strong epidemiological evidence indicates that a sedentary lifestyle leads to an increased risk of developing certain cancers , including colon , prostate , breast , and endometrial cancers [ 13 ] .
by contrast , physical activity has been shown to have a protective effect against their development .
igf - i is a potent mitogen that promotes cellular proliferation and prevents apoptosis in normal and cancer cells [ 46 ] .
igf - i axis hormones are important factors implicated in the beneficial influence of exercise .
epidemiological studies have shown that increased levels of circulating igf - i or increased igf - i relative to igfbp-3 are associated with a higher risk of developing several forms of cancer , including prostate and breast cancers [ 712 ] .
the combination of a low - fat diet and exercise program is known to reduce igf levels .
[ 13 , 14 ] showed a decrease in the serum concentration of igf - i and an increase in igfbp-1 with the implementation of a low - fat diet and exercise program .
furthermore , they reported that serum from men undergoing this form of intervention showed reduced cancer cell growth and increased apoptosis in lncap prostate cancer cells in vitro [ 13 , 15 ] . in conjunction with the changes in serum igf - i and igfbp-1 , reductions have also been shown in insulin and free testosterone , along with increases in sex hormone - binding globulin [ 15 , 16 ] .
when igfbp-1 was added to preintervention serum , lncap cancer cells underwent apoptosis ; whereas , when igf - i was added to postintervention serum , the reduction in growth was eliminated .
thus , the down - regulation of igf - i and up - regulation of igfbp-1 , as a result of the diet modification and exercise intervention program , may have protective effects against the development of cancerous cells .
however , the training intensity and/or duration of exercise required to induce such favorable alterations has not yet been fully elucidated . a number of intervention studies
have shown increased [ 1823 ] , decreased [ 24 , 25 ] , or unaltered [ 26 , 27 ] levels of igf - i after endurance or resistance training .
similarly , many cross - sectional observational studies have examined the association of physical activity with igf - i levels in the general population ; however , their findings have been inconsistent [ 2832 ] .
additionally , some reports have shown that circulating levels of igfbp-1 and igfbp-3 are also modulated with exercise [ 23 , 33 , 34 ] , whereas other groups saw no effects in their levels with moderate - intensity aerobic exercise or strength training [ 35 , 36 ] .
the different responses of igf axis hormones to the intensity and/or duration of various types of exercise could be the reason why exercise is not necessarily protective against all forms of cancer .
furthermore , it also has been reported that very heavy exercisers demonstrate high mortality ratios for lung , colorectal , and pancreatic cancers . whether exercise induces desirable ( i.e. , downregulation of igf - i and upregulation of igfbp-1 ) or undesirable ( i.e.
, up - regulation of igf - i and down - regulation of igfbp-1 ) effects on cancer prevention is highly dependent on training intensity . as high - intensity exercise produces an acute increase in circulating igf - i levels [ 38 , 39 ] , the exercise intervention that induces a reduction in igf - i levels may be in the low or moderate categories . to the best of our knowledge
, only one cross - sectional study has shown a reduction in serum igf - i levels and increase in igfbp-1 levels in participants of an exercise program , without emphasis on diet modification , in comparison to a control group . despite the fact that physical exercise is considered a strong intervention for cancer prevention , there are few studies that specifically assess the effects of exercise on specific biomarkers of cancer . in addition
, it has been described in a previous review that persons at varying risks of developing cancer should be examined in exercise intervention studies , as the magnitude of protection caused by exercise may differ in high - versus low - risk individuals .
furthermore , no previous intervention study has been conducted to examine whether an exercise regimen alone can elicit favorable changes in both igf - i and igfbp-1 levels for cancer prevention in healthy men . additionally , insulin is another factor which has the potential to influence the levels of igf - i and igfbp-1 after exercise training .
hyperinsulinemia stimulates liver production of igf - i and suppresses igfbp-1 production [ 4 , 41 ] .
it is also known that insulin itself promotes cellular growth in normal as well as malignant tissues [ 42 , 43 ] .
in addition , leptin may also regulate changes in igf - i following exercise intervention .
the lactate threshold ( lt ) represents the oxygen uptake ( vo2 ) or work rate above which there is a systemic rise in blood lactate levels during incremental exercise .
the lt level corresponds to approximately 50%  vo2max , and exercise at lt can be performed easily and safely even in the elderly and individuals with metabolic syndrome [ 46 , 47 ] . in a previous study by our group ,
low - intensity aerobic training at lt level caused an increase in insulin sensitivity ( si ) , with a concomitant decrease in the basal level of insulin . in this study
we used this exercise training program as it was designed to have an insulin - sensitizing effect .
we hypothesized that lt - level aerobic training , which does not stimulate igf - i production and reduces basal insulin levels , would result in simultaneous alterations in both the down - regulation of igf - i and up - regulation of igfbp-1 .
thus , we investigated the effect of mild aerobic exercise training at lt level on the circulating levels of igf - i , igfbp-1 , and igfbp-3 to determine an optimal exercise intervention that can induce favorable changes in igf - i and igfbp-1 levels for cancer prevention in healthy men .
fourteen healthy men ( 22.6  0.5 years ) who had not undergone any regular exercise for at least 2 years were examined .
all subjects were nonsmokers , had no evidence of chronic disease , such as diabetes , hypertension or cancer , and were not taking any medication .
all subjects were also asked to maintain their normal dietary habits and not to engage in any strenuous physical activity . before beginning the study , the nature , purpose , and risks of the study
each subject 's body fat percentage was measured by hydrostatic weighing before commencing training and 2 days after the last training session .
this was estimated based on the hydrostatic density with a correction for the residual lung volume . to measure physical fitness , a graded exercise test
was performed on a mechanically braked ergometer ( electric bicycle ergometer , lode 's instrumenten b. v. , groningen , holland ) before commencing the training program and 2 days after the final training session .
the work rate was initially set at 10 watts and increased every 4 seconds by 1 watt , until physical exhaustion .
the volume of the expired gas was quantified with a twin - drum - type respirometer ( fukuda irika cr-20 , tokyo , japan ) , and both the o2 and co2 fractions were analyzed by a mass spectrometer ( arco-1000 , arco system inc . ,
blood samples were obtained from the earlobe every 30 seconds to measure blood lactate levels .
the blood lactate concentration was plotted against the exercise workload for each subject , and the workload at the first breaking of lactate was used to calculate the exercise training intensity for each subject .
the lt was determined for each subject based on a visual inspection , according to the estimations of three experts , who were blinded to the purpose of our study , and the average was used to establish the exercise intensity for training .
cycle ergometer aerobic training at the lt level was performed at our laboratory for 60 minutes per day , five times a week for 6 weeks .
blood samples were obtained from an antecubital vein each morning between 0700 and 0900  h , following overnight fasting , prior to training , and 1672 hours after the final training session .
plasma glucose levels were measured spectrophotometrically using glucose oxidase ( glucose b - test ; wako pure chemical , osaka , japan ) ; serum insulin ( phadeseph insulin radioimmunoassay kit , shionogi , osaka , japan ) and leptin ( human leptin kit , linco research , missouri , usa ) concentrations were measured by radioimmunoassay ; and serum igf - i ( somatomedin - cii [ chiron ] measurement kit , chiron inc . , tokyo , japan ) , igfbp-1 ( dsl-7800 , diagnostic systems laboratories , inc .
, texas , usa ) , and igfbp-3 ( ab tube igf - bp-3 eiken , diagnostic systems laboratories , inc . , texas , usa )
the intra- and interassay coefficient variations were 3.9% and 2.8% for igf - i , 4.6% and 6.0% for igfbp-1 , and 7.2% and 10.5% for igfbp-3 , respectively .
ivgtts were performed before commencing the training program and 16 hours after the last training session .
following overnight fasting , subjects were allowed to rest while lying down for at least 30 minutes prior to blood sampling .
baseline samples for glucose and insulin were obtained , followed by glucose administration via the contralateral antecubital vein ( 300  mg / kg body weight ) within 2 minutes .
subsequent samples were obtained at frequent intervals until 180  min , as previously described .
insulin ( humalin ; shionogi , osaka , japan ) was infused ( 20  mu / kg ) via an antecubital vein between the periods of 2025 minutes post glucose administration . on the day before undergoing ivgtt , all subjects were provided with an evening meal consisting of 140  g carbohydrate , 30  g fat , and 33  g protein .
the si index represents the net increase in glucose disappearance rate , which also depends on the rise in insulin above basal levels .
the minimal model program was written using pascal programming ( borland international , ca ) on a macintosh iicx ( apple computer , ca ) .
pearson 's correlation coefficient was used for the analysis of the correlation between the changes of variables after the exercise training .
weight and body fat percentage did not change after the training period ( table 1 ) .
by contrast , mild training significantly increased indices of aerobic fitness . both basal glucose and insulin levels significantly reduced after training ( table 2 ) .
although iri , which was calculated using matthews ' formula , increased only slightly , the increase was significant .
lt exercise was found to significantly decrease the circulating levels of igf - i , whereas igfbp-1 was significantly increased .
there was no significant relationship between the baseline level of igf - i and baseline measures of vo2max   ( r = 0.15 ) or lt - vo2 ( r = 0.20 ) .
there were also no significant correlations between the change in circulating igf - i levels and the changes in aerobic fitness ( vo2max , r =    0.10 ) , basal insulin ( r = 0.08 ) , iri ( r = 0.12 ) , and si ( r = 0.41 ) after exercise intervention .
similarly , relationships between the change in igfbp-1 and changes in basal insulin ( r = 0.33 ) and si ( r = 0.27 ) were not statistically significant .
furthermore , the change in leptin levels after exercise was not significantly correlated with the changes in igf - i ( r = 0.22 ) or igfbp-1 ( r = 0.45 ) .
conversely , there was a negative correlation between pre - training igf - i levels and individual changes in igf - i after training ( r = 0.77 ; p < .01 ) ( figure 1 ) .
changes in vo2max   showed a positive correlation with changes in igfbp-1 ( r   =   0.61 ; p < .05 ) ( figure 2 ) .
the main findings of this study were as follows : ( 1 ) short - term cycle ergometer aerobic training at lt level decreases circulating igf - i concentrations and increases igfbp-1 levels , without changing body weight , in previously sedentary men ; ( 2 ) there is an inverse relationship between pre - training igf - i levels and individual changes in igf - i after training , suggesting that individuals with a higher pre - training igf - i level will have a more substantial decrease in igf - i following exercise intervention ; and ( 3 ) increases in aerobic fitness ( vo2max  ) positively correlates with changes in igfbp-1 level after training .
it is known that alterations in the igf axis , including a reduction in igf - i and an increase in igfbp-1 , by lifestyle modification are associated with an in vitro reduction in prostate cancer cell ( lncap ) growth and increased apoptosis [ 13 , 16 ] .
thus , the current insulin - sensitizing exercise program is a safe and easily - performed exercise program that simultaneously induces a down - regulation of igf - i and up - regulation of igfbp-1 .
the physiological effects of decreased igf - i and increased igfbp-1 levels after mild aerobic training have not been clarified by this study . however , since igf - i infusion causes hypoglycemia , primarly by stimulating peripheral glucose uptake , and igfbps buffer the acute hypoglycemic effect of igf - i , we thus speculate that the alterations in igf - i and igfbp-1 levels may be an adaptive response to prevent hypoglycemia following insulin - sensitizing training . in a previous study of exercise - induced energy deficit ,
leptin administration significantly increased circulating levels of igf - i in healthy men and women . in this study ,
leptin levels were unchanged after the training program , and the individual changes in the levels of igf - i were not significantly correlated with the changes in leptin concentration .
thus , leptin may not play a role in the alteration of igf - i after mild exercise in healthy men .
the principal factor enhancing the production of igf - i in the liver is growth hormone , which stimulates igf - i synthesis and is further enhanced by insulin [ 41 , 52 ] . as fasting insulin levels
are slightly but significantly decreased after exercise intervention , it could potentially contribute to the reduction in igf - i levels . some [ 19 , 22 , 39 ] , but not all [ 5355 ] , previous studies have reported increases in igf - i after acute exercise ; however , these increases are transient and typically return to baseline levels within 1015  min after exercise .
increases in igf - i after acute exercise are considered to be unrelated to exercise - induced increases in growth hormone .
moreover , increases in igf - i after acute exercise were observed in growth hormone - deficient subjects .
we previously showed that acute bout of exercise at lt transiently increases growth hormone level .
however , it is likely that resting levels of growth hormone are not influenced by low - intensity training .
it is worthwhile noting that this study examines changes in systemic igf - i levels and that changes in local production ( i.e. , paracrine / autocrine effects ) are not assessed .
thus , this study could not capture the potential effect of exercise on igf changes at the tissue level . a single bout of acute resistance exercise upregulates local ( i.e. , skeletal muscle ) igf - i [ 5961 ] . to the best of our knowledge , whether local igf - i is upregulated by low - intensity aerobic exercise
a recent review suggested that local changes in igf - i are independent of changes in circulating igf - i , indicating that serum igf - i is not necessarily a reflection of local concentrations .
thus , in this study , the reduced levels of systemic igf - i post - exercise intervention may not have been influenced by local igf - i .
it has been considered that reduced insulin levels after exercise may contribute to the up - regulation of igfbp-1 .
furthermore , exercise - induced changes in basal insulin levels did not significantly correlate with changes in igfbp-1 ; however , this may be due to the low number of subjects .
conversely , the present results show a significant relationship between changes in vo2max   and circulating igfbp-1 levels .
additionally , it seems noteworthy that correlations between the change in igfbp-1 and changes in basal insulin ( r = 0.33 ) and si ( r = 0.27 ) were moderate and in the expected direction , although not statistically significant .
although we are unable to explain the underlying mechanisms , the enhancement of aerobic fitness might be important in the up - regulation of igfbp-1 with low - intensity training .
that low - intensity aerobic exercise ( 2 to 3 times / week at an intensity of 6080% maximal heart rate for 3045  min ) for 6 months improved si and increased igfbp-1 in healthy middle - aged men . although that study did not assess the level of aerobic fitness ( vo2max  ) , fasting insulin levels decreased in the exercise group by 14% , with a 15% increase in igfbp-1 after training for 6 months . in this
study a similar decrease in fasting insulin ( 13% ) caused a similar increase in igfbp-1 ( 16% ) after exercise intervention .
this indicates that increases in igfbp-1 are regulated by changes in insulin induced by exercise training .
a previous study showed that the changes in igf - i and igfbp-1 levels , induced by a combined low - fat diet and exercise program , were accompanied by a reduction in body weight .
furthermore , in this cross - sectional study , participants in the exercise program with a lower igf - i and higher igfbp-1 had a much lower bmi , compared with the control group .
by contrast , another report on the effects of aerobic exercise combined with a low - fat , high - complex carbohydrate diet showed reduced serum insulin and positive control over aspects of metabolic syndrome , including hypertension and hypertriglyceridemia , over a period of only 3 weeks , even though the subjects remained overweight or obese .
examined igf - i and body mass changes associated with 7-day strenuous exercise and found a decrease in igf - i levels , even in weight - stable subjects .
similarly , this study showed that alterations of circulating igf - i and igfbp-1 , basal insulin , and si after lt - level training were observed without changes in body weight and body fat percentage .
thus , in conjunction with previous results , this suggests the importance of exercise alone , rather than changes in body composition , on the regulation of igf - i and igfbp-1 . there were some limitations of this study that should also be described .
the short period ( 6 weeks ) of training intervention was a limiting factor in this study .
further studies are needed to examine whether longer periods of exercise intervention induce sustained and greater impacts on the changes in insulin sensitivity , fasting insulin , and igf - i and igfbp-1 levels .
information on dietary intake before and during the intervention was not recorded , despite the fact that diet is an important modifier of igf levels .
because of this limitation , we are unable to perform a cross - sectional analysis of the relationship between dietary components and igf levels .
since body weight did not decrease in this study , dietary intake does not need to be reduced during the exercise intervention .
thus , reduced igf levels after the current aerobic training might not be affected by decreased dietary intake .
the potential problems with the absence of a control group are the unwitting incorporation of a sampling bias .
for example , the possibility that an inverse relationship between the initial ( baseline ) igf - i levels and the change in igf - i levels after training could be due to a convergence towards the mean effect can not be fully excluded .
however , previous reports have shown that a single igf - i measurement is generally representative of the levels over a period of time   and igf - i levels appear to have no detectable diurnal or circadian variation [ 29 , 65 ] .
it is also worth mentioning that , although a lower level of igf - i is associated with a lower cancer risk in prospective healthy population , several studies have shown that lower igf - i is associated with an increased risk of cardiovascular disease , type ii diabetes , obesity [ 56 , 66 ] , osteoporosis , and cognitive decline .
there are also reports of conflicting data showing that subjects with obesity or type ii diabetes have normal levels of total igf - i [ 67 , 68 ] and no significant correlation between igf - i and bone mineral density in women [ 69 , 70 ] .
nindl and pierce have described in their recent review that the fact that there are studies claiming that both increases and decreases in igf - i concentrations have beneficial effects on health presents a contradictory situation .
furthermore , they also stated that , even though local igf - i is consistently up - regulated with both acute and chronic exercises , circulating igf - i may actually decrease . however , despite lowering igf - i , the current exercise program would be expected to have beneficial effects on all of these various conditions . in this study , subjects were healthy men with a relatively low risk of developing cancer . although the changes in igf - i were most dramatic in men with high baseline levels , it is not clear whether this will apply to populations with different baseline levels .
serum levels of igf - i are inversely associated with age [ 29 , 31 ] , and igf - i levels are higher in women than in men in western population .
conversely , in the japanese population , the circulating igf - i level was found to be higher in men than in women .
further work is needed to extend the present outcome to a wider population by examining whether the same exercise regimen at the lt can induce such favorable changes in individuals who have elevated igf - i levels and are at increased risk of developing cancer . in conclusion , we found that short - term aerobic exercisetraining at lt levels decreased circulating igf - i and increased igfbp-1 levels , without changing body composition , in previously sedentary men .
these results are consistent with those of a previous rodent study demonstrating the beneficial effects of low - level exercise on cardiovascular , as well as cancer risk factors .
it has been described that physical exercise deserves particular attention in the prevention of neoplasia , especially as it also exerts consistent beneficial effects on other major chronic diseases prevalent in the western world , such as atherosclerosis and type 2 diabetes .
the current low - intensity aerobic training regimen is thus considered to be an effective approach in healthy men for down - regulating igf - i and up - regulating igfbp-1 levels .
 increased concentrations of circulating insulin - like growth factor - i ( igf - i ) or igf - i relative to igf - binding proteins ( igfbps ) are associated with increased risk of developing several forms of cancer . 
 conversely , exercise is linked with reduced risk . 
 this study aims to investigate the effect of a low - intensity exercise program on circulating levels of igf - i , igfbp-1 , and igfbp-3 , in previously sedentary males . 
 fourteen healthy men participated in cycle ergometer training at lactate threshold intensity for 60  min / day , 5 days / week for 6 weeks . 
 after aerobic training , insulin sensitivity improved by 20% , while fasting insulin levels decreased by 13% . 
 simultaneously , low - intensity aerobic training decreased the circulating levels of igf - i by 9% , while igfbp-1 levels increased by 16% . 
 an interesting finding was that higher pretraining level of igf - i was associated with greater decline in igf - i with training . 
 insulin - sensitizing low - intensity aerobic exercise is thus considered to be an effective method for downregulating igf - i and upregulating igfbp-1 levels . 
1. Introduction
2. Methods
3. Results
4. Discussion