Oral peanut immunotherapy in children with peanut anaphylaxis.

BACKGROUND: The only treatment option for peanut allergy is strict avoidance. OBJECTIVE: To investigate efficacy and safety of oral immunotherapy (OIT) in peanut allergy. METHODS: Twenty-three children (age, 3.2-14.3 years) with IgE-mediated peanut allergy confirmed by positive double-blind, placebo-controlled food challenge (DBPCFC) received OIT following a rush protocol with roasted peanut for 7 days. If a protective dose of at least 0.5 g peanut was not achieved, patients continued with a long-term buildup protocol using biweekly dose increases up to at least 0.5 g peanut. A maintenance phase for 8 weeks was followed by 2 weeks of peanut avoidance and a final DBPCFC. Immunologic parameters were determined. RESULTS: After OIT using the rush protocol, patients tolerated a median dose of only 0.15 g peanut. Twenty-two of 23 patients continued with the long-term protocol. After a median of 7 months, 14 patients reached the protective dose. At the final DBPCFC, patients tolerated a median of 1 g (range, 0.25-4 g) in comparison with 0.19 g peanut at the DBPCFC before OIT (range, 0.02-1 g). In 2.6% of 6137 total daily doses, mild to moderate side effects were observed; in 1.3%, symptoms of pulmonary obstruction were detected. OIT was discontinued in 4 of 22 patients because of adverse events. There was a significant increase in peanut-specific serum IgG(4) and a decrease in peanut-specific IL-5, IL-4, and IL-2 production by PBMCs after OIT. CONCLUSION: Long-term OIT appears to be safe and of some benefit in many patients with peanut allergy. With an increase in threshold levels and a reduction of peanut-specific T(H)2 cytokine production, the induction of tolerance may be feasible in some patients.

LMNA mutations, skeletal muscle lipid metabolism, and insulin resistance.

CONTEXT: Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated. OBJECTIVE: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect. PATIENTS AND METHODS: Carbohydrate and lipid metabolism was studied on 10 FPLD patients, one patient with limb-girdle muscular dystrophy (LGMD1B, a different lamin A/C disease), and 10 healthy control subjects before and during an oral glucose tolerance test by indirect calorimetry and im microdialysis. Muscle biopsies were taken for in vitro studies. RESULTS: We observed marked increased skeletal muscle fatty acid beta-oxidation rate in vitro and in vivo, even after glucose ingestion in FPLD patients. However, fatty acid oxidation was largely incomplete and accompanied by increased ketogenesis. The lipid oxidation abnormality was associated with impaired glucose disposition through reduction in glucose oxidation, rather than decreased cellular glucose uptake. A microarray showed down-regulation of complex I respiratory chain, glycolysis, and nuclear transport genes. Although not overtly insulin resistant, the LGMD1B patient showed similar metabolic derangements as the FPLD patients. CONCLUSIONS: Our study suggests imbalance between lipid oxidation and oxidative glucose metabolism in FPLD and LGMD1B patients. The observation suggests an intrinsic defect in skeletal muscle metabolism due to lamin A/C dysfunction. The metabolic FPLD phenotype likely results from this intrinsic defect combined with lipodystrophic "lipid pressure" due to decreased adipose tissue lipid storage capacity.

Dipeptidyl-peptidase-IV inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients.

CONTEXT: Dipeptidyl-peptidase-IV (DPP-4) inhibition increases endogenous GLP-1 activity, resulting in improved glycemic control in patients with type 2 diabetes mellitus. The metabolic response may be explained in part by extrapancreatic mechanisms. OBJECTIVE: We tested the hypothesis that DPP-4 inhibition with vildagliptin elicits changes in adipose tissue and skeletal muscle metabolism. DESIGN AND SETTING: We conducted a randomized, double-blind, crossover study at an academic clinical research center. PATIENTS: Twenty patients with type 2 diabetes, body mass index between 28 and 40 kg/m(2), participated. INTERVENTION: INTERVENTION included 7 d treatment with the selective DPP-4 inhibitor vildagliptin or placebo and a standardized test meal on d 7. MAIN OUTCOME MEASURES: Venous DPP-4 activity, catecholamines, free fatty acids, glycerol, glucose, (pro)insulin, dialysate glucose, lactate, pyruvate, glycerol were measured. RESULTS: Fasting and postprandial venous insulin, glucose, glycerol, triglycerides, and free fatty acid concentrations were not different with vildagliptin and with placebo. Vildagliptin augmented the postprandial increase in plasma norepinephrine. Furthermore, vildagliptin increased dialysate glycerol and lactate concentrations in adipose tissue while suppressing dialysate lactate and pyruvate concentration in skeletal muscle. The respiratory quotient increased with meal ingestion but was consistently lower with vildagliptin. CONCLUSIONS: Our study is the first to suggest that DPP-4 inhibition augments postprandial lipid mobilization and oxidation. The response may be explained by sympathetic activation rather than a direct effect on metabolic status.