type 2 diabetes mellitus ( t2 dm ) is a chronic metabolic disease characterized by 
 hyperglycemia and , resulting from insulin resistance and impaired insulin secretion
. 
 clinical management of t2 dm consists of nutrition therapy , pharmacological therapy , and 
 exercise1 .
the american college of 
 sports medicine ( acsm ) and american diabetes association ( ada ) have published positional 
 statements recommending the use of exercise as an intervention for t2dm2 , 3 .
regular exercise 
 and physical activity are well known as an effective strategy for the prevention and 
 treatment of t2 dm . most studies testing the therapeutic effects of exercise on t2 dm involve 
 continuous low- to moderate - intensity exercise , such as walking , jogging , or cycling , for  
 30 minutes per session2 .
however , the 
 variables inherent in these exercise training programs , such as type of exercise and 
 intensity , have varied .
two separate meta - analyses , meanwhile , have concluded that 
 high - intensity exercise may be more effective for improving glycemic control in t2dm4 , 5 . 

clinical tests comparing the effects of different exercise intensities on t2 dm should be 
 completed to better identify the precise intensity of exercise needed to achieve an optimal 
 outcome6 .
high - intensity interval 
 exercise training ( hie ) , which involves repeated bursts of vigorous exercise interspersed 
 with periods of recovery , may be an attractive option in implementing a high - intensity 
 exercise training program in t2dm7 .
the 
 efficacy of hie for improving disease outcomes has been demonstrated in patients with heart 
 failure , chronic obstructive pulmonary disease , and metabolic syndrome ( ms)8 . in low - intensity exercise training ( lie ) , 
 energy consumption is increased , but fatigue and monotonous and generally dreary feelings 
 make this option difficult to maintain . however , the potential benefits of hie on the disease parameters within t2 dm have yet to be 
 fully established .
recently , hie protocols have been evaluated in participants with ms and 
 t2dm7 , 9 .
these studies have demonstrated drastic improvement in body 
 composition , glycemic control , and physical fitness factors , and although the high intensity 
 training used may limit the feasibility of living freely under unsupervised conditions , it 
 also highlights the potential of interval training modalities in t2 dm patients10 , 11 .
recent studies have shown that hie offers either similar or superior 
 benefits in terms of glycemic control , insulin , and -cell function outcomes compared with 
 traditional continuous exercise11,12,13 .
most of the previous studies have been centered around comparison between hie and 
 moderate - intensity exercise ( mie ) , and research data comparing hie and lie , under the 
 assumption that lie and t2 dm patients perform different amounts of exercise .
this study 
 looks at the progress related to diabetes management in relation to the function of the 
 endoplasmic reticulum14,15,16 .
the function of 
 the endoplasmic reticulum and the onset of metabolic diseases are closely related .
also , in 
 the pathogenesis of genetic and metabolic disorders , such as obesity , hyperlipidemia , and 
 diabetes , it has been reported that there is a correlation between the function of the 
 endoplasmic reticulum15 , 16 . among the endoplasmic reticulum stress responses
is a 
 phenomenon that occurs in the regulation of synthesis and the transport of proteins that 
 occurs through the endoplasmic reticula of eukaryotic organisms ; not only does it have a 
 close relationship with the differentiation of cells , survival rate , immunity and 
 physiological changes , but it also has both direct and indirect relationships with various 
 immunology and pathology related diseases17 .
unfortunately , however , research on er stress and glucagon - like 
 peptide-1 ( glp-1 ) , in relation to diabetes has been very scarce .
therefore , the aim of this study was to test the feasibility of low - intensity exercise 
 training compared with high - intensity exercise training in adolescents with t2 dm . 
 furthermore , we compared the efficacy of hie with energy expenditure - matched lie with regard 
 to changes in the endoplasmic reticulum ( er ) stress level , glp-1 , and glycemic control .
we 
 hypothesized that exercise training could be successfully performed and that hie would be 
 superior to lie with regard to improvements in er stress and glp-1 , despite expected equal 
 improvements in body composition .
adolescents with t2 dm were recruited by newspaper advertisements and by contacting local 
 diabetes patient organizations .
initially , subjects were included in the study and 
 randomized into two groups : the hie group ( n=10 ) and lie group ( n=10 ) .
their mean age was 
 15.3  2.2  years , mean height was 162.8  11.5  cm , mean body mass index ( bmi ) was 24.0  
 3.8  kgm , and mean duration of diagnosis was 4.0  2.2  years .
all volunteers 
 were selected from d university hospital outpatients with result of a 2-hour glucose 
 tolerance test of 140  mg / dl  blood sugar  200  mg / dl and no other complicating 
 diseases .
all volunteers underwent medical screening , including a health status interview , physical 
 exam , and blood analysis .
also , no 
 subjects received insulin therapy , and no medications were altered during the exercise 
 treatments .
the study was approved by the d university hospital institutional review board 
 ( irb ) , and the subjects were included after medical examination and diagnosis by medical 
 specialists . before beginning the exercise program
, all subjects underwent anthropometric 
 measurements ( body weight , body mass index , percentage of fat ) . body composition was 
 measured by the bioelectrical impedance method ( venus 5.5 , jawon medical , seoul , republic of 
 korea ) .
, 
 gyeonggi - do , republic of korea ) exercise test and maximum oxygen uptake ( vo2max ; 
 mlkg-1min-1 ) was determined using a quark b2 analyzer ( cosmed , rome , italy ) after a 
 3-minute rest .
rating of perceived exertion ( rpe ) was rated every minute using the borg 
 scale .
attainment of vo2max was determined by the suspension of movement criteria of the 
 acsm in consideration of subject safety18 .
based on each subject s vo2max and maximum heart rate ( hrmax ) in a maximal graded exercise 
 test , it was possible to calculate treadmill speeds and heart rates for superordinate and 
 subordinate goals using the metabolic equation for running of the acsm18 . in order to achieve the target heart rate ( thr ) , workload 

was gradually increased during trials depending on the participant s heart rate which was 
 monitored with a polar heart rate monitor ( polar electro , kempele , finland ) , and rpe .
the 
 lie performed supervised exercise on a treadmill six times weekly for 12 weeks at  40% 
 heart rate reserve ( hrr ) ( 6 days / week , lie ) .
lie subjects completed supervised exercise 
 continuously during each session , which burned 200  kcal .
the hie group performed supervised 
 walking and running on treadmill three times weekly for 12 weeks at  80% hrr ( 3 days / week , 
 hie ) .
hie subjects completed supervised high - intensity interval exercise ( 30  s sprint , 30  s 
 recovery ) continuously throughout session , which burned 400  kcal .
blood samples were drawn from the antecubital vein after an 8  h overnight fast .
blood 
 samples were centrifuged for 15 minutes ( 3,000  rpm , 4  c ) , stored at 80  c , and directly 
 analyzed .
biochemical analyses of serum glucose - regulated protein 78 ( grp78 ) , glucagon - like 
 peptide-1 ( glp-1 ) , dipeptidyl peptidase-4 ( dpp-4 ) , and leptin were performed using 
 enzyme - linked immunosorbent assays for quantitative detection of human bip / grp78 , glp-1 , 
 human dpp-4 ( abnova corporation , walnut , ca , usa ) and leptin ( r&d systems , minneapolis , 
 mn , usa ) .
all factors were quantified using polyclonal antibodies that recognized native 
 human grp78 , glp-1 , dpp-4 , and leptin a series of plates containing wells coated with 
 predetermined amounts of recombinant human grp78 , glp-1 , dpp-4 , and leptin .
hba1c levels were 
 determined by high performance liquid chromatography using commercially available kit 
 reagents ( bio - rad , hercules , ca , usa ) .
insulin resistance in the fasting state was 
 determined by homeostasis model assessment ( homa - ir ) using the following formula : [ fasting 
 plasma glucose ( mgdl )  fasting plasma insulin ( udl ) ]  
 405 .
data analysis was performed ibm spss statistics for windows version 19.0 ( ibm corp . , 

two - way anova 
 was used to control for differences between groups , test periods , body composition , and 
 blood component changes caused by exercise type , and the paired and independent t - test 
 method was used for the post hot test .
a level of statistical significance of p < 0.05 
 was adopted for this study .
the characteristics of the hie and lie groups at the beginning of the study are shown in 
 table 1table 1.the changes in body composition after 12 weeks of exercise trainingvariablegroupprepostdiff ( % ) weight ( kg)hie62.213.360.014.42.2 ( 3.5)lie66.720.965.423.01.3 ( 1.9)bmi ( kg / m)hie25.23.324.44.00.8 ( 3.2)lie22.84.222.44.80.4 ( 1.8)fat ( % ) hie29.92.927.63.32.3 ( 7.7)lie24.24.123.94.90.4 ( 1.6)vo2max 
 mlkgminhie2,223.5384.72,496.2577.8273 ( 12.9)lie2,382.5665.12,505.2547.2123 ( 5.2)values are meanssd , hie : high - intensity exercise ; lie : low - intensity exercise ; bmi : 
 body mass index . *
there were significant difference in body weight and percentage body fat 
 between the lie and hie groups ( p < 0.05 , respectively ) . also , hie resulted in a greater 
 reduction in percentage body fat than the lie ( p < 0.05 ) .
values are meanssd , hie : high - intensity exercise ; lie : low - intensity exercise ; bmi : 
 body mass index . * significant difference within group ( p<0.05 ) . 
 significant difference compared with lie ( p<0.05 ) table 2table 2.the changes in glycemic control after 12 weeks of exercise trainingvariablegroupprepostdiff ( % ) c - peptide ( ng / ml)hie2.91.34.72.11.8 ( 62.1)lie3.92.35.42.21.5 ( 38.5)insulin ( u / ml)hie42.127.418.78.8l23.4 ( 55.6)lie58.338.846.541.411.8 ( 20.2)glucose ( mg / dl)hie174.325.5138.835.735.5 ( 20.1)lie175.318.5131.826.470.2 ( 36.6)homa - irhie17.410.56.53.410.9 ( 62.6)lie24.916.713.511.411.4 ( 45.8)hba1c ( % ) hie8.83.36.61.02.2 ( 25.0)lie7.41.26.40.41.0 ( 13.5)leptin ( ng / dl)hie1,9236701,178406745 ( 38.7)lie1,423683979618444 ( 31.2)values are meanssd , hie : high - intensity exercise ; lie : low - intensity exercise . 
 *
significant difference 
 compared with lie ( p<0.05 ) shows the changes in glycemic control after the 12-week exercise training 
 programs in the c - peptide level increased after the 12-week programs and was significantly 
 different between groups ( p < 0.05 ) .
the insulin level was significantly decreased after 
 the 12-week exercise training program in the hie group .
fasting glucose , homa - ir , and leptin 
 decreased after the 12-week exercise programs and were significantly different between 
 groups ( p < 0.05 , p < 0.05 , p < 0.05 , respectively ) . however , hba1c showed no 
 significant difference after the 12-week exercise training programs .
values are meanssd , hie : high - intensity exercise ; lie : low - intensity exercise . 

significant difference 
 compared with lie ( p<0.05 ) table 3table 3.the changes in glp-1 , grp78 and dpp-4 after 12 weeks of exercise trainingvariablegroupprepostdiff ( % ) glp-1 ( ng / dl)hie0.210.020.390.040.18 ( 85.7)lie0.210.020.360.020.15 ( 71.4)grp78 ( ng / dl)hie3.884.016.336.652.45 ( 63.1)lie2.541.453.171.980.63 ( 24.8)dpp-4 ( ng / dl)hie29.2320.2322.8521.436.38 ( 21.8)lie34.1623.9829.2024.004.96 ( 14.5)values are meanssd , hie : high - intensity exercise ; lie : low - intensity exercise ; 
 glp-1 : glucagon - like peptide-1 ; grp78 : glucose - regulated protein 78 ; dpp-4 : dipeptidyl 
 peptidase-4 . *
significant 
 difference compared with lie ( p<0.05 ) shows the changes in er stress factors after the 12-week exercise training 
 programs . glp-1
increased after the 12-week exercise programs and was significantly 
 different between groups ( p < 0.05 ) .
values are meanssd , hie : high - intensity exercise ; lie : low - intensity exercise ; 
 glp-1 : glucagon - like peptide-1 ; grp78 : glucose - regulated protein 78 ; dpp-4 : dipeptidyl 
 peptidase-4 . *
the main findings of this study are that hie can be implemented as an exercise treatment 
 method in t2 dm patients and that it is superior to energy expenditure - matched lie with 
 regard to improvements in body composition , glycemic control , and glp-1 under the conditions 
 used in this study .
our research design included careful and successful matching of the 
 exercise training energy expenditures and mean intensities of the training groups .
the results of this study indicate statistically significant improvements in all outcomes 
 in both groups . however , the gains in body composition ( bmi ) and er stress factors ( grp78 , 
 dpp-4 ) were not significantly different between the groups . participants in the hie group 
 demonstrated significant and similar gains in glycemic control and glp-1 during the 3-month 
 trial .
the acsm and ada recommend moderate- and vigorous - intensity exercise for people with t2 dm 
 and provide evidence - based guidelines for prescribing exercise training , in terms of 
 intensity , volume , frequency , duration , and rate of progression1 , 18 . in this study , 

the variable of intensity was different between the groups , whereas the variables of volume , 
 duration , and rate of progression were identical .
on the basis of the findings of this 
 study , individuals who have type 2 diabetes and participate in exercise training at either a 
 moderate- or high - intensity level , as defined by the acsm and ada , may experience similar 
 gains in body composition and glycemic control .
our finding indicate that the hie program resulted in more positive changes in weight , bmi , 
 body fat percentage , and glycemic control ( c - peptide , fasting glucose , homa - ir ) in t2 dm 
 patients than the typical lie program that is usually recommended to existing diabetic 
 patients .
hie also showed positive changes in grp78 , dpp-4 , and glp-1 , which are major 
 factors of er stress , showing more effective improvement for t2 dm patients .
as low- to moderate - intensity exercise , the acsm exercise guidelines18 for diabetes patients recommends an aerobic exercise 
 program involving more than 150 minutes of exercise per week .
however , the hie program 
 maintains homeostasis ; increases energy consumption ; prevents metabolic diseases , such as 
 obesity , and diabetes ; and is known to reduce stress7 , 
 19 , 20 .
sedentary diabetic patients report many barriers to physical 
 activity , but the most common reason given is a  lack of time  for exercise .
however , there 
 is a growing body of literature that compares the metabolic risk factor reduction effects of 
 traditional endurance training programs with the reduction of risk resulting from novel 
 exercise interventions that require minimal amounts of time for patients .
for this reason , 
 hie was recognized as an effective compromise that improves on the tediousness of lie21 , 22 .
moreover , it is effective in inducing insulin sensitivity and 
 controlling weight for t2 dm patients23 . 

it has been shown that the changes in physiological function , performance , and 
 health - related markers resulting from hie are similar to those resulting from lie and that 
 hie results in more positive change in the health of patients than lie9 . in this study ,
the hie group showed a significant reduction 
 in body fat percentage after the exercise compared with before the exercise . in terms of the 
 amount of reduction in body fat percentage , the hie group showed a higher reduction ( 7.69% ) 
 than the lie group .
both groups showed improvement in glycemic control , but the hie group 
 was more effective .
previous studies showed that exercise proved to be effective in 
 regulating glycometabolism by bringing about changes in body weight and percentage body 
 fat .
glycemic control is medically important for t2 dm patient treatment and is an independent 
 risk factor that can predict the possibility of diabetes patients developing 
 complications24 .
in particular , most 
 studies demonstrated that glycemic control is improved through hie (  80% peak power output ) 
 after body weight loss25 , 26 .
it has the effect of reducing insulin secretion , 
 cholesterol , and triglycerides ; it also improves blood sugar levels and suppresses the 
 direct stimulation of glucose intake in the skeletal muscle20 .
the present study shows improvements in blood glucose levels 
 according to the change in body weight , with the hie group showing a greater reduction than 
 the lie group .
it also shows that leptin was reduced in both groups , but hie was 
 particularly more effective .
t2 dm is caused by interactions between genetic and acquired factors , such as overeating and 
 insufficient exercise , and is characterized by hyperglycemia due to relative insulin 
 insufficiency and insulin resistacne27 . 

exercise has been studied regarding its 
 role in improving insulin resistance and it has been classified by type , intensity , and 
 activity period29 .
dube et al.30 recently reported that a graded 
 dose - response relationship exists between exercise intensity and improvements in insulin 
 sensitivity .
when matched for caloric expenditure , high - intensity exercise appears to be at 
 least as effective as moderate - intensity exercise for improving insulin sensitivity31 .
our findings indicated that the hie group 
 showed more positive changes in c - peptide level , fasting glucose , and homa - ir than the 
 typical lie group .
the imbalance between the protein handling capability of the er and its 
 load is referred to as er stress32 .
ozcan 
 et al.32 confirmed that reduction of er 
 stress in the hypothalamus resulted in improvement of leptin resistance ; in addition , it was 
 confirmed that er stress is a major cause of leptin resistance32 and that it is also a major factor that induces leptin 
 resistance .
the present study showed that er stress increased as a result of the increase in 
 physical stress during exercise in participants in the hie group but not in those in the lie 
 group , but the changes in weight , obesity , and insulin resistance ( characterized by positive 
 changes in body fat ) demonstrated that exercise also had positive effects on leptin changes 
 in adolescents with t2 dm .
grp78 plays a significant role in maintaining the viability of cells exposed to various 
 stress environments and helps in the response to immune attacks as well as in resisting the 
 effects of various drugs33 .
grp78 is 
 increased in patients with t2 dm , and it has been reported that insulin resistance can be 
 improved through an exercise - induced increase in grp7834 . in addition , it has been reported that exercise during hypoxia 
 improves insulin sensitivity .
treatment with hypoxia has been reported to be an effective 
 for prevention and treatment of diabetes35 . according to previous studies
, exercise increases the amount of 
 grp-78 , which has a positive effect on improvement of insulin resistance36 .
the present study showed that both groups 
 had increased levels of expression of grp-78 , but the hie group showed a larger increase . 

the cause seems to be an oxygen deficiency occurring during hie , the exhaustion of glucose 
 in the blood , and more physical stress during the exercise .
recently , the role of glp-1 in 
 the treatment of obesity and t2 dm has emerged .
glp-1 , an incretin hormone that regulates 
 blood glucose levels37 , improves insulin 
 sensitivity by stimulating the pancreas to secrete insulin3 and is reported to increase the hydrolysis of triglyceride in 
 adipose tissue38 .
also , 
 previous exercise - related studies have shown that healthy people have increased levels of 
 incretin hormones such as glp-115 .
people 
 who are obese showed similar results to people with normal weight through weight loss 
 resulting from exercise40 . since exercise 
 is considered to be the first line of intervention for the prevention and management of 
 t2 dm , improving glp-1 through exercise is of the utmost importance .
glp-1 , secreted through 
 food stimulation , is decomposed at a very high speed by the enzyme dipeptidyl peptidase-4 
 ( dpp-4 ) , and its involvement in the physiological regulation of eating causes weight 
 loss41 . in this study , both groups were 
 found to have significantly increased levels of glp-1 , with the hie group appearing to have 
 a greater increase .
ddp-4 also affects the amount of glp-1 , and is an important factor in 
 predicting the onset of insulin resistance and ms ; it also has a direct association with 
 insulin resistance42,43,44 .
higher levels of it were 
 also found in people with obesity or ms43 , and it is suggested to have a close relationship with the levels of 
 bmi in healthy young people44 .
the 
 present study showed that dpp-4 decreased in both groups , but the hie group showed an 
 approximately 21% greater reduction .
these results are believed to be due to the reduction 
 of bmi and body fat percentage , which resulted in suppression of dpp-4 activity and in turn 
 creation of incretin hormones that normally control glucose levels , and this is believed to 
 have resulted in the reduction of insulin resistance that ultimately improved the function 
 of glycemic control in t2dm45 .
therefore , high - intensity interval exercise training , as defined in this study , may cause 
 improvements in body composition , glycemic control , and glp-1 in adolescents with t2 dm . in summary , we compared the efficacy of hie with energy expenditure - matched lie in regard 
 to changes in body composition , glycemic control , er stress level ( grp78 , dpp-4 ) , and glp-1 . 

we have showed that hie can be implemented in individuals with t2 dm . furthermore , we showed 
 that hie counteracts deteriorations in glycemic control , and that it is superior to lie with 
 regards to improvements in body composition ( body fat percentage ) , glycemic control , and 
 glp-1 .
hie may therefore be a good option when considering which type of exercise training 
 t2 dm patients should be recommended in primary care .
 [ purpose ] the primary objective of this study was to investigate the effect of 
 low - intensity exercise training compare with high - intensity exercise training on 
 endoplasmic reticulum stress and glucagon - like peptide-1 in adolescents with type 2 
 diabetes mellitus . [ subjects and methods ] the low - intensity exercise training group 
 performed aerobic exercise training at an intensity of  45% of the heart rate reserve . 
 the high - intensity interval exercise training group performed interval exercise training 
 at an intensity of  80% of the heart rate reserve . the exercise - related energy 
 consumption was determined for both groups on a per - week basis ( 1,200 kcal / week ) . 
 
 [ results ] both groups showed improvement in the glucose - regulated protein 78 and 
 dipeptidyl peptidase-4 , but the size of the between - group effect was not statistically 
 significant . 
 the high - intensity interval exercise training group showed a significant 
 reduction in percentage body fat . 
 the c - peptide level increased after the 12-weeks 
 programs and was significantly different , between the groups . 
 fasting glucose , insulin 
 resistance in the fasting state according to homeostasis model assessment , and leptin 
 decreased after the 12-weeks exercise program and were significantly different between the 
 groups , and glucagon - like peptide-1 increased after the 12-week exercise programs and was 
 significantly different between the groups . [ conclusion ] in conclusion high - intensity 
 interval exercise training , as defined in this study , may lead to improvements in body 
 composition , glycemic control , endoplasmic reticulum stress , and the glucagon - like 
 peptide-1 in adolescents with type 2 diabetes mellitus . 
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION