inhaled glucocorticoids are widely recommended as first - line treatment , and short - term treatment with oral glucocorticoids is often used during exacerbations .
exogenous glucocorticoids  inhaled as well as oral  may cause a wide range of dose - dependent adverse systemic effects [ 4 , 5 ] . these include suppression of hypothalamic - pituitary - adrenal function , growth retardation , catabolic effects on bone metabolism , suppressive effects on connective tissue including atrophy of the skin , cataracts , haematological effects , and , finally , but not least , metabolic effects [ 5 , 6 ] .
the metabolic effects include elevated serum glucose concentration and hyperlipidaemia , both of which are closely linked to the  metabolic syndrome  with a greatly increased risk for cardiovascular disease , stroke , and type ii diabetes [ 7 , 8 ] .
such glucocorticoid - induced effects are mediated by binding to receptors in the liver and in muscle as well as adipose tissue and may partly be due to reduced insulin sensitivity [ 79 ] .
little attention has been paid to the possible effects of glucocorticoid treatment on carbohydrate and lipid metabolism in children despite potentially very harmful long - term consequences .
the effects of inhaled glucocorticoids which often may be used during many years in the treatment of asthma have been studied few times in adults [ 1012 ] and once in children .
these studies were flawed by methodological shortcomings , and the results were largely conflicting [ 1013 ] . the study conducted in children suggested effects of high - dose treatment with inhaled glucocorticoids on carbohydrate as well as on lipid metabolism .
there are no available studies of the effects of oral glucocorticoid treatment on neither carbohydrate nor lipid metabolism in children .
we conducted the present study to assess effects of short - term treatment of inhaled and oral glucocorticoid treatment on carbohydrate and lipid metabolism in children as measured by serum fructosamine , an indicator of the average serum glucose concentration during the preceding 2 - 3 weeks , serum total cholesterol , and high - density lipoprotein ( hdl ) .
both trials included two treatments , run - in and washout periods of one - week duration .
in one trial 5  mg prednisolone once daily in the evening was compared with placebo , in the other 200  g budesonide from a dry powder inhaler ( spirocort turbuhaler ) twice daily was compared with no treatment .
the sequence of active versus placebo and no treatment , respectively , was allocated by a computerized randomization scheme prepared in balanced blocks .
only study medication and inhaled 2-agonist ( bricanyl turbuhaler 0.5  mg ) as rescue medication were allowed throughout the study .   the two studies were designed to investigate a wide range of systemic effects during glucocorticoid treatment , including short - term growth of the lower leg assessed by knemometry .
the power calculations were based on previous knemometry data and showed that to be able to detect a 50% reduction in lower leg growth rate with 80% probability , 16 children had to complete the study [ 16 , 17 ] .
thus , the prednisolone and budesonide trials included 20 and 17 children with asthma , respectively .
all children had suffered from asthma for more than one year and had been treated with inhaled glucocorticoids at least 6 months prior to inclusion .
blood samples were collected at the last day of the treatment periods at the same time of the afternoon 30 minutes , centrifuged 10  min at 4000  rpm , and stored at 80c .
the children were nonfasting at the time of sampling . at the completion of both trials ,
serum fructosamine was batch assayed by means of a commercially available colorimetric assay with a reproducibility of 0.9% ( roche ) .
total cholesterol and hdl were assessed using commercially available enzyme assays ( chod - pap for total cholesterol with a coefficient of variation ( cv ) of 1.9% and direct assay for hdl with a cv of 2.7% ) from roche on a hitachi 917 .  
pulmonary function tests were performed with the vitalograph at each visit with measurement of forced vital capacity ( fvc ) , forced expiratory volume in 1 second ( fev1 ) , and peak expiratory flow ( pef ) . throughout the trials , all children performed daily measurement of pef in the morning and in the evening with the mini - wright peak - flow meter and recorded the results in asthma diaries along with symptom scores on a scale from 0 to 3 and use of 2-agonist .
the trials were conducted in accordance with international guidelines issued by the european commission in 1990 and the declaration of helsinki and were approved by the local ethics committee .
serum fructosamine , total cholesterol , hdl , pef , and fev1 were compared between the treatment periods in both trials by means of a paired t - test .
all data were tested for period and carry - over effects as described for crossover designs .
serum fructosamine , total cholesterol , and hdl and the results of the statistical tests are given in table 2 .
serum fructosamine was increased during active treatment in both trials . though numerically increased total cholesterol and hdl were not statistically significantly increased during prednisolone treatment .
small and insignificant differences were observed in total cholesterol and hdl during budesonide treatment . no period or carry over effects were detected in fructosamine , total cholesterol , or hdl .  
no significant differences were found in any parameter of pulmonary function in any of the trials .
insulin is one of the primary factors in the regulation of the blood glucose concentration .
insulin secretion is stimulated by glucose and other energy rich substances in the blood , that is , the higher the blood glucose , the higher the insulin secretion in healthy subjects .
insulin subsequently lowers blood glucose by stimulating uptake of glucose in fat and muscle tissue and by stimulating glycogen synthesis and inhibiting glycogenolysis in the liver .
endogenous cortisol counteracts insulin and increases blood glucose by inhibiting uptake into muscle and fat tissue and by increasing glycogenolysis and gluconeogenesis in the liver .
these effects are mimicked by prednisolone and budesonide which bind to glucocorticoid receptors and , thus , may increase mean blood glucose [ 20 , 21 ] . however , in healthy subjects , a compensatory increase in insulin secretion will tend to reduce mean blood glucose to normal or near normal levels .
this counter regulatory mechanism most likely explains the small but significant increases in mean blood glucose concentration reflected by the increased serum fructosamine in the present studies . fasting serum samples could not be obtained for practical reasons , and therefore it is not possible to assess standardised values of serum insulin , proinsulin , or c - peptide , which may had been used to confirm the hypothesis .
an earlier study in asthmatic school children found no effect on fasting blood glucose or insulin concentration during treatment with inhaled budesonide 800  g daily from a spacer , but significantly increased insulin levels were measured during an oral glucose tolerance test .
the systemic availability from a spacer device is approximately 10% compared to 20% from a turbuhaler , so similar systemic activity should be expected from 800 g budesonide daily from a spacer and 400  g daily from a turbuhaler .
thus , the results from both the studies suggest that normal or close to normal blood glucose concentrations are found during treatment with a moderate dose inhaled budesonide , but a somewhat higher insulin concentration is required to maintain normal glucose levels . whether minute increases in mean blood glucose may have long - term clinical importance remains unknown ; however , it is well known that long - term -cell stress with elevated insulin production is associated with development of type ii diabetes .
two studies reported no effects on carbohydrate turnover after treatment with inhaled budesonide 800 or 1600  g daily from a spacer in asthmatic adults   or after treatment with inhaled beclomethasone 2000  g daily in young healthy or elderly diabetic adults .
the third study that was in healthy young adults reported increased fasting insulin levels and increased blood glucose levels during oral glucose tolerance testing after inhaled beclomethasone 1000  g daily .
furthermore , results obtained in adult populations should only be extrapolated to children with great caution .
it was quite surprising to us that 400  g inhaled budesonide was found to cause a comparable increase in mean blood glucose to 5  mg prednisolone .
the observation raises the question whether stimulatory effects may be caused by even lower doses of inhaled budesonide .
we found significant increases in serum fructosamine already after one - week glucocorticoid treatment in both trials ; however , one might speculate whether larger increases would be found after 2 - 3 weeks treatment .  
the activity of the enzyme is increased by glucocorticoids , which may thereby increase serum total cholesterol and hdl .
increased lipoprotein lipase activity in the endothelium seems to increase the risk of arteriosclerosis , whereas increased activity in muscle and fat tissue seems to lower the risk .
it is currently debated whether the overall effect of increased enzyme activity is beneficial or harmful .
the present finding of numerically increased serum total cholesterol and hdl during prednisolone treatment may well be explained by stimulation of lipoprotein lipase .
however , the observed changes in our study were small and statistically insignificant , and there are no previous data for comparison .
it is highly questionable whether the small increases are insignificant due to a type 2 error .
it is more likely that the changes are too small to be significant and that significant changes may occur during treatment with higher doses .
possible clinical long - term consequences should be evaluated in long - term follow up trials .
a similar trial found small and insignificant increases in total cholesterol , but significant increases in hdl during treatment with inhaled budesonide 800  g daily but not during treatment with 400  g daily from a spacer in children . in a study in healthy adults ,
significant increases in both total cholesterol and hdl were found during treatment with inhaled beclomethasone 1000  g daily , whereas others have found small but insignificant increases in total cholesterol during treatment with 2000  g daily .
so at present it seems fair to conclude that inhaled glucocorticoids in high doses may cause increases in total cholesterol and hdl ; however , 400  g budesonide daily from a turbuhaler does not cause such effects in school age children .
the present study has suggested that in children with asthma short - term treatment with prednisolone 5  mg daily or inhaled budesonide 400  g daily may increase mean blood glucose as measured by serum fructosamine .
further studies are needed to clarify possible short - term prednisolone stimulatory effects on total cholesterol and hdl . whether our findings may have clinical implications awaits long - term follow - up trials .
 
 background / aims . glucocorticoids may have adverse effects on carbohydrate and lipid metabolism . 
 the present study was conducted to investigate possible effects on carbohydrate and lipid metabolism of inhaled and oral glucocorticoids in children with asthma . 
 methods . 
 two randomised controlled trials with blinded crossover designs were performed . 
 active treatment was 400  g inhaled budesonide or 5  mg prednisolone orally daily during one week . 
 the budesonide trial included 17 and the prednisolone trial 20 school children . 
 serum fructosamine , total cholesterol and high - density lipoprotein were assessed . results . 
 serum fructosamine was increased during active treatment ( prednisolone 252.3  m versus placebo 247.3  m ; p = 0.03 and budesonide 228.1  m versus no treatment 223.1  m ; p = 0.02 ) . 
 total cholesterol and high - density lipoprotein were not statistically significantly increased . 
 conclusion . 
 short - term treatment with oral prednisolone and inhaled budesonide may adversely affect mean blood glucose concentration . 
 possible long - term consequences require further investigations . 
1. Introduction
2. Patients and Methods
3. Statistics
4. Results
5. Discussion
6. Conclusions