dipeptidyl peptidase4 ( dpp4 ) inhibitors improve glycemic control in patients with type 2 diabetes by preventing degradation of two incretin hormones , glucagonlike peptide1 ( glp1 ) and glucosedependent insulinotropic polypeptide ( gip ) , that are secreted from the intestine on ingestion of various nutrients .
recent studies have shown associations of dpp4 inhibitors efficacy with age and fasting plasma glucose levels , as well as baseline glycated hemoglobin ( hba1c ) and body mass index ( bmi ) , but clinical parameters that predict the efficacy of dpp4 inhibitors are largely unknown .
the present study showed that alterations in hba1c level on administration of dpp4 inhibitors as monotherapy are associated with estimated intake of fish , estimated intake of dietary n3 polyunsaturated fatty acid ( pufa ) , and serum levels of eicosapentaenoic acid ( epa ) and docosahexaenoic acid ( dha ) .
the protocol was approved by the ethics committee of kansai electric power hospital , and carried out in accordance with the principles of the declaration of helsinki . a total of 72 untreated japanese patients with type 2 diabetes ( the japan diabetes society criteria of 2010 ; age 64.6    11.3  years ; duration of diabetes 9.0   8.9  years ; baseline hba1c 7.2    0.7% ; bmi 24.5    4.3  kg / m ) who had been on diet and exercise therapies participated in the current study .
dpp4 inhibitors ( sitagliptin , alogliptin or vildagliptin ) were given for 4  months and no other antidiabetic drugs were used during the period .
a total of 59 patients received sitagliptin , 12 received alogliptin and one received vildagliptin .
hba1c levels were determined before the initiation of dpp4 inhibitors and 4  months after the initiation of dpp4 inhibitors , and were shown in national glycohemoglobin standardization program values , as recommended by the japan diabetes society . fasting serum levels of dha , epa and arachidonic acid ( aa ) were determined based on fatty acid composition of total lipids including phospholipids , triglycerides and cholesteryl esters in the serum of 20 patients ( age 63.1    11.7  years ; duration of diabetes 6.7    5.7  years ; baseline hba1c 7.0    0.8% ; bmi 24.2    3.1  kg / m ) before initiation of dpp4 inhibitors .
selfadministered 3day food records , which were recorded during the 4month period , were analyzed for estimated intake of various nutrients using healthy maker pro 501 ( mushroomsoft co. , ltd . ,
all statistical calculations were carried out using pasw statistics 18 ( sas institute inc . ,
cary , nc , usa ) , including linear regression analyses of the associations between changes in hba1c levels and various parameters .
multiple linear regression analyses were carried out to identify the parameters potentially associated with hba1c reduction , and simple regression analyses were carried out to evaluate their contributions .
in the present study , dpp4 inhibitors , similarly to previous reports , significantly reduced hba1c levels , but not bodyweight ( before initiation of dpp4 inhibitors 7.2    0.7% ; 4  months after initiation of dpp4 inhibitors 6.7    0.6% [ paired ttest , p  <  0.01 vs before ] ) .
multiple regression analysis of hba1c reduction ( hba1c ) taking into account sex , age , duration of diabetes , bmi , baseline hba1c and estimated intake of various food categories in 3day food records showed that hba1c was well correlated with baseline hba1c , but not with bmi ( table  1 ) .
hba1c also showed a significant association with estimated intake of fish and seafood in the food records ( figure  1a and table  1 ) . among fish and seafood , estimated intake of fish , but not shellfish and other seafood , showed a significant association with hba1c ( table  s1 ) .
the beneficial effects of fish on human health have been partly attributed to pufa , such as epa and dha .
hba1c was significantly correlated with estimated intake of epa and dha , along with baseline hba1c ( figure  1b and table  s2 ) . as
serum epa and dha levels might serve as markers for intake of corresponding fatty acids ( figure  s1 ) , we analyzed associations of hba1c with serum epa and dha levels .
serum levels of epa and dha , but not n6 pufa arachidonic acid , were well correlated with hba1c ( figure  1c ) .
although hba1c reduction showed a significant association with estimated intake of milk products ( table  1 ) , we were unable to find nutrients in milk products , including saturated fatty acids , that were responsible for the association .
multiple regression analysis regarding changes of glycated hemoglobin ( hba1c ) levels ( hba1c ) by taking into account sex , age , duration of diabetes , body mass index ( bmi ) , baseline hba1c ( national glycohemoglobin standardization program [ ngsp ] ) and estimated intake of various food categories in 3day food records in 72 patients with type 2 diabetes .
statistical calculation was carried out using pasw statistics 18 ( sas institute inc . ) .
b and  denote nonstandardized and standardized regression coefficients , respectively . for analysis of changes of hba1c levels ,
the correlation coefficient squared ( r ) was 0.550 and the fvalue with 15 degrees of freedom was 3.499 for a pvalue of 0.003 . 
( a ) correlation between estimated intake of fish and seafood with glycated hemoglobin ( hba1c ) reduction ( national glycohemoglobin standardization program [ ngsp ] , % ) 4  months after initiation of dipeptidyl peptidase4 inhibitors ( hba1c ; n  =  72 ) .
( b ) correlation between estimated intake of eicosapentaenoic acid ( epa ) , docosahexaenoic ( dha ) with hba1c ( n  =  72 ) .
( c ) correlation between serum levels of epa , dha and arachidonic acid ( aa ) with hba1c ( n  =  20 ) .
linear regression analyses were carried out to calculate the correlation coefficient ( r ) and pvalues .
we find that changes of hba1c levels on administration of dpp4 inhibitors are associated with estimated intake of fish and estimated intake of dietary n3 pufa , as well as serum epa and dha levels . despite being a retrospective cohort study with a limited sample size ,
these findings are clinically important in two respects : ( i ) the efficacy of dpp4 inhibitors can be predicted by serum epa and dha levels ; and ( ii ) consuming more fish with diet therapy can enhance the efficacy of dpp4 inhibitors .
furthermore , the current findings suggest that the differing efficacies of dpp4 inhibitors found among different ethnicities might be partly a result of differences in fish consumption .
although many studies have shown the beneficial effects of dietary n3 pufa from fish , the mechanisms involving dietary n3 pufa in dpp4 inhibitor efficacy have not yet been investigated .
although epa and dha have been shown to prevent excessive adiposity , thereby ameliorating insulin resistance in animal models , the effects of n3 pufa on glycemic control in type 2 diabetes itself are somewhat controversial .
interestingly , it has been found that epa and dha enhance glp1 secretion , possibly through free fatty acid receptors , such as gpr120 , in glp1secreting cells and mice .
it is thus possible that dietary n3 pufa and dpp4 inhibitors synergistically increase biologicallyactive glp1 levels to facilitate maintenance of glycemic control , but it remains to be determined whether epa and dha enhance glp1 secretion in patients with type  2 diabetes . in addition , whether the present findings hold true for dpp4 inhibitors in general is not known , as most of the patients in the current study received sitagliptin or alogliptin , and vildagliptin patients were limited .
we find that the reduction of hba1c by dpp4 inhibitors significantly correlates with estimated intake of fish , estimated intake of epa and dha , and serum levels of epa and dha .
figure s1 correlation between estimated intakesand serum concentrations of eicosapentaenoic acid ( epa ) anddocosahexaenoic ( dha ; n  =  16 ) .
table s1 association of glycated hemoglobin(hba1c ) reduction and estimated intake of fish , shellfish and other seafood table s2 association of glycated hemoglobin(hba1c ) reduction and estimated intake ofpolyunsaturated fatty acids click here for additional data file .
 abstractthis study was initiated to identify clinical and dietary parameters that predict efficacy of dipeptidyl peptidase4 inhibitors . 
 a total of 72 untreated japanese patients with type 2 diabetes who received dpp4 inhibitors ( sitagliptin , alogliptin or vildagliptin ) for 4  months were examined for changes of glycated hemoglobin ( hba1c ) and body mass index ( bmi ) , and selfadministered 3day food records , as well as serum levels of eicosapentaenoic acid ( epa ) and docosahexaenoic acid ( dha ) . 
 dpp4 inhibitors significantly reduced hba1c ( before initiation of dpp4 inhibitors 7.2    0.7% , 4  months after initiation of dpp4 inhibitors 6.7    0.6% [ paired ttest , p  <  0.01 vs before ] ) . 
 multiple regression analysis showed that changes of hba1c were significantly correlated with baseline hba1c , as well as estimated intake of fish . 
 furthermore , changes of hba1c were significantly correlated with serum levels of epa ( r  =  0.624 , p  <  0.01 ) and dha ( r  =  0.577 , p  <  0.01 ) . 
 hba1c reduction by dpp4 inhibitors is significantly correlated with estimated intake of fish and serum levels of epa and dha . 
 ( j diabetes invest , doi : 10.1111/j.20401124.2012.00214.x , 2012 ) 