Once-daily budesonide: 400 micrograms once daily is as effective as 200 micrograms twice daily in controlling childhood asthma. PETITE Research Group.

One hundred and sixty seven children on 0-200 microgram/day of inhaled steroid with asthma symptoms and sub-optimal peak flow values (less than 90% of that predicted for their height) were randomly allocated either 400 microgram once daily (nocte with placebo o.m.) or 200 mircrogram twice daily of budesonide Turbohaler for 8 weeks. Bronchdilator usage and symptoms were reduced in both groups at 4 and 8 weeks compared with baseline. There was a significant increase within both groups in morning and evening PEF after 4 and 8 weeks. The increase in evening PEF after 8 weeks was greater in the once-daily group than in the twice-daily group but there were no other significant differences between the groups (morning: +24.6 l/min vs 15.2 l/min, p = 0.059; evening: + 19.7 l/min vs +8.31 l/min; p = 0.013). Budesonide Turbohaler 400 microgram once daily is therefore as effective as 200 microgram twice daily in achieving asthma control in children.

Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective postreceptor insulin resistance.

Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor.

Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC-1 in dermal fibroblasts from patients with syndromes of severe insulin resistance.

OBJECTIVE: To date, mutations in the insulin receptor gene are the only clearly defined cause of extreme insulin resistance in man. Recently, however, some patients with severe insulin resistance have been reported to have marked over-expression of the transmembrane glycoprotein PC-1 in their cultured fibroblasts. This protein appears to act as an endogenous inhibitor of the insulin receptor tyrosine kinase which suggests that primary over-expression of PC-1 may play an aetiological role in some forms of insulin resistance. One sub-type of extreme insulin resistance in which the insulin receptor gene has been reported to be normal is pseudo-acromegalic insulin resistance. The main aim of this study was to determine whether overexpression of PC-1 might contribute to the severe insulin resistance exhibited by some patients with pseudo-acromegaly. DESIGN AND PATIENTS PC-1 phosphodiesterase activity and PC-1 protein and mRNA content were measured in cultured dermal fibroblast from three severely insulin resistant pseudo-acromegalic patients. These were compared with fibroblasts from normoinsulinaemic normoglycaemic controls and from subjects with known genetic defects in the insulin receptor or IRS-1. RESULTS: In the fibroblasts from pseudo-acromegalic insulin resistant subjects PC-1 activity and PC-1 protein and mRNA levels were indistinguishable from the normoinsulinaemic controls. Consistent with this observation, insulin receptor tyrosine kinase activity was similar in extracts from fibroblasts of pseudo-acromegalic subjects and normal controls. Surprisingly, subjects with insulin receptor or IRS-1 mutations had a profound reduction in PC-1 activity (p < or = 0.005), protein (p < or = 0.05) and mRNA levels (P < or = 0.005). CONCLUSIONS: The results indicate that PC-1 over-expression does not appear to contribute to the insulin resistant state of pseudo-acromegalic patients. The finding of normal insulin receptor tyrosine kinase activity in these subjects suggests that the site of defective insulin signalling is likely to be distal to the receptor. The unexpected finding that PC-1 activity, protein and mRNA were all dramatically reduced in patients with lesions early in the insulin signalling cascade provides further evidence for a link, albeit as yet poorly understood, between cellular insulin action and the expression of PC-1.