. Both treatments were well tolerated with comparable rates of adverse events. IDeg achieved equivalent long-term glycemic control, as measured by HbA1c with a significant FPG reduction at a 30% lower basal insulin dose when compared with IDet. Rates of hypoglycemia did not differ significantly between the two treatment groups; however, hyperglycemia with ketosis was significantly reduced in those treated with IDeg., (© 2015 The Authors. Pediatric Diabetes published by John Wiley & Sons Ltd.)

To assess burden and clinical features of type 1 diabetes in migrant with respect to Italian children. Prevalent children with type 1 diabetes were identified through a multicenter study, including 46 pediatric outpatients diabetic clinics. A nested case-control study was also performed, comparing features at diabetes onset and after 1 year of insulin treatment in 84 migrants and 75 Italian children with onset in 2011, matched for age and sex. Out of 7,812 children cared for by pediatric diabetologists, 761 (10%) were migrant and 548 of them were born in Italy. Age at diagnosis was lower in migrants born in Italy (5.1 years, interquartile range (IQR) 2.2-7.7) than in those born in their original countries (7.8 years, IQR 5.3-10.3) and in Italians (9.8 years, IQR 5.9-13.0, p < 0.001). At diabetes onset, migrants had lower frequencies of positivities of markers of β-cell autoimmunity (96 vs. 99.5%, p < 0.01), higher values of weight loss (11 vs. 7%, p < 0.01), HbA1c (70 vs. 58 mmol/mol, p < 0.001), and insulin requirement (0.70 ± 0.03 vs. 0.63 ± 0.10 UI/kg/die, p = 0.05) and lower levels of 25-OH vitamin D3 (15.0 ± 2.8 vs. 20.8 ± 1.3, p = 0.03). Moreover, they experienced higher frequencies of hospitalizations during the first year of disease (19.2 vs. 2.7%, p < 0.001). Burden of type 1 diabetes in migrant children is increasing in Italy, with younger age at onset and different clinical features than in Italian children. Higher hospitalization rates and poorer glycemic control over the first year underline that approach to diabetes care in migrants needs to be improved.

A panel of experts of the Italian Society of Pediatric Endocrinology and Diabetology comprehensively discussed and approved the Italian recommendations regarding self-monitoring of blood glucose, continuous glucose monitoring and other measures of glycemic control in children and adolescents with type 1 diabetes. After an extensive review of the literature, we took these issues into account: self-monitoring blood glucose, continuous glucose monitoring, glycemic variability, glycosuria, ketonuria, ketonemia, glycated hemoglobin, fructosamine and glycated albumin, logbook, data downloading, lancing devices, carbohydrate counting, and glycemic measurements at school. We concluded that clinical guidelines on self-management should be developed in every country with faithful adaptation to local languages and taking into account specific contexts and local peculiarities, without any substantial modifications to the international recommendations. We believe that the National Health Service should provide all necessary resources to ensure self-monitoring of blood glucose and possibly continuous glucose monitoring of all children and adolescents with type 1 diabetes, according to the standards of care provided by these recommendations and internationally.

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.

Background/aim: Combined growth hormone (GH) and insulin therapy is rarely prescribed by pediatric endocrinologists. We investigated the attitude of Italian physicians to prescribing that therapy in the case of short stature and type-1 diabetes (T1DM)., Methods: A questionnaire was sent and if a patient was identified, data on growth and diabetes management were collected., Results: Data from 42 centers (84%) were obtained. Of these, 29 centers reported that the use of combined therapy was usually avoided. A total of 17 patients were treated in 13 centers (GH was started before T1DM onset in 9 patients and after the onset of T1DM in 8). Height SDS patterns during GH therapy in the 11 patients affected by GH deficiency ranged from -0.3 to +3.1 SDS. In the 8 diabetic patients in whom GH was added subsequently, mean insulin dose increased during the first 6 months of therapy from 0.7 ± 0.2 to 1.0 ± 0.2 U/kg (p = 0.004). HbA1c was unchanged during the first 6 months of combined therapy., Conclusions: Most Italian physicians do not consider prescribing the combined GH-insulin therapy in diabetic children with growth problems. However, the results of the 17 patients identified would confirm that the combined therapy was feasible and only caused mild insulin resistance. GH therapy was effective in promoting growth in most patients and did not affect diabetes metabolic control.

Objective: To compare the effect of the prepubertal duration of diabetes on the occurrence of complications in two groups of patients after the same number of years of the disease., Research Design and Methods: This multicenter study enrolled 105 patients aged 16-40.3 years; 53 were prepubertal at diagnosis (aged 0-3) and 52 were pubertal (Tanner stage) and aged 9-14.9. The mean duration of disease was 19.8 and 19.5 years for prepubertal and pubertal patients, respectively. In all patients, retinal photographs were taken and centrally graded. Urinary albumin excretion (UAE; 86 case subjects), blood pressure (BP; 89 case subjects), and lifetime HbA(1c) (72 case subjects) were also evaluated., Results: The prevalence of diabetic retinopathy (DR) was higher in pubertal than in prepubertal patients, both for any grade DR (71 vs. 40%, P = 0.002) and for mild or more severe DR (P = 0.005). The prevalence of abnormal UAE was not different in the two groups. Hypertension was found only in three patients, all pubertal at diagnosis. In the small group with moderate-to-severe DR, lifetime HbA(1c) levels, as percentages above the upper normal reference value, were higher (P < 0.01) in prepubertal than in pubertal patients., Conclusions: If diabetes is diagnosed in infants or toddlers and the prepubertal duration of diabetes is very long, the patients seem to be protected against DR. This protection disappears if lifetime metabolic control is bad. Instead, when onset is at puberty, the DR risk is higher and less dependent on metabolic control and may be influenced by age-related factors, such as BP.

Objective: Hypoglycemia remains a central problem in the management of type 1 diabetes mellitus (T1DM) and limits the achievement of good or normal glycemic control. The Diabetes Control and Complication Trial showed that intensive treatment of T1DM increased the risk of severe hypoglycemia (SH) when compared to conventional therapy. The aim of our study was to determine the incidence of SH and associated variables in a population of children and adolescents with T1DM., Research Design and Methods: We performed a 7.5-yr prospective study enrolling 195 patients aged 13.9 ± 6.6 yr. The study was carried out by referring to the T1DM population-based register in the Abruzzo region of Italy. The incidence of SH, defined as blood glucose levels <50 mg/dL (<2.77 mmol/L) associated with altered states of consciousness (including confusional state, seizures, and coma) was recorded. Glycated hemoglobin (HbA1c) percentage, insulin dose, insulin regimen, time since diagnosis, and age at onset were also recorded., Results: One hundred and thirty-three severe hypoglycemic events occurred during the study period; the overall incidence was 9.4 episodes per 100 patient-years. Significant predictors of hypoglycemia were diabetes duration >10 yr (p = 0.01), basal/bolus insulin ratio (ratio of daily basal insulin units to daily bolus insulin units) >0.8 (p = 0.01). No relationship was found between hypoglycemic episodes and HbA1c levels, daily insulin requirements, or insulin regimen., Conclusions: In these patients, a relatively low incidence of SH was recorded, without pronounced association with lower HbA1c or multiple daily injection insulin therapy. SH seems to be mainly related to management of diabetes. We believe that the main path to SH prevention is through patient and family education in the management of T1DM., (© 2010 John Wiley & Sons A/S.)

Background: Compared to older children and adolescents very young patients with type 1 diabetes represent a unique population. We analyzed the age-dependent characteristics and parameters of continuous subcutaneous insulin infusion (CSII) in children under 6 years of age with type 1 diabetes., Methods: We evaluated metabolic control and pump-dependent characteristics in 46 children with type 1 diabetes after 0.89 +/- 0.62 years of CSII., Results: Metabolic control significantly improved after CSII initiation (glycosylated hemoglobin, 8.12 +/- 1.24% vs. 7.30 +/- 0.67%; P < 0.05), without increased risk for diabetic ketoacidosis or hypoglycemia. Interestingly, very young patients required bigger boluses than expected, especially in the morning and at the afternoon snack., Conclusions: These data support the need to personalize pump-dependent characteristics, especially in very young children with type 1 diabetes, in order to optimize CSII therapy in this unique age group of patients.

Background and Aim: A panel of experts of the Italian Society of Paediatric Endocrinology and Diabetology translated into Italian the international insulin pump therapy recommendations in children and adolescents with type 1 diabetes., Methods: After an extensive review of the literature using evidence-based recommendations, several issues were taken into account, such as patient selection, advantages and disadvantages, instrument choice, insulin type, therapy planning and follow-up, emergencies, nutrition, particular occasions (like parties, holidays, sick days, travels), exercise, continuous glucose monitoring and integrated system, neonatal diabetes. The panel evaluated the cost-effectiveness of insulin pump therapy compared to multiple daily injection therapy, analysing the cost-benefit ratio., Results: Some tweak was needed due to the Italian dietetic singularity, meal schedule, climate and lifestyle. Insulin pump therapy in neonatal diabetes is a new issue and no guidelines have been published yet for this age-group. Moreover, legal issues according to the Italian law have been added and are peculiarity of our recommendations. An "informed therapeutic agreement" between the patient and his/her family and the diabetic team has to be signed before starting insulin pump therapy., Conclusions: We think that nowadays the need for clinical guidelines is important and worth the effort that all countries develop faithful adaptation into their local languages taking into account specific contexts and local peculiarities, without making substantial modifications to the original text.

Mutations in the pancreatic ATP-sensitive K(+) channel (K(ATP) channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the K(ATP) channel mutations examined result in decreased ATP inhibition, which in turn is predicted to suppress insulin secretion. Here we describe a patient with severe PNDM, which includes developmental delay and epilepsy, in addition to neonatal diabetes (developmental delay, epilepsy, and neonatal diabetes [DEND]), due to a G334D mutation in the Kir6.2 subunit of K(ATP) channel. The patient was wholly unresponsive to sulfonylurea therapy (up to 1.14 mg . kg(-1) . day(-1)) and remained insulin dependent. Consistent with the putative role of G334 as an ATP-binding residue, reconstituted homomeric and mixed WT+G334D channels exhibit absent or reduced ATP sensitivity but normal gating behavior in the absence of ATP. In disagreement with the sulfonylurea insensitivity of the affected patient, the G334D mutation has no effect on the sulfonylurea inhibition of reconstituted channels in excised patches. However, in macroscopic rubidium-efflux assays in intact cells, reconstituted mutant channels do exhibit a decreased, but still present, sulfonylurea response. The results demonstrate that ATP-binding site mutations can indeed cause DEND and suggest the possibility that sulfonylurea insensitivity of such patients may be a secondary reflection of the presence of DEND rather than a simple reflection of the underlying molecular basis.

Objective: The aim of the present study was to evaluate serum and urinary nitric oxide (NO) concentrations in children and adolescents with diabetes compared with age-matched healthy control subjects to find out whether Doppler ultrasonography could be used to detect changes in renal resistive indexes (RIs) in children with diabetes and to assess whether there are correlations between these parameters and NO excretion., Research Design and Methods: We studied 42 children with type 1 diabetes and 41 matched healthy control subjects, both divided into prepubertal or pubertal children. Serum and urinary nitrite and nitrate (NO2-+NO3-) concentrations were evaluated as an index of NO production. Doppler ultrasonographic registration of intrarenal RI was performed., Results: Compared with healthy control subjects, children with diabetes had significantly increased concentrations of serum (30.26 +/- 6.52 vs. 24.47 +/- 7.27 mmol/l, P = 0.001) and urinary NO2-+NO3- (345.07 +/- 151.35 vs. 245.86 +/- 80.25 mmol/l, P = 0.002); the same was true for Doppler RI values (0.64 +/- 0.03 vs. 0.60 +/- 0.04, P = 0.035). This occurs in both prepubertal and the pubertal children. A significant positive correlation was found between serum and urinary NO2-+NO3- levels (P = 0.002, r = 0.374). Serum NO2-+NO3- concentrations also correlated positively with Doppler RI (P = 0.032, r = 0.262) and HbA1c (A1C) (P = 0.004, r = 0.329); urinary NO2-+NO3- concentrations correlated positively with A1C (P = 0.001, r = 0.394). Doppler RI correlated positively with A1C (P = 0.000, r = 0.424)., Conclusions: This study demonstrates that in children with diabetes, chronic hyperglycemia may act through a mechanism that involves increased NO production and/or action and contributes to generating intrarenal hemodynamic abnormalities, which are detectable by Doppler ultrasonography even in early diabetic nephropathy.

Microalbuminuria is the earliest clinical evidence of diabetic nephropathy, but the mechanisms linking hyperglycemia and kidney complications are not clear. The aim of this study was to evaluate whether enhanced oxidative stress in patients with microalbuminuria can contribute to diabetic nephropathy development through downregulation of the antiapoptotic gene Bcl-2 that promotes in turn a pro-inflammatory status. We studied 30 patients with type 1 diabetes (15 with and 15 without microalbuminuria) compared to 15 matched healthy controls. Plasma oxidant status, and expression of Bcl-2, activated NF-kB, inducible Nitric Oxide synthase (iNOS), and monocyte chemoattractant protein (MCP)-1 in circulating monocytes were evaluated at baseline and after 8-week oral vitamin E treatment (600 mg b.i.d.). Bcl-2 expression was significantly reduced in microalbuminuric diabetic patients as a consequence of increased oxidant burden secondary to persistent hyperglycemia. Bcl-2 down-regulation was associated with enhanced expression of NF-kB, iNOS and MCP-1, and showed a strong correlation with the albumin excretion rate. Low Bcl-2 expression and high inflammatory status were normalized by vitamin E both in vivo and in vitro. Our study showed that Bcl-2 down-regulation in diabetic patients with poor glycemic control results in the activation of the NF-kB pathway leading to the development of nephropathy. Vitamin E might provide a novel form of therapy for prevention of nephropathy in diabetic patients in which an acceptable glycemic control is difficult to achieve despite insulin therapy.

The objective was to evaluate HLA DR/DQ alleles and their risk factor for type 1 diabetes in the Abruzzo region (central Italy). Sixty incident cases from the Abruzzo region were studied together with 120 unrelated control subjects living in the same administrative areas. The relative risk of diabetes associated with the alleles under study was calculated by deriving the odds ratio (OR) maximum likelihood estimates and their 95% confidence intervals (CI) by the exponentiation of the logistic regression beta-parameter. The combination DRB1*03/DQA1*0501/DQB1*0201 was found in 20.0% of patients and 7.1% of the control subjects, conferring an OR of 4.04 and a CI of 1.97-8.49. The combination DRB1*04/DQA1*0301/DQB1*0302 was found in 23.3% of diabetic patients and 6.7% of controls, giving an OR of 5.69 and a CI of 2.77-12.05. DRB1*11/DQA1*0505/DQB1*0301 and DQA1*0505/DQB1*0301 were negatively associated with type 1 diabetes (OR=0.27, CI 0.11-0.57; OR=0.07, CI 0.02-0.19). The DQA1 genotype at risk was found to be DQA1*0301/DQA1*0501: OR=23.80, CI 2.97-190.89, as it occurred with the highest frequency in the patient group. The DQB1 genotype at risk was found to be DQB1*0201/DQB1*0302, which occurred in 13.3% of patients but in only 1.1% of the control group (OR=29.75, CI 5.36-549.25). Our results shed further light on the risk of development of this disease during a specific time period in an area where the overall incidence of type 1 diabetes is known.

Aims/hypothesis: Inflammation plays a pathogenic role in the development of accelerated atherosclerosis in diabetes. Soluble CD40 ligand (sCD40L) is enhanced in diabetes; however, the molecular mechanisms linking sCD40L to accelerated atherosclerosis in diabetes are still unclear. We tested the hypothesis that sCD40L may be involved in the vascular complications in diabetes and exerts its effect by triggering inflammatory reactions on mononuclear and endothelial cells (ECs)., Methods: We studied 70 patients, 40 with type 2 and 30 with type 1 diabetes, with a history or physical examination negative for cardiovascular disease, and 40 non-diabetic and 30 healthy subjects, matched with the type 2 and type 1 diabetic patients, respectively. Plasma and serum sCD40L, and plasma soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, E-selectin and monocyte chemo-attractant protein-1 (MCP-1) were measured. Adhesion molecules and MCP-1 release, the ability to repair an injury in ECs, and O2- generation in monocytes were analysed in vitro after stimulation with serum from patients or controls., Results: Type 2 and type 1 diabetic patients had significantly higher sCD40L levels than controls. Furthermore, high sCD40L was associated with in vitro adhesion molecules and MCP-1 release, impaired migration in ECs and enhanced O2- generation in monocytes. Improved metabolic control was associated with a reduction of plasma sCD40L by 37.5% in 12 type 1 diabetic patients. Furthermore, elevated sCD40L in diabetic patients was significantly correlated with HbA1c levels., Conclusions/interpretation: Upregulation of sCD40L as a consequence of persistent hyperglycaemia in diabetic patients results in EC activation and monocyte recruitment to the arterial wall, possibly contributing to accelerated atherosclerosis development in diabetes.

Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. To evaluate the effects on IAP of vitamin E administration in adolescents with type 1 diabetes and early signs of microangiopathy, 12 adolescents (aged 11-21 y; diabetes duration 10-18) were studied. Eight had retinopathy [background (four), preproliferative (three), or proliferative (one)], four had persistent microalbuminuria, and seven had both. Skin fibroblasts were obtained by biopsies and cultured in Dulbecco's modified Eagle's medium. CuZn superoxide dismutase (SOD), MnSOD, catalase (CAT), and glutathione-peroxidase (GPX) activity and mRNA expression were measured before and after 3 mo of synthetic vitamin E supplementation (600 mg twice daily); on both occasions, IAP was evaluated at different ex vivo glucose concentrations (5 and 22 mM). Ten adolescents with type 1 diabetes (aged 12-20 y) without angiopathy and eight healthy volunteers (aged 15-22 y) participated as control subjects. Vitamin E serum levels were measured throughout the study. In normal glucose concentrations, CuZnSOD, MnSOD, CAT, and GPX activity and mRNA expression were not different among the groups. In high glucose, CuZnSOD activity and mRNA increased similarly in all groups [angiopathics: 0.96 +/- 0.30 U/mg protein; 9.9 +/- 3.2 mRNA/glyceraldehyde-3-phosphate dehydrogenase). CAT and GPX activity and mRNA did not increase in high glucose only in adolescents with angiopathy (0.35 +/- 0.09; 4.2 +/- 0.1 and 0.52 +/- 0.14; 2.4 +/- 0.9, respectively). MnSOD did not change in any group. Vitamin E supplementation had no effect on any enzymatic activity and mRNA in both normal and hyperglycemic conditions. Adolescents with early signs of diabetic angiopathy have defective IAP and activity, which are not modified by vitamin E.

Summer camps for children and adolescents with Type I Diabetes Mellitus (T1DM) represent an alternative setting to improve DSME (Diabetes Self Management Education) which is the cornerstone of care for all individuals with diabetes who want to achieve a successful health related outcome. Since the first camp was set up, summer camps have become widespread throughout the world. In literature, there are many studies that involve diabetes camps but none show enough evidence to assess the their effectiveness. The examined outcome does not involve the evaluation of quality of life enough which represents a multidimensional construct covering micro e macro cultural behaviours that underline different aspects between different regions. It is necessary to improve studies in this way. In any case present day camping experiences are invaluable.

This study is aimed at answering the question whether the demands of the intensified diabetes management and good metabolic control may influence the Quality of Life (QOL) of adolescents with Type 1 Diabetes (T1D), and that of their parents. Overall, 153 adolescents were involved (78 males, mean age 15.0 +/- 2.3 median age 14.6 years; average diabetes duration 6.5 +/- 3.5 years) from the Regional Centres of the Universities of Chieti and Parma. HbA1c determination was centralized and the adolescents were tested according to the adolescent version of the questionnaire developed by Ingersoll and Marrero on the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. The burden on the family was assessed following a newly constructed questionnaire. The average HbA1c value was 7.7 +/- 1.4% (boys 8.0 +/- 1.4 and girls 7.5 +/- 1.2%). The impact of diabetes was similar for both boys and girls (average scores: 44.68 vs 45.00) with no effect regarding age or the duration of diabetes, but the influence of HbA1c values was significant (p < 0.001). Compared with boys, girls had an earlier (at about 12 years of age) and more significant increase in worries (p < 0.01). Lower HbA1c values were associated with fewer worries (p < 0.02). Satisfaction deterioration appeared earlier in girls than in boys and was associated with high levels of HbA1c (p < 0.01). Health perception was poorer in girls than in boys and was influenced by HbA1c values (p < 0.005) in both girls and boys. The burden on the family with diabetes decreased with the age of the adolescent. In conclusion, in our group of adolescents with T1D, lower HbA1c was also associated with better QOL and with a lower perception of a burden on the family. These findings justify the efforts to assess QOL perception in adolescents in order to facilitate achieving better metabolic control.

Objectives: To investigate the possible role of hyperglycemia-dependent monocyte chemoattractant protein (MCP)-1 biosynthesis in the pathophysiology of early nephropathy in type 1 diabetes., Research Design and Methods: We studied 30 patients with type 1 diabetes (15 with and 15 without microalbuminuria) compared with matched healthy control subjects. Plasma MCP-1 and plasma oxidant status (vitamin E, fluorescent products of lipid peroxidation [FPLPs], malondialdehyde [MDA]), HbA(1c), and albumin excretion rate [AER]) were evaluated at baseline. Furthermore, MCP-1, vitamin E, AER, and HbA(1c) were also analyzed in the microalbuminuric diabetic patients and in the healthy volunteers after 8 weeks of high-dose (600 mg b.i.d.) vitamin E treatment., Results: FPLPs, MDA, and MCP-1 were significantly higher, whereas vitamin E was significantly lower in patients with microalbuminuria and poorer glycemic control as compared with normoalbuminuric patients and healthy control subjects. Plasma MCP-1 was positively correlated with HbA(1c), FPLPs, MDA, and AER, whereas plasma MCP-1 showed an inverse correlation with vitamin E. Interestingly, both MCP-1 and AER decreased significantly after vitamin E treatment, despite no changes in HbA(1c) values., Conclusions: This study suggests that prolonged hyperglycemia may lead to early renal complications in type 1 diabetes by inducing MCP-1 biosynthesis via enhanced oxidative stress. Long-term treatment of high-dose vitamin E significantly decreased MCP-1, thus providing a rationale basis for evaluating vitamin E supplementation as therapy adjuvant to conventional insulin treatment in type 1 diabetic patients in whom an acceptable glycemic control is difficult to achieve despite appropriate insulin treatment.

Background: Angiogenin serum levels were measured in a large group of type 1 diabetic young patients, looking at whether increased Angiogenin concentrations are associated with long-term glycemic control and microvascular complications., Materials and Methods: Four groups of patients were compared to 223 age- and sex- matched healthy controls: 196 type 1 diabetic patients (age range 3-24 years, onset of diabetes before the age of 12 years; duration of disease longer than 2 years), without microvascular complications were divided into three groups on the basis of age (group 1, n = 37, age < 6 years; group 2, n = 71, age 6-12 years; group 3, n = 88, age > 12 years); 53 adolescents and young adults (age 16.1-29.7 years) with diabetic microvascular complications (background, preproliferative or proliferative retinopathy, albumin excretion rate 20-200 microg min-1) (group 4)., Results: Angiogenin serum levels were significantly increased in diabetic pre-school and pre-pubertal children, and particularly elevated in pubertal subjects compared with age- and sex-matched controls. Adolescents and young adults with microvascular complications had very high angiogenin concentrations. One-year mean HbA1c values were correlated with angiogenin levels (r = 0.389; p < 0.01). In poorly controlled diabetics (HbA1c > 10%), long-term (2 years) improvement of glycemic control determined a significant reduction of angiogenin concentrations in both pre-school and pre-pubertal children as well as in pubertal youngsters., Conclusions: Angiogenin serum concentrations are increased in diabetic children even before puberty. Severity of microvascular complications is associated with markedly increased angiogenin serum levels. Long-term tight glycemic control determines a consistent reduction of angiogenin concentrations.

Type 1 diabetes mellitus poses a significant health burden, particularly as a result of its microvascular complications. Clinically evident diabetes-related microvascular complications are extremely rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease. Therefore, regular screening for diabetic microvascular disease, particularly retinopathy and nephropathy, are of foremost importance in paediatric diabetes care. Early detection of diabetic microangiopathy and timely treatment of early signs of these complications have a pivotal role in prevention of blindness and end-stage renal failure in children and adolescents with diabetes., (Copyright 2002 S. Karger AG, Basel)

Aims: Associated autoimmune phenomena might influence metabolic control in children and adolescents with Type 1 diabetes mellitus. A retrospective case control study was performed in order to explore the effect of subclinical hypothyroidism on metabolic control in Type 1 diabetes mellitus., Patients and Methods: For this purpose each patient with Type 1 diabetes and subclinical hypothyroidism (cases) was matched for age, duration of disease and, if possible, for sex, with two to three diabetic patients without hypothyroidism (controls). Parameters of metabolic control such as HbA1c, total insulin requirement and frequency of symptomatic hypoglycaemia were retrieved for 12, 6 and 3 months before and after diagnosis of hypothyroidism., Results: Thirteen patients (two male/11 female) patients were diagnosed with subclinical hypothyroidism and were matched with 31 controls (nine male/22 female). There was no difference (mean and range) in terms of age (11.9 years (4.4-18.1) vs. 11.7 years (3.5-18.1), P = 0.9) and duration of disease (5.1 years (1.2-10.5) vs. 4.38 years (0.9-10.8), P = 0.6) between the two groups. There was no difference in HbA1c and total insulin requirement between the two groups at any time point of assessment (anova P = 0.8 and P = 0.1, respectively). Patients with hypothyroidism had significantly more symptomatic hypoglycaemic episodes during the 12 months before diagnosis (anova P = 0.05), increasing progressively during this time period and reaching a peak at time 0 (5.5+/-0.4 vs. 1.6+/-0.1 episodes/month, P = 0.01). No difference could be detected within 6 months of starting substitution therapy (2.4+/-0.2 vs. 1.6+/-0.1 episodes/week, P = 0.8)., Conclusions: These data suggest that subclinical hypothyroidism is associated with an increased risk of symptomatic hypoglycaemia. The prompt introduction of substitution therapy is recommended as it reduces its frequency.

This study was designed to evaluate whether vascular endothelial growth factor serum concentrations may identify adolescents with onset of type 1 diabetes during childhood at greater risk to develop persistent microalbuminuria and incipient diabetic nephropathy. In January 1989, vascular endothelial growth factor serum levels were measured in 101 normoalbuminuric diabetic children and adolescents (aged 7-14.9 yr; onset of diabetes before age 18 yr; duration of diabetes >7 yr). Participants were clinically examined at baseline and annually thereafter. Vascular endothelial growth factor serum concentrations were measured every year during the 8-yr follow-up period. Over 8 yr, 11 of 101 patients (10.9%) developed persistent microalbuminuria; no patient developed overt nephropathy. The risk of developing microalbuminuria was higher in children with increased vascular endothelial growth factor serum levels (using 160 pg/ml as the arbitrary cut-off point; group 1) compared with those with normal vascular endothelial growth factor serum levels at the beginning of the study (group 2; 19.2 vs. 2.0%; P < 0.01; sensitivity, 90.9%; specificity, 53.3%). The odds ratio for the occurrence of microalbuminuria after adjustment for confounding variables (albumin excretion rate, sex, hemoglobin A(1c), mean blood pressure, cholesterol, and triglycerides) in type 1 diabetic adolescents with elevated vascular endothelial growth factor serum levels was 4.1 (95% confidence interval, 2.0-10.9). These results suggest that vascular endothelial growth factor serum concentrations may be one of the predictors and risk factors for microalbuminuria and incipient diabetic nephropathy in adolescents and young adults with onset of diabetes during childhood. Persistently increased vascular endothelial growth factor serum levels may help to identify normotensive, normoalbuminuric patients with type 1 diabetes who are predisposed to develop persistent microalbuminuria later in life.

Background: Symptomatic hypoglycemia is an unavoidable problem in the treatment of type I diabetes. Celiac disease is associated with malabsorption and may therefore represent an important risk factor., Methods: The frequency of symptomatic hypoglycemia in patients with type I diabetes and celiac disease (cases) was compared with those of patients who had diabetes without celiac disease (controls). For this purpose, each case was matched for age, sex, and duration of disease with one to two control patients. Indices of metabolic control (hemoglobin [Hb]A1c, frequency of hypoglycemia, and total insulin requirement) were retrieved for the 18 months before and after diagnosis of celiac disease., Results: Eighteen patients (6 males and 12 females) had diagnosed celiac disease and were matched with 26 control patients (10 males and 16 females). There was no difference in age (11.0 years; range, 1.8-21.9 vs. 13.1 years; range, 2.3-22; P = 0.3) and duration of disease (8.4 years; range, 1.2-19.3 vs. 8.3 years; range, 1.1-18.7; P = 0.3) between the two groups. During the 6 months before and after diagnosis of celiac disease the cases had significantly more hypoglycemic episodes than the controls (means +/- SD; 4.5+/-4 vs. 2.0+/-2.2 episodes/months, P = 0.01). This was reflected by a progressive reduction in insulin requirement over the 12 months before diagnosis reaching a nadir at time 0 (0.6+/-0.2 vs. 0.9+/-0.3, P = 0.05)., Conclusion: These data suggest that underlying celiac disease is associated with an increased risk of symptomatic hypoglycemia and that the introduction of a gluten-free diet with normalization of the intestinal mucosa may reduce its frequency.

Objective: To assess plasma homocysteine levels in adolescents and young adults with type 1 (insulin-dependent) diabetes with and without microvascular complications., Study Design: Homocysteine levels were measured during fasting and after methionine loading in plasma of 61 patients with onset of diabetes before the age of 12 years and duration of disease longer than 7 years. They had an albumin excretion rate (AER) between 20 and 200 microg/min in 2 of 3 overnight urine collections in a period of 6 months and/or retinopathy. Patients with persistent microalbuminuria were divided into 2 groups: subjects with AER of 20 to 70 microg/min and patients with AER of 70 to 200 microg/min. Adolescents (n = 54) without signs of diabetic retinopathy or nephropathy and matched control subjects (n = 63) were also studied., Results: Homocysteine concentrations before and after methionine load were higher in adolescents with diabetic complications than in healthy subjects (fasting values: 12. 4 +/- 7.9 micromol/L vs 7.8 +/- 4.2 micromol/L; P <.01; after methionine load: 28.1 +/- 13.2 micromol/L vs 16.6 +/- 7.3 micromol/L; P <.005). Values of 11.9 micromol/L or higher were considered to constitute fasting hyperhomocysteinemia. The increase of homocysteine concentrations was particularly evident in young diabetic patients with AER >70 microg/min (fasting values: 14.7 +/- 5.6 micromol/L; after methionine load: 34.2 +/- 12.6 micromol/L) and in patients with proliferative retinopathy (fasting values: 15.1 +/- 5.0 micromol/L; after methionine load: 36.8 +/- 12.5 micromol/L)., Conclusions: Increased plasma homocysteine concentrations may contribute to increased morbidity and death from cardiovascular disease in adolescents and young adults with diabetic retinopathy and nephropathy.

Aims: To evaluate serum levels of vascular endothelial growth factor (VEGF) in a large group of children, adolescents and young adults with Type 1 diabetes mellitus to investigate whether increased VEGF concentrations are associated with long-term glycaemic control and microvascular complications., Methods: The study involved 196 patients with Type 1 diabetes mellitus (age range 2-24 years, onset of diabetes before the age of 12 years, duration of disease longer than 2 years), without clinical and laboratory signs of microvascular complications; they were divided into three groups (group 1 - n = 37, age < 6 years; group 2 - n = 71, age 6-12 years; group 3 - n = 88, age > 12 years). Fifty-three adolescents and young adults (age 16.1-29.7) with different grades of diabetic retinopathy and microalbuminuria were also selected (group 4). A total of 223 healthy controls were matched for age and sex with each group of patients with diabetes mellitus., Results: VEGF serum levels were significantly increased in pre-school and pre-pubertal children with diabetes as well as in pubertal patients compared to controls. VEGF concentrations were markedly increased in adolescents and young adults with microvascular complications compared with both healthy controls and diabetic patients without retinopathy or nephropathy. Multivariate analysis showed that elevation of VEGF in serum was an independent correlate of complications. One-year mean HbA1c values were significantly correlated with VEGF concentrations (r = 0.372; P < 0.01). Children with HbA1c levels greater than 10% had significantly higher VEGF concentrations when compared with matched patients whose HbA1c levels were lower than 10%. In poorly controlled diabetic children (HbA1c > 10%), long-term (2 years) improvement of glycaemic control (aiming at HbA1c < 7%) resulted in a significant reduction of VEGF levels., Conclusions: VEGF serum concentrations are increased in prepubertal and pubertal children with diabetes. Glycaemic control influences VEGF serum levels. Severity of microvascular complications is associated with marked increase of VEGF concentrations in the serum of these patients.

The aim of this study was to evaluate serum advanced glycation end products (S-AGEs) in a group of adolescents and young adults with type 1 (insulin-dependent) diabetes mellitus and with diabetic microvascular complications (nephropathy or retinopathy). Fifty-two patients were included in the study (age range 14.2-28.8 years, onset of diabetes before the age of 12 years, duration of diabetes longer than 7 years); 45 patients without diabetic angiopathy and 63 healthy controls were also selected. S-AGEs were significantly increased in patients with diabetic angiopathy compared with controls (19.9+/-3.8 vs. 11.8+/-2.8 U/ml, P<0.001). Higher S-AGE levels were found in patients with severe diabetic nephropathy and retinopathy. When the albumin excretion rate (AER) was >100 microg/min per 1.73 m2, S-AGE levels were 23.1+/-2.4 U/ml; when the AER was 50-100 microg/min per 1.73 m2 levels were 19.8+/-1.9 U/ml, and for an AER of 20-50 microg/min per 1.73 m2 the corresponding value was 16.1+/-2.1 U/ml (P<0.005). Patients with proliferative retinopathy had S-AGE levels of 22.2+/-2.6 U/ml, those with preproliferative retinopathy 20.7+/-2.2 U/ml, and background retinopathy 17.6+/-1.9 U/ml (P<0.01). A significant correlation was found between levels of glycosylated hemoglobin (HbA1c) and S-AGE (r=0.43, P<0.01). S-AGE concentrations are markedly increased in type 1 diabetic adolescents and young adults with diabetic nephropathy and retinopathy. The severity of diabetic angiopathy is related to the serum levels of AGEs.

Hyperglycemia has been causally linked to vascular and glomerular dysfunction by a variety of biochemical mechanisms, including a glucose-dependent abnormality in nitric oxide (NO) production and action. NO is a candidate for mediating hyperfiltration and the increased vascular permeability induced by diabetes. Serum nitrite and nitrate (NO2-+ NO3-) concentrations were assessed as an index of NO production in 30 adolescents and young adults with type 1 diabetes, 15 with and 15 without microalbuminuria (albumin excretion rate [AER] between 20 and 200 microg/min), compared with a well-balanced group of healthy control subjects. In all subjects, glomerular filtration rate (GFR) was determined by radionuclide imaging. Our study showed that NO2- + NO3- serum content and GFR values were significantly higher in microalbuminuric diabetic patients than in the other 2 groups. GFR was significantly and positively related to AER levels (r2 = 0.75, P < 0.0001), whereas NO2- + NO3- serum content was independently associated with both AER and GFR values (beta = 2.086, P = 0.05, beta = 1.273, P = 0.0085, respectively), suggesting a strong link between circulating NO, glomerular hyperfiltration, and microalbuminuria in young type 1 diabetic patients with early nephropathy. Interestingly, mean HbA1c, serum concentration was significantly higher in microalbuminuric than in normoalbuminuric diabetic subjects (P < 0.05) and was independently associated with AER values, suggesting a role for chronic hyperglycemia in the genesis of diabetic nephropathy. Moreover, HbA1c serum concentration was significantly and positively related to NO2 + NO3 serum content (r2 = 0.45, P = 0.0063) and GFR values (r2 = 0.57, P = 0.0011), suggesting that chronic hyperglycemia may act through a mechanism that involves increased NO generation and/or action. In conclusion, we suggest that in young type 1 diabetic patients with early nephropathy, chronic hyperglycemia is associated with an increased NO biosynthesis and action that contributes to generating glomerular hyperfiltration and persistent microalbuminuria.

Objective: To evaluate whether erythrocyte sodium-lithium countertransport (Na+/Li+ CT) activity may identify adolescents and young adults with childhood-onset of type 1 diabetes to be at greater risk to develop persistent microalbuminuria and incipient diabetic nephropathy., Research Design and Methods: In January 1989, Na+/Li+ CT was measured in 170 normoalbuminuric diabetic adolescents and young adults (age 12-23 years; onset of diabetes before age 18 years; duration of diabetes longer than 7 years). Participants were clinically examined at baseline and biennially thereafter. Na+/Li+ CT activity was measured every 2 years during the 8-year follow-up period. Na+/Li+ CT activity was measured also in parents of diabetic offspring., Results: Over 8 years, 18 (10 male, 8 female) out of 170 patients (10.5%) developed persistent microalbuminuria; no patient developed overt nephropathy. The risk of developing microalbuminuria was higher in children with increased Na+/Li+ CT (using 300 mumol.1 erythrocytes-1.h-1 as the arbitrary cutoff point) (group 1) compared with those with normal Na+/Li+ CT at the beginning of the study (group 2) (18.98 vs. 3.29%, P < 0.01; sensitivity 96.7%; specificity 57.9%). Sex did not influence predictive value, sensitivity, or specificity. Na+/Li+ CT was not significantly correlated with HbA1c or duration of type 1 diabetes. The percentage of offspring with both parents having Na+/Li+ CT activity above the median values was significantly higher in patients in group 1 than in group 2. The odds ratio for the occurrence of microalbuminuria after adjustment for confounding variables (albumin excretion rate [AER], sex, HbA1c, mean blood pressure, cholesterol, triglycerides) in type 1 diabetic adolescents with elevated baseline erythrocyte Na+/Li+ CT was 4.5 (95% CI of 2.1-11.4)., Conclusions: These results confirm those of previous studies and suggest that Na+/Li+ CT may be one of the predictors and risk factors for incipient diabetic nephropathy in adolescents and young adults with onset of diabetes during childhood. Persistently increased Na+/Li+ CT activity may help to identify normotensive, normoalbuminuric patients with type 1 diabetes who are predisposed to develop microalbuminuria and incipient diabetic nephropathy.

A survey on glycemic control in 201 diabetic children and adolescents, aged 0-18 years, was performed in two Italian Centers for Childhood Diabetes (Chieti and Parma). Mean HbA1c was 7.8+/-1.4 (range 4.8-13.3%; median 7.6%). With progression of diabetes duration, deterioration of glycemic control was observed (r=0.20; p< 0.002), more evident in girls than in boys, with peaks at 14 (8.9+/-2.0 vs 6.9+/-1.7%; p<0.05) and 16 years (9.5+/-1.4% vs 8.1+/-1.1; p<0.02). No differences were found in BMI values in boys or girls, or for insulin doses which were increased significantly in both sexes according to age (r= 0.33, p<0.04). The number of insulin injections did not influence glycemic control. Only one severe hypoglycemic episode was reported during the period of observation. This study demonstrates that modern management, continuous education and patient and family empowerment are effective in attaining excellent glycemic control without increasing the risk of hypoglycemia.

Objective: To provide incidence data of insulin dependent diabetes mellitus (IDDM) in the Abruzzo Region, Italy in 0-14 year-old children and contribute to a better understanding of IDDM geographical variability throughout Italy., Subjects and Methods: All incident cases younger than 15 years first diagnosed with IDDM according to the WHO criteria between 1 January 1990 and 31 December 1995 and resident in the Abruzzo Region were recorded. The primary sources were divisions of pediatrics, endocrinology or medicine, diabetic centers for adult patients and the Regional Pediatric Diabetology Centre. Secondary independent sources included registered prescriptions for insulin in local district units of the National Health System and the regional IDDM association for children., Results: During the six years, 117 new cases of IDDM in the age-group 0-14 were identified, with an overall standardized incidence rate of 9.34/100,000/year (95% C.I. 7.76-10.95). The crude incidence rate was highest in the 10-14 year age-group (10.64, 95% C.I. 7.66-13.62). Teramo province showed the highest standardized incidence rate, 10.30/100,000/year (95% C.I. 6.58-14.02); it is noteworthy that the IDDM rate in Teramo (15.40/100,000/year) was the highest in peninsular Italy in 1994. Abruzzo Region shows significantly higher rates than other central Italian regions. No significant difference in rates between males and females was observed. Seasonality was not observed from incidence data., Conclusions: We report the highest incidence rate for IDDM in children in the Italian mainland in the years 1990-95. Our findings confirm the need for epidemiological research to provide more information about the distribution of genetic markers and the etiologic role of environmental factors in Italian regions.

We studied thirty diabetic patients and we evaluated their knowledge of main topics of diabetes mellitus. The level of the knowledge was evaluated by multiple choice questionnaires. On the basis of score obtained the patients were divided into two groups: Group A, with high knowledge level, Group B, with low knowledge level. All the patients were followed-up for a 12 months period after a careful education. At the end of follow-up, we compared the Group A patients with another group of 14 diabetic children, who have followed an educational programme from the diagnosis of the disease (Group C). We assessed the knowledge score and the principal metabolic parameters in the three groups of patients; during the follow-up, we found a significant increase of these parameters in Group A and B patients, more evident in Group A patients. At the end of follow-up, the Group C patients showed a higher knowledge score and metabolic parameters than the Group A children. This study shows that education of disease is important for the increase of metabolic parameters and its usefulness is higher if is carried out from the onset of the disease.

In order to analyse the role of long-term metabolic control on serum lipids of diabetic children, the authors studied 61 diabetics for a period of time of 18 months. The age of the patients ranged from 7.2 to 19.5 years; the patients were divided into two groups according to the presence of albumin excretion rate more than 15 micrograms/min: group A 46 children with albumin excretion rate less than 15 micrograms/min; group B 15 children with albumin excretion rate more than 15 micrograms/min. During the study, all the patients improved the quality of metabolic control but only in the diabetics of group A serum cholesterol and triglycerides levels fell significantly. The patients of group B did not modify their serum lipids concentrations in spite of the improvement of metabolic control. This study suggests that in the diabetic children with microalbuminuria it is difficult to normalize the lipid abnormalities by means of optimized insulin conventional therapy.

A controlled trial of a new microprocessor device for insulin-dosage adjustment was undertaken in two matched groups of a priori well-controlled diabetic children. A prospective study design with three equal 8-wk periods was used. In the first period, both groups used manual methods for insulin-dosage adjustment after manual criteria. In the second period, one group of children adjusted insulin dosage by computer algorithms, whereas the other continued to use manual methods. In the third period, both groups again adjusted insulin by traditional methods. Mean premeal glycemia and glycosylated hemoglobin levels did not change in either group throughout the study. During the second period, episodes of hypoglycemia were more frequent in children without the computer than in those who used the device. In keeping with the latter outcome, the group that used the microprocessor device was given less insulin in the second period than the first (0.88 +/- 0.02 vs. 0.94 +/- 0.02 U.kg-1.day-1, P less than 0.0001) and in comparison to the control group of patients who concurrently were given an increased insulin dose in the second period compared with the first. This study showed that insulin treatment through specific computer-mediated dosage-adjusting algorithms was safe and minimized hypoglycemia by effectively accommodating seasonally changing insulin requirements. We recommend the device to help diabetic children and their families in the care of insulin-dependent diabetes.