Originl Article Others Dibetes Metb J 215;39:335-341 http://dx.doi.org/1.493/dmj.215.39.4.335 pissn 2233-679 eissn 2233-687 DIABETES & METABOLISM JOURNAL Effects of 6-Month Sitgliptin Tretment on Insulin nd Glucgon Responses in Koren Ptients with Type 2 Dibetes Mellitus He Kyung Yng, Bormi Kng, Seung-Hwn Lee, Hun-Sung Kim, Kun-Ho Yoon, Bong-Yun Ch, Je-Hyoung Cho Divison of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Seoul St. Mry s Hospitl, College of Medicine, The Ctholic University of Kore, Seoul, Kore Bckground: This study imed to evlute the effect of sitgliptin, n orl dipeptidyl peptidse-4 inhibitor, on insulin secretion nd glucgon suppression in Koren subjects with type 2 dibetes mellitus. Methods: Twenty-four subjects underwent 75-g orl glucose tolernce test (OGTT) before nd fter 6 months of sitgliptin tretment. Sitgliptin, insulin, nd sulfonylure were withdrwn for 3 dys before OGTT to eliminte ny cute effects on β-cell insulin or α-cell glucgon secretion. Venous smples were drwn five times during ech OGTT to mesure plsm glucose, insulin, nd glucgon. Indices on insulin secretion nd resistnce were clculted. Results: Erly phse insulin secretion, mesured by the insulinogenic index significntly incresed fter 6 months of sitgliptin tretment, especilly in the higher bseline body mss index group nd higher bseline glycosylted hemoglobin (HbA1c) group. There were no significnt differences in the insulin resistnce indices before nd fter sitgliptin tretment. Although no significnt differences were observed in the bsolute levels of glucgon nd the glucgon-to-insulin rtio, there ws significnt reduction in the percentile chnge of glucgon-to-insulin rtio t 3- nd 12-minute during the OGTT. Conclusion: Although the HbA1c level did not decrese significntly fter 6 months of sitgliptin tretment, n increse in insulin secretion nd reduction in erly phse postprndil plsm glucgon-to-insulin rtio excursion ws confirmed in Koren subjects with type 2 dibetes. Keywords: Dipeptidyl-peptidse 4 inhibitors; Glucgon; Glucose tolernce test; Insulin; Kore INTRODUCTION Type 2 dibetes mellitus in ptients from Asin countries differs in severl spects from tht seen in ptients from Western countries. The clinicl chrcteristics of Asin type 2 dibetes include rpid increse in the prevlence of dibetes during reltively short period of time nd erly disese onset with lesser degree of obesity compred to tht observed in ptients from Western countries [1,2]. Pronounced dysfunction in erly-phse insulin secretion with lower degree of compenstory insulin secretion hs been suggested s explntions for the ethnic differences [3,4]. Becuse β-cell dysfunction is one of the key pthogenetic defects in ptients with type 2 dibetes, worsening of β-cell function mrks the progression of the disese nd is mjor trget for tretment [5]. Glucgon-like peptide-1 (GLP-1) nd glucose-dependent insulinotropic polypeptide potentite glucose-dependent insulin relese. In ddition, GLP-1 suppresses glucgon relese nd slows down gstric emptying [6]. Augmented insulin relese nd reduction in glucgon concentrtion, reduce the Corresponding uthor: Je-Hyoung Cho Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Seoul St. Mry s Hospitl, College of Medicine, The Ctholic University of Kore, 222 Bnpo-dero, Seocho-gu, Seoul 6591, Kore E-mil: drhopper@ctholic.c.kr Received: Jul. 29, 214; Accepted: Sep. 15, 214 This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License (http://cretivecommons.org/licenses/by-nc/3./) which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. Copyright 215 Koren Dibetes Assocition
Yng HK, et l. postprndil rise in glucose concentrtion. Given the differences in the contribution of the insulin secretory defect nd insulin resistnce in the pthophysiology of type 2 dibetes between Asin nd Western popultions, the glucose-lowering efficcy of dipeptidyl peptidse-4 (DPP-4) inhibitors is thought to differ by ethnic group. Severl studies hve shown tht DPP-4 inhibitors exhibit better glucose lowering efficcy in Asins thn in other ethnic groups [7]. However, only few studies hve mesured blood insulin nd glucgon concentrtions during 75-g orl glucose tolernce test (OGTT) in Koren ptients. We imed to evlute the chnges in insulin nd glucgon secretion during 75-g OGTT before nd fter 6 months of sitgliptin tretment in Koren ptients with type 2 dibetes. METHODS Study popultion A prospective study ws conducted using ptients who hd begun sitgliptin therpy for type 2 dibetes between Februry 29 nd My 29 t Seoul St. Mry s Hospitl, Seoul, Kore. Ptients ged less thn 8 yers, who underwent 75-g OGTT before nd fter 6-month sitgliptin tretment were included. Subjects with impired liver or renl function (lnine minotrnsferse levels more thn 2-fold bove the upper limit of the norml rnge, serum cretinine level >133 μmol/l, or glomerulr filtrtion rte [GFR] <6 ml/min/1.73 m 2 ), type 1 dibetes, ctive infection or inflmmtion, or mlignncy were excluded. Subjects who were lredy tking DPP-4 inhibitors or GLP-1 nlogues were lso excluded from this study. GFR ws estimted from serum cretinine nd ge using the Modifiction of Diet in Renl Disese study eqution s follows: GFR [ml/min/1.73 m 2 ]=186.3 Cr 1.154 ge.23.742 [if femle]). Explntory vribles All subjects underwent 75-g OGTT fter 12 hours of overnight fsting before nd fter 6-month tretment with dily 1 mg sitgliptin. Sitgliptin ws withdrwn for 3 dys before the 75-g OGTT. The 3-dy wshout period ws designed to eliminte ny cute effects of sitgliptin on β-cell insulin or α-cell glucgon secretion during the OGTT. Also, insulin s well s sulfonylure ws withdrwn 3 dys before the OGTT while voiding the development of hyperglycemi by prescribing non-insulin secretgogue. Glucose, insulin, nd glucgon levels were obtined during the 75-g OGTT from smples collected t, 3, 6, 9, nd 12 minutes. Plsm glucose levels were mesured using the hexokinse method, nd insulin ws mesured using rdioimmunossy kit (Dinbot, Tokyo, Jpn) in our hospitl lbortory. We clculted severl indices to mesure insulin resistnce nd insulin secretion. The Mtsud index of insulin sensitivity ws clculted s follows: 1, (fsting plsm glucose (mmol/l) fsting insulin (µu/ml) men of glucose during OGTT men of insulin during OGTT) The homeosttic model ssessment-β (HOMA-β) nd homeosttic model ssessment for insulin resistnce (HOMA-IR) were clculted by using the fsting insulin nd fsting glucose levels s follows: fsting glucose (mmol/l) fsting insulin (μu/ml) HOMA-IR= 22.5 HOMA-β= 2 fsting insulin (μu/ml) fsting glucose (mmol/l) 3.5 The totl re under the curve (insulin/glucose) (totl AUC [I/G]) ws clculted using trpezoid method. The insulinogenic index ws clculted s the erly-phse insulin response reltive to the glucose stimulus during OGTT s follows: (insulin [μu/ml] t 3 minutes during OGTT fsting insulin)/ (plsm glucose [mmol/l] t 3 minutes during OGTT fsting plsm glucose). The subjects heights nd weights were mesured, nd their body mss index (BMI) ws clculted by dividing their weight (kg) by the squre of their height (m 2 ). Sttisticl nlysis Dt re presented s men±stndrd error, or s numbers with proportions. A chi-squre nlysis ws used for discontinuous vribles, nd Wilcoxon signed rnk test ws used for continuous vribles becuse of the smll smple size. Comprison of time course curves during OGTT were nlyzed by repeted mesures nlysis of vrince (ANOVA), nd is described s P for trend. Additionlly, Wilcoxon signed rnk test ws used for ech time point to compre the glucose, insulin nd glucgon level before nd fter sitgliptin tretment. The SPSS version 18. (SPSS Inc., Chicgo, IL, USA) ws used for sttisticl nlysis nd P<.5 ws considered sttisticlly significnt. 336 Dibetes Metb J 215;39:335-341
Effect of sitgliptin on insulin nd glucgon responses Ethics sttement This study protocol ws pproved by the Institutionl Review Bord of The Ctholic University of Kore (KC14RISI357). Only de-identified ptient dt from the dtbse were ccessed nd were nlyzed nonymously. Therefore, the Institutionl Review Bord wived the need for written informed consent from the prticipnts. This study ws conducted ccording to the principles expressed in the Declrtion of Helsinki. RESULTS Bseline clinicl chrcteristics of subjects Among the 37 subjects who begn tking sitgliptin during the study period, 13 were unble to repet the OGTT fter 6 months of tretment. Therefore 24 subjects were included; 14 men nd 1 women (Tble 1). Their men ge nd BMI were 53.8±1.36 yers nd 23.1±3.5 kg/m 2, respectively. The bseline glycosylted hemoglobin (HbA1c) ws 55.4±9.62 mmol/ mol (7.2%±1.27%). Among 24 subjects, three ptients were drug nive, three ptients switched from or dded on insulin therpy, 15 ptients switched from sulfonylure (glimepiride or gliclzide), two ptients switched from metformin, nd one ptient switched from crbose. Tble 1. Bseline clinicl chrcteristics Chrcteristic Bseline Number 24 Age, yr 53.75±2.11 Sex, mle:femle 14:1 Weight, kg 62.45±2.1 Height, cm 164.37±1.57 BMI, kg/m 2 23.5±.62 HbA1c, % 7.22±.26 Durtion of dibetes, yr 5.83±5.18 Totl cholesterol, mmol/l 4.15±.13 Triglyceride, mmol/l 3.27±.71 HDL-C, mmol/l 1.31±.7 LDL-C, mmol/l 2.21±.11 AST, IU/L 23.57±2.42 ALT, IU/L 24.45±2.8 Vlues re presented s number or men±stndrd error. BMI, body mss index; HbA1c, glycosylted hemoglobin; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; AST, sprtte minotrnsferse; ALT, lnine minotrnsferse. Chnges in plsm glucose, insulin, nd glucgon response during 75-g OGTT. There were no significnt interction between the effects of time nd tretment sttus for glucose, insulin, nd glucgon from repeted mesures ANOVA nlysis during the 75g- OGTT (Fig. 1). However, the insulin/glucose rtio curve ws significntly higher fter sitgliptin tretment (P for trend=.4). Although there ws no significnt chnge in the glucgon/insulin curve fter sitgliptin tretment (P for trend=.88), significnt reduction in the percentile chnge of plsm glucgon/insulin rtio t 3- nd 12-minute ws observed during the OGTT (P=.49, P=.24, respectively). Chnges in insulin sensitivity nd secretion The insulinogenic index nd totl AUC (I/G) incresed significntly fter 6-month sitgliptin tretment, even though the mediction hd been withdrwn for 3 dys before the OGTT (Tble 2). There were no significnt differences in HOMA-IR, Mtsud index, or HOMA-β level fter 6 months of sitgliptin tretment. The HbA1c level tended to decrese fter sitgliptin tretment, but this chnge ws not significnt. Subgroup nlysis ccording to initil BMI nd HbA1c level Subjects were divided into two groups ccording to BMI: the lower BMI group (<23 kg/m 2 ) nd the higher BMI group ( 23 kg/m 2 ). In both groups, totl AUC (I/G) significntly incresed with sitgliptin tretment (Tble 3). However, the insulinogenic index significntly incresed only in the higher BMI level group. There were no significnt differences in other indices in both groups, with the exception of HOMA-β in lower BMI group. The HbA1c level tended to decrese in both BMI groups, but this chnge ws not significnt. Subjects were lso divided into two groups ccording to initil HbA1c level: the lower HbA1c level group (<7%, 53 mmol/ mol) nd the higher HbA1c level group ( 7%, 53 mmol/mol). Totl AUC (I/G) nd insulinogenic index significntly incresed only in the higher HbA1c level group. Also, the decrese in HbA1c level ws significnt only in the higher HbA1c level group. DISCUSSION In this study, we evluted the effect of sitgliptin on plsm glucose, insulin, nd glucgon responses during 75-g OGTT. As demonstrted by the insulinogenic index, erly phse insu- Dibetes Metb J 215;39:335-341 337
Yng HK, et l. Before sitgliptin tretment After sitgliptin tretment 4 3 Glucose (mmol/l) 3 2 1 P for trend=.61 Insulin (pmol/l) 2 1 P for trend=.9 A B 12 2 Glucgon (ng/l) 1 8 6 4 2 P for trend=.62 Insulin/Glucose 15 1 5 P for trend=.4 C D Glucgon/Insulin 3 2 1 P for trend=.88 E Glucgon/Insulin (% chnge) 2 4 6 8 P for trend=.22 F Fig. 1. Chnges in plsm glucose (A), insulin (B), nd glucgon (C), insulin-to-glucose rtio (D), glucgon-to-insulin rtio (E) nd percent chnge of glucgon-to-insulin rtio (F) response during 75-g orl glucose tolernce test (OGTT) before nd fter sitgliptin tretment. Vlues re presented s men±stndrd error. (Glucgon/insulin) %chnge=1 [(glucgon/insulin t 3, 6, 9, or 12-minute) (glucgon/insulin t minute)]/(glucgon/insulin t minute). Open circles nd dshed lines indicte mesures before sitgliptin tretment; closed squres nd solid lines indicte mesures fter sitgliptin tretment. P for trend indictes the comprison of time course curves during OGTT, nlyzed by repeted mesures nlysis of vrince. P<.5 t the, 3, 6, 9, or 12-minute time points using Wilcoxon signed rnk test for pired vlues. lin secretion incresed fter 6 months of tretment with sitgliptin, especilly in the higher BMI subgroup nd in the higher HbA1c level subgroup. Although no significnt differences in the bsolute levels of glucgon nd glucgon/insulin rtio were observed, there ws significnt reduction in the percentile chnge of glucgon/insulin rtio t 3- nd 12-minute 338 Dibetes Metb J 215;39:335-341
Effect of sitgliptin on insulin nd glucgon responses Tble 2. Chnges in β-cell function nd insulin sensitivity fter 6 months of sitgliptin tretment Glucose, mmol/l Bseline (n=24) After tretment (n=24) P vlue min 9.1±.64 8.62±.58.29 12 min 16.52±.89 15.8±1.3.72 Insulin, pmol/l min 45.21±5.36 52.36±7.64.361 12 min 148.62±21.27 234.6±29.88.1 C-peptide, nmol/l min.68±.9.63±.36.695 12 min 1.94±.17 1.91±.98.76 Glucgon, ng/l min 72.73±3.54 79.54±17.32.14 12 min 74.7±3.26 82.47±21.6.12 Totl AUC (insulin/glucose) 8.76±1.53 15.1±2.4.1 HOMA-IR 2.78±.39 3.9±.7.797 Mtsud index 6.37±.96 5.22±.73.317 Insulinogenic index.63±.11 1.18±.27.1 HOMA-β 26.95±3.31 33.57±4.15.61 Totl AUC (glucgon/insulin) 1.95±1.9 1.56±1.3.33 HbA1c, % 7.22±.26 6.96±.2.98 Vlues re presented s men±stndrd error. AUC, re under the curve; HOMA-IR, homeostsis model ssessment of insulin resistnce; HOMA-β, homeostsis model ssessment of β-cell function; HbA1c, glycosylted hemoglobin. Tble 3. Subgroup nlysis ccording to the initil BMI nd HbA1c BMI <23 (n=13) Bseline After tretment P vlue Totl AUC (I/G) 11.26±2.43 17.52±3.12.34 HOMA-IR 1.78±.42 2.24±.42.116 Mtsud index 7.96±1.46 5.27±.73.152 Insulinogenic index.83±.16 1.46±.48.82 HOMA-β 26.46±4.29 36.86±4.44.46 HbA1c, % 6.57±.26 6.38±.13.357 BMI 23 (n=11) Totl AUC (I/G) 7.51±1.51 11.26±2.26.7 HOMA-IR 3.96±.49 4.9±1.43.594 Mtsud index 4.49±.98 5.15±1.38.929 Insulinogenic index.49±.13.83±.15.5 HOMA-β 27.52±5.38 29.67±7.45.689 HbA1c, % 7.98±.36 7.64±.31.166 HbA1c <7% (53 mmol/ mol) (n=11) Totl AUC (I/G) 12.51±2.64 17.52±1.89.92 HOMA-IR 1.7±.34 2.28±.49.75 Mtsud index 7.13±1.9 5.4±.84.11 Insulinogenic index.83±.19 1.11±.17.152 HOMA-β 33.66±5.24 42.69±6.68.11 HbA1c, % 6.19±.15 6.27±.14.722 HbA1c 7% (53 mmol/ mol) (n=13) Totl AUC (I/G) 6.26±1.4 12.51±3.11.3 HOMA-IR 3.69±.55 3.77±1.22.463 Mtsud index 5.73±1.54 5.6±1.17.972 Insulinogenic index.56±.14 1.25±.5.3 HOMA-β 21.26±3.69 25.85±4.31.294 HbA1c, % 8.8±.29 7.54±.27.31 Vlues re presented s men±stndrd error. BMI, body mss index; AUC (I/G), re under the curve (insulin/ glucose); HOMA-IR, homeostsis model ssessment of insulin resistnce; HOMA-β, homeostsis model ssessment of β-cell function; HbA1c, glycosylted hemoglobin. Denotes P<.5 compred with the bseline vlue of ptients in BMI <23 or HbA1c <7% subgroup. during the OGTT. In most studies, improvements in the proinsulin-to-insulin rtio nd the insulinogenic index were noted with sitgliptin monotherpy or combintion therpy [8], the ltter being confirmed in our study. An inhibitory effect of GLP-1 nlogue on glucgon secretion hs been observed in Asin [9] nd non- Asin popultions [1]. However, only few studies hve reported glucgon responses fter use of DPP-4 inhibitors in Asin popultion. Eto et l. [11] reported decresed glucgon response fter teneligliptin tretment in Jpnese ptients with type 2 dibetes. Regrding sitgliptin, Hermn et l. [12] demonstrted decresed glucgon nd reduced glycemic excursion t 2 nd 24 hours during n OGTT in non-asin popultion fter single orl dose of sitgliptin (25 or 2 mg). DeFronzo et l. [13] reported 2-week tretment of sitgliptin reduced postprndil glucgon secretion reltive to bseline in non-asin subjects. In our study, sitgliptin tretment for 6 months did not suppress the bsolute glucgon level or glucgon/insulin rtio. This discrepncy in the glucgon response might be relted to Dibetes Metb J 215;39:335-341 339
Yng HK, et l. lower level of bseline nd pek glucgon level in our study compred to former studies. Differences in ethnicity, tretment durtion nd bseline HbA1c might hve dditionlly ttributed to this discrepncy. Reports on glucgon response during OGTT following sitgliptin tretment in Asin popultion hve been lcking, nd further studies re needed to confirm our results. In contrst to previous studies, there ws no significnt decrese in HbA1c level fter 24 weeks of sitgliptin tretment. However, HbA1c significntly decresed in those with higher bseline HbA1c level ( 7%). Insignificnt chnge of HbA1c in the overll study popultion might be the consequence of reltively low level of bseline HbA1c in our study, while most outcome studies hve included subjects with higher bseline HbA1c levels [14]. Furthermore, the tendency towrd incresed HOMA-IR level my in prt ttribute to insignificnt chnge in HbA1c level. Recent study showed tht glimepiride tretment for 24-week ppered to enhnce insulin secretion from β-cell, s well s glucgon secretion from α-cell compred to exentide or sitgliptin, even fter 5 dys of drug wshout to eliminte ny cute effects of the study drugs [15]. In our study, 15 out of 24 ptients were prescribed with glimepiride (11 ptients) or gliclzide (three ptients), which my hve ffected bseline glucgon level. Therefore, studies in subjects who hve not been tking sulfonylure re lso needed. There hve been severl reports on sitgliptin tretment in Koren popultions. Kim et l. [16] evluted predictive clinicl prmeters for the therpeutic efficcy of sitgliptin in Koren subjects with type 2 dibetes mellitus. The study showed greter response mong younger subjects with lower BMIs. In nother report, Kim et l. [17] showed tht the tretment filure group hd longer dibetes durtion nd higher HbA1c levels compred with the good-response group. In our study, the higher BMI group showed significntly incresed insulinogenic index, which ws not observed in the lower BMI group. Moreover, significnt decrese in HbA1c level nd improvement in insulinogenic index ws observed only in the higher HbA1c level group. The inconsistency between our study nd the previous studies might be the result of different bseline chrcteristics of the enrolled subjects; smll number of enrolled ptients with lower bseline HbA1c level nd BMI in our study. Improved insulinogenic index in the higher BMI subgroup might be ssocited with higher bseline HbA1c nd HOMA-IR level compred with lower BMI subgroup. When subjects were ctegorized into two groups ccording to the chnges in insulinogenic index ( insulinogenic index=insulinogenic index fter sitgliptin tretment insulinogenic index t bseline), those with higher insulinogenic index showed higher bseline HbA1c (P=.1) nd HOMA-IR level (P=.3) compre to those with lower insulinogenic index levels. While Decon [18] suggested tht higher bseline HbA1c would be predictor of greter HbA1c reduction with DPP-4 inhibitor, some other reports reveled no effect on bseline HbA1c on the efficcy of DPP-4 inhibitors [7]. Therefore, further studies re required to clrify the prmeters ssocited with the therpeutic efficcy of DPP- 4 inhibitors, including sitgliptin. There re severl limittions in this study. First, the smple size ws very smll, nd most of the ptients were middle-ged; between 4 nd 5 yers old. Second, bseline HbA1c ws 7.22%, which is close to the recommended trget of 7.%. Also, those who were unble to follow-up OGTT fter 6 months of sitgliptin tretment were not evluted, nd therefore we could not rule out the potentil selection bis. Finlly, diet nd exercise were not monitored during the 6-month tretment period. In this study, we evluted the chnges in insulin nd glucgon secretion during 75-g OGTT before nd fter 6 months of sitgliptin tretment in Koren ptients with type 2 dibetes. Although HbA1c level did not decrese significntly fter sitgliptin tretment, n increse in insulin secretion nd reduction in erly phse of postprndil plsm glucgon excursion ws confirmed in Koren subjects with type 2 dibetes. Further studies with lrger number of ptients representtive of Koren popultion re needed to vlidte our study result. CONFLICTS OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. REFERENCES 1. Prk YW, Allison DB, Heymsfield SB, Gllgher D. Lrger mounts of viscerl dipose tissue in Asin Americns. Obes Res 21;9:381-7. 2. He Q, Horlick M, Thornton J, Wng J, Pierson RN Jr, Heshk S, Gllgher D. Sex nd rce differences in ft distribution mong Asin, Africn-Americn, nd Cucsin prepubertl children. J Clin Endocrinol Metb 22;87:2164-7. 3. Fukushim M, Suzuki H, Seino Y. Insulin secretion cpcity in 34 Dibetes Metb J 215;39:335-341
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