Stefano Tumini

Vascular endothelial growth factor (VEGF) in children, adolescents and young adults with Type 1 diabetes mellitus: relation to glycaemic control and microvascular complications.

SUMMARY

Celiac disease in children and adolescents with type I diabetes: importance of hypoglycemia.

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.

An ATP-Binding Mutation (G334D) in KCNJ11 Is Associated With a Sulfonylurea-Insensitive Form of Developmental Delay, Epilepsy, and Neonatal Diabetes

Mutations in the pancreatic ATP-sensitive K+ channel (KATP channel) cause permanent neonatal diabetes mellitus (PNDM) in humans. All of the KATP 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 KATP 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.

Controlled Study in Diabetic Children Comparing Insulin-Dosage Adjustment by Manual and Computer Algorithms

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 wasused. 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 < 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 insulindependent diabetes.

Prevalence of hypospadias in Italy according to severity, gestational age and birthweight: an epidemiological study

BackgroundHypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world.MethodsWe reviewed all the newborns file records (years 2001–2004) in 15 Italian Hospitals.ResultsWe found an overall hypospadias prevalence rate of 3.066 ± 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10th percentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1).ConclusionIn our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3–4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.

Effects of Vitamin E Supplementation on Intracellular Antioxidant Enzyme Production in Adolescents with Type 1 Diabetes and Early Microangiopathy

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 Dulbeccos modified Eagles 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.

Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes

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.

Advanced glycation end products in adolescents and young adults with diabetic angiopathy.

Abstract 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 µg/min per 1.73 m2, S-AGE levels were 23.1±2.4 U/ml; when the AER was 50–100 μg/min per 1.73 m2 levels were 19.8±1.9 U/ml, and for an AER of 20–50 μg/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.

Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population-based study.

Blasetti A, Di Giulio C, Tocco AM, Verrotti A, Tumini S, Chiarelli F, Altobelli E. Variables associated with severe hypoglycemia in children and adolescents with type 1 diabetes: a population‐based study.

Insulin Pump Therapy Management in Very Young Children with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion

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.