GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus.

BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

Current use of metformin in addition to insulin in pediatric patients with type 1 diabetes mellitus: an analysis based on a large diabetes registry in Germany and Austria.

BACKGROUND: With increasing obesity in childhood and adolescence, weight gain, and insulin resistance become also more frequent in patients with type 1 diabetes mellitus (T1DM). Especially during puberty, insulin therapy often has to be intensified and higher insulin doses are necessary. Some studies point to a beneficial effect of metformin in addition to insulin in these patients. In order to describe current practice and possible benefits, we compared pediatric T1DM patients with insulin plus metformin (n = 525) to patients with insulin therapy only (n = 57 487) in a prospective multicenter analysis. METHODS: Auxological and treatment data from 58 012 patients aged <21 yr with T1DM in the German/Austrian Diabetes Patienten Verlaufsdokumentation (DPV) registry were analyzed by multivariable mixed regression modeling. RESULTS: Patients with additional metformin were older [median (interquartile range)]: [16.1 (14.1-17.6) vs. 15.2 (11.5-17.5) yr] with female preponderance (61.0 vs. 47.2%, p < 0.01). They had higher body mass index-standard deviation score (BMI-SDS) [+2.03 (+1.29 to +2.56) vs. +0.51 (-0.12 to +1.15); p < 0.01] and glycated hemoglobin (HbA1c) (9.0 vs. 8.6%, p < 0.01). Hypertension (43.7 vs. 24.8%) and dyslipidemia (58.4 vs. 40.6%) were significantly more prevalent. Adjusted insulin dose was significantly higher (0.98 vs. 0.93 IU/kg bodyweight). In a subgroup of 285 patients followed-up longitudinally (average treatment period 1.42 yr), addition of metformin resulted in a slight reduction of BMI-SDS [-0.01 (-2.01 to +1.40)], but did not improve HbA1c or insulin requirement. CONCLUSION: Additional metformin therapy in T1DM is primarily used in obese females. Additional therapy with metformin was associated with minor benefits.

Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center.

BACKGROUND: Congenital hyperinsulinism (CHI) is a rare disease with an estimated incidence of 1:40,000 live births. Here, we characterize 11 patients treated at Munich Children's Hospital Schwabing. METHODS: We analyzed data on birth, treatment and laboratory results including genetic testing and evaluated the long-term course with a follow-up visit. RESULTS: All patients had severe, diazoxide-(DZX)-resistant hypoglycemia, beginning immediately after birth. Two patients were treated by medical therapy, eight underwent subtotal pancreatectomy and one had a partial resection. Both patients who had medical therapy still suffer from occasional hypoglycemia. Six patients with subtotal pancreatectomy were affected by mild hypoglycemia. Seventy-five percent of patients who had surgical treatment developed diabetes mellitus (DM) at a median age of 10.5 (8-13) years. In 89% of patients with available genetic testing, mutations of the ABCC8 gene were detected. CONCLUSIONS: The majority of CHI-patients not responding to DZX underwent surgery. After subtotal pancreatectomy, patients typically developed diabetes around early puberty.

Severe pretreatment cerebral edema in newly diagnosed type 1 diabetes.

INTRODUCTION: Cerebral edema (CE) is a rare and dangerous complication of diabetic ketoacidosis. In typical cases, it may develop during several hours after the beginning of ketoacidosis therapy. Nevertheless, CE sometimes occurs before the start of any therapy - as for the patient in this report here. CASE REPORT: We describe a 12-year-old girl with newly diagnosed type 1 diabetes, presenting with severe headache and disorientation. Diabetes-related symptoms were not reported by the family. Clinical investigation revealed signs of meningeal irritation and Kussmaul breathing. In the laboratory, severe ketoacidosis (pH 6.95) and hyperglycemia (blood glucose 20.9 mmmol/l) were found. Cranial computed tomography showed CE. The patient was treated with a very cautious fluid and insulin therapy and recovered within 3 days. MRI after recovery showed normal findings without residuals of CE. CONCLUSION: CE before any treatment of ketoacidosis is a very rare complication of type 1 diabetes. Early diagnosis and effective treatment are extremely important for the patient's outcome and prognosis.

GCK-MODY (MODY 2) Caused by a Novel p.Phe330Ser Mutation.

Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes inherited as an autosomal dominant trait. The second most common cause is GCK-MODY due to heterozygous mutations in the GCK gene which impair the glucokinase function through different mechanisms such as enzymatic activity, protein stability, and increased interaction with its receptor. The enzyme normally acts as a glucose sensor in the pancreatic beta cell and regulates insulin secretion. We report here a three-generation nonobese family diagnosed with diabetes. All affected family members presented with mild hyperglycemia and mostly slightly elevated hemoglobin A1c values. Genetic testing revealed a novel heterozygous T → C exchange in exon 8 of the GCK gene which resulted in a phenylalanine(330) TTC → serine (TCC)/p.Phe330Ser/F330S substitution.

Parenteral fat emulsions based on olive and soybean oils: a randomized clinical trial in preterm infants.

OBJECTIVE: To evaluate in premature infants a new parenteral lipid emulsion based on olive and soybean oils (ratio 4:1), with less polyunsaturated fatty acids (PUFA) and more alpha-tocopherol than standard soybean oil emulsion. STUDY DESIGN: Premature infants (gestational age, 28-<37 weeks) were randomized to receive one of the two emulsions within the first 72 hours of life. The triglyceride dose was increased to 2 g/kg/day within 3 days. Plasma phospholipid fatty acids, alpha-tocopherol/lipid ratio, and urinary malondialdehyde (MDA) excretion were determined at baseline and after 7 days. RESULTS: Of 45 recruited infants, 33 completed the study per protocol (15 soybean oil, 18 olive oil emulsion). At study end, groups did not differ in plasma phospholipid arachidonic acid, total n-6 and n-3 metabolites, but the olive oil group showed higher values of the PUFA intermediates C18:3n-6 (0.19% +/- 0.01% vs. 0.13% +/- 0.02%, P < 0.05) and C20:3n-6 (2.92% +/- 0.12% vs. 2.21% +/- 0.17%, P = 0.005). The plasma alpha-tocopherol/total lipd ratio was higher in the olive oil group (2.45 +/- 0.27 micromol/mmol vs. 1.90 +/- 0.08 micromol/mmol, P = 0.001), whereas urinary MDA excretion did not differ. CONCLUSION: The lower PUFA supply with the olive/soybean oil emulsion appears to enhance linoleic acid conversion. The reduced PUFA content, combined with a higher antioxidant intake in the olive oil group, results in an improved vitamin E status. The olive oil-based emulsion is a valuable alternative for parenteral feeding of preterm infants who are often exposed to oxidative stress, while their antioxidative defense is weak.