Endocrine Journal 2014, 61 (3), 249-256

Or i g i n a l Effects of miglitol, vildagliptin, or their combination on serum and peptide YY levels and plasma glucose, , , and obestatin levels

Kazutaka Aoki1), 2), Hiroshi Kamiyama2), Kiyomi Masuda2), Kazunari Kamiko2), Yoshihiko Noguchi2), Kazuki Tajima2) and Yasuo Terauchi2)

1) Department of Biostatistics and Epidemiology, Yokohama City University Hospital, Yokohama 236-0004, Japan 2) Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan

Abstract. We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.

Key words: Miglitol, Vildagliptin, Gut hormones

α-Glucosidase inhibitors (αGIs) decrease active GLP-1 concentrations via different mechanisms, plasma glucose and serum insulin levels in healthy sub- we previously examined the effect of their combined jects [1, 2] and reduce the development of type 2 dia- administration. Combination therapy using these drugs betes in subjects with impaired glucose tolerance (IGT) increased the active GLP-1 levels and decreased the [3, 4]. αGIs reportedly enhance active glucagon-like total GIP levels, compared with monotherapy, in non- peptide-1 (GLP-1) responses and reduce total glucose- diabetic men [10]. Interestingly, the administration dependent insulinotropic polypeptide (GIP) responses of miglitol only at breakfast increased the AUC of the [5-8]. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such active plasma GLP-1 levels from breakfast to 2 hours as sitagliptin or vildagliptin, increase active GLP-1 after the start of lunch in sitagliptin-treated Japanese and GIP by inhibiting DPP-4 enzymatic activity and patients with type 2 diabetes [11]. improve hyperglycemia in a glucose-dependent fash- With the exception of GLP-1 and GIP, several gut ion by increasing serum insulin and decreasing serum hormones are secreted by the stomach or small intes- glucagon levels in diabetic patients [9]. tine and regulate appetite. Peptide YY (PYY) is a Because miglitol and sitagliptin enhance plasma 36-amino acid protein secreted mainly by L cells in the intestine [12, 13]. After release, DPP-4 cleaves Submitted Sep. 25, 2013; Accepted Dec. 3, 2013 as EJ13-0399 the N-terminal tyrosine-proline residues and forms Released online in J-STAGE as advance publication Dec. 27, 2013 Correspondence to: Yasuo Terauchi, Department of Endocrinology PYY3-36, and PYY3-36 represents about 63% of the and Metabolism, Yokohama City University Graduate School total PYY after feeding and about 37% after fasting [14, of Medicine, Fuku-ura 3-9, Kanazawa-ku, Yokohama 236-0004, 15]. The administration of PYY3-36 reportedly reduces Japan. E-mail: [email protected] food intake in mice and humans [16]. Cholecystokinin ©The Japan Endocrine Society 250 Aoki et al.

(CCK) is secreted from the I cells in the duodenum grams; fat: 27.5 grams; carbohydrate: 125.0 grams). and jejunum [17]. CCK stimulates pancreatic enzyme For the study, the subjects were requested to fast for at secretion and gall bladder contraction and delays gas- least 12 hours before eating breakfast. Blood samples tric emptying and food intake via the stimulation of the were collected at 0, 30, 60 and 120 min after the start vagus nerve [18, 19]. Ghrelin, a 28-amino acid acy- of breakfast. They were obtained from the antecubital lated peptide, is an orexigenic peptide secreted by the vein into fluoride tubes for the analysis of glucose lev- stomach [20]. Plasma ghrelin concentrations increase els, into EDTA-2Na/aprotinin tubes for the analysis of with fasting and decrease after feeding [21]. Obestatin cholecystokinin, ghrelin, and obestatin levels, and into is a 23-amino acid peptide that has been isolated from plain siliconized tubes for the analysis of insulin and the rat stomach. This peptide, encoded by the ghrelin PYY. The blood samples were then immediately cen- gene, reduces the food intake, gut motility, and body trifuged at 4°C and the plasma fractions obtained from weight [22]. EDTA-2Na/aprotinin tubes were mixed with hydro- Some previous reports have investigated the changes chloride yielding a final concentration of 0.1 N for the in PYY, ghrelin, and CCK levels after the administra- measurement of active ghrelin levels. All blood sam- tion of αGI as well as the changes in PYY and ghre- ples except the plasma glucose and serum insulin were lin levels after the administration of DPP-4 inhibitors. stored at − 70°C until assayed. The plasma glucose and However, since the PYY, CCK, ghrelin, and obestatin serum insulin levels were measured by Hokenkagaku levels in subjects receiving combined treatment with Institute Inc. (Yokohama, Japan). The serum total PYY αGIs and DPP-4 inhibitors have not been previously (PYY1-36 and PYY3-36) and plasma obestatin levels reported, we evaluated the effects of miglitol, vilda- were measured using an EIA kit (Yanaihara Institute gliptin, and their combined administration on these Inc., Shizuoka, Japan), and the plasma CCK (CCK26-33) parameters in healthy men. levels were also measured using an EIA kit (Phoenix Pharmaceutical, Inc., USA). Active ghrelin was mea- Materials and Methods sured using an ELISA (Sceti, Tokyo, Japan). Data were expressed as the mean ± SD. The areas We conducted the study with the approval of the under the curve (AUC) from just before the meal to 120 Institutional Ethics Review Committee of Yokohama min after the start of the meal were calculated using the City University Hospital, and the protocol was reg- trapezoid method. The analyses for each hormone at istered in the UMIN Clinical Trial Registry as 0, 30, 60 and 120 min and the AUCs were performed UMIN000010481. Informed consent was obtained using one-way layout analysis of variance (ANOVA) from each of the subjects before the start of the study. with Bonferroni type comparisons. All statistical analy- Eleven healthy men aged 37.7 ± 10.1 years with body ses were conducted using Ekuseru-Toukei 2012 (Social height of 170.2 ± 6.0 cm, body weight of 70.0 ± 9.6 kg Survey Research Information Co., Ltd, Tokyo, Japan). and a BMI of 24.3 ± 4.3 kg/m2, who had never been Differences with P values of less than 0.05 were consid- diagnosed as having diabetes or IGT were enrolled in ered significant. the present study. Miglitol and/or vildagliptin were administered according to four different intake sched- Results ules (C: no drug, M: miglitol administered just before a meal [50 mg]; V: vildagliptin administered 2 hours The time profiles and AUCs of the plasma glucose before the start of a meal [50 mg], M+V: miglitol and serum insulin levels are shown in Fig. 1 and Table 1. administered just before a meal [50 mg] and vildaglip- The plasma glucose levels at 30 min after the start of tin administered 2 hours before the start of a meal [50 breakfast were significantly lower in the M, V, and M+V mg]). As the vildagliptin tmax are 1.5-2 hours, vildaglip- groups than in the C group, while the plasma glucose lev- tin was administered 2 hours before the start of the meal els at 60 min after the start of breakfast were significantly [23]. The subjects were randomized to one of the four lower in the M+V group than in the C group (Fig. 1A). interventions using a crossover design. Subjects were The AUCs of the plasma glucose levels in the M and asked to take each medication after a drug-free wash- M+V groups were significantly lower than that in the C out period lasting more than 1 week. All the subjects group. The AUC of the plasma glucose levels in the V received a standard breakfast (849 kcal; protein: 25.3 group tended to be lower than that in the C group, but the Effect of miglitol and vildagliptin 251

Fig. 1 Time profiles of A) plasma glucose and B) serum insulin levels. C, M, V, and M+V indicate the control, miglitol, vildagliptin, and miglitol+ vildagliptin treatment groups, respectively. C: filled circles; M: clear circles; V: triangles; M+V: squares. Data are expressed as the means ± SD. ** P<0.01, *** P<0.001 vs. C. ### P<0.001 vs. M. ††† P<0.001 vs. V.

Table 1 Comparison of each area under the curve (AUC)s among groups C M V M+V Plasma glucose (mg·min/dL) 15062.7 ± 2531.1 12654.5 ± 1151.7** 13671.8 ± 2766.2 11360.4 ± 1138.1*** †† Serum insulin (μU·min/mL) 9488.7 ± 7547.5 3860.7 ± 3798.6*** 7151.8 ± 4613.7 2741.3 ± 1773.3*** † Serum PYY (ng·min/mL) 30.1 ± 23.1 37.9 ± 9.4** 26.5 ± 21.3### 30.8 ± 25.9# Plasma CCK (ng·min/mL) 8.5 ± 3.1 9.1 ± 5.2 9.6 ± 4.9 9.4 ± 5.1 Plasma ghrelin (fmol·min/mL) 993.0 ± 550.8 1147.4 ± 707.9 948.8 ± 616.0 1112.5 ± 650.2 Plasma obestatin (ng·min/mL) 182.1 ± 54.4 196.6 ± 50.7 187.9 ± 49.4 193.1 ± 51.3 Plasma ghrelin/obestatin 659.8 ± 307.4 725.1 ± 374.9 603.2 ± 279.2 714.6 ± 360.2 Data are expressed as the means ± SD. C, M, V, and M+V indicate the control, miglitol, vildagliptin, and miglitol and vildagliptin treatment groups, respectively. **P<0.01, ***P<0.001 vs. C. #P<0.05, ###P<0.001 vs. M. †P<0.05, ††P<0.01, vs. V.

difference was not statistically significant (Table 1). in the M+V group were significantly lower than in The serum insulin levels at 30 and 60 min after the the M group (Fig. 2A). As a result, the AUC of the start of breakfast were significantly lower in the M and serum total PYY level in the M group was significantly M+V groups than in the control group (Fig. 1B). The greater than that in the C group, and the AUCs of the serum insulin levels at 120 min after the start of break- serum total PYY level in the V and M+V groups were fast were significantly lower in the M+V group than in significantly lower than that in the M group (Table 1). the C group (Fig. 1B). The AUCs of the serum insu- The AUC of the serum total PYY level in the V group lin levels in the M and M+V groups were significantly tended to be lower than that in the C group, but the smaller than that in the C group (Table 1). By contrast, difference was not statistically significant. The AUCs the AUC of the serum insulin levels was unaffected in of the plasma CCK level did not differ significantly the V group. among the groups (Fig. 2B and Table 1). The time profiles and the AUCs of the serum total The time profiles and the AUCs of the plasma active PYY and plasma CCK levels are shown in Fig. 2. The ghrelin, obestatin, and ghrelin/obestatin levels are total PYY levels at 60 and 120 min after the start of shown in Fig. 3 and Table 1. The plasma active ghrelin breakfast were significantly higher in the M group levels at 60 min after the start of breakfast were signifi- than in the C group, and the total PYY levels at 30, cantly lower in the V group than in the M group, and 60 and 120 min in the V group and at 60 and 120 min the obestatin levels at 30 min after the start of breakfast 252 Aoki et al.

Fig. 2 Time profiles of A) serum PYY and B) plasma CCK levels. C, M, V, and M+V indicate the control, miglitol, vildagliptin, and miglitol+vildagliptin treatment groups, respectively. C: filled circles; M: clear circles; V: triangles; M+V: squares. Data are ex- pressed as the means ± SD. *P<0.05, **P<0.01, vs. C. #P<0.05, ##P<0.01, ###P<0.001 vs. M.

Fig. 3 Time profiles of A) plasma ghrelin, B) obestatin, and C) ghrelin/obestatin levels. C, M, V, and M+V indicate the control, migli- tol, vildagliptin, and miglitol+vildagliptin treatment groups, respectively. C: filled circles; M: clear circles; V: triangles; M+V: squares. Data are expressed as the means ± SD. * P<0.05 vs. C. # P<0.05 vs. M. †† P<0.01 vs. V. Effect of miglitol and vildagliptin 253 were significantly lower in the V group than in the M 27]. Our results for the effect of vildagliptin on the group (Fig. 3A and B). The obestatin levels at 30 min serum total PYY level were in accordance with these after the start of breakfast were significantly higher in previous reports; however, the effect of combination the M+V group than in the C and V group. The ghrelin/ therapy on serum PYY levels has not been previously obestatin level at 60 min after the start of breakfast was reported. In this study, we demonstrated that com- significantly lower in the V group than in the M group bination therapy decreased the increment in the total (Fig. 3C). However, the AUCs of the plasma active PYY level induced by the administration of miglitol. ghrelin, obestatin, and ghrelin/obestatin levels did not PYY1-36 is considered to be increased by the admin- differ significantly among the groups (Table 1). istration of miglitol, based on its pharmacological effect, and also to be increased by the administration Discussion of vildagliptin, as previously reported [28]. Therefore, the combination therapy increased the PYY1-36 level The most important finding in this study is that the and decreased the PYY3-36 level, leaving the total PYY combination therapy of miglitol and vildagliptin did level unaffected when compared with that of the con- not change the AUCs of the total PYY, CCK, active trol group. As PYY 3-36 decreases appetite and PYY ghrelin, and obestatin levels, compared with the values 1-36 stimulates appetite [13-15], the combination thera- for the control group. By contrast, the administration py’s effect on PYY might not result in appetite suppres- of miglitol alone increased the AUC of the total PYY sion and body weight reduction. level. Based on the results of the present study, the The administration of acarbose reportedly increased combination therapy did not appear to have any effect the postprandial CCK level in healthy men, although on intestinal appetite regulation hormones, such as total the mechanism responsible for this increase was unclear PYY, CCK, active ghrelin, and obestatin, unlike the [28]. Unlike acarbose, miglitol is partially absorbed previously reported additive increase in active GLP-1 from the proximal portion of the small intestine [29], levels [10, 11]. and this leads to a decrease in absorbed carbohydrates The effects of miglitol, vildagliptin, and their combi- from the proximal portions of the small intestine. As nation on plasma glucose and serum insulin were con- CCK is secreted from the upper portion, a difference in sistent with our previous report [10, 11]. The absence the postprandial CCK levels as a result of the admin- of an increase in serum insulin levels in the V and M+V istration of miglitol or acarbose can be observed. The groups might be favorable for sparing insulin secretion AUC of the CCK level for the M group was not larger by β cells in individuals with NGT. than that for the C group in the present study. The rea- The AUC of the total PYY level in the M group son for this finding might be due to the difference in the was higher than that in the C group, as shown in pre- pharmacological effects of acarbose and miglitol. As vious reports discussing the administration of miglitol the CCK level after treatment with DPP-4 inhibitors or or acarbose [24, 25]. This result was considered to be combination therapy has not been previously reported, due to an increase in PYY secretion because of changes we evaluated these effects but did not observe any sig- in the proportion of absorbed carbohydrates from the nificant differences among the four groups in this study. proximal to distal portions of the small intestine. The Kaku et al. reported that the administration of migli- administration of vildagliptin for 10 days reportedly tol increased the active ghrelin level at 60 min and decreased the total PYY level in patients with type 2 decreased the level at 180 min after a meal in healthy diabetes [26], and the administration of sitagliptin for subjects [24]. Treatment with acarbose decreased the 3 months also reduced the total PYY and PYY3-36 lev- postprandial total ghrelin levels in patients with type els and increased the PYY1-36 level [27]. No study has 2 diabetes [30]; however, treatment with acarbose clearly demonstrated a reduction in total PYY secretion increased the plasma total ghrelin level in healthy sub- through the action of DPP-4 inhibitors. DPP-4 inhibi- jects [31]. In the present study, the AUC of the active tors increased PYY1-36, as DPP- 4 changes PYY 1-36 to ghrelin level in the M group tended to be higher than PYY 3-36, and the decrease in total PYY in response to that in the C group, although the difference was not DPP-4 inhibitors may be due to the negative feedback statistically significant. The administration of sitaglip- inhibition of the secretion from L cells from increased tin for three months decreased the fasting total ghrelin PYY 1-36 or active GLP-1, as previously described [26, levels; however, the single administration of sitagliptin 254 Aoki et al. did not change the post-prandial total ghrelin levels in and alogliptin for three months [35]. We did not evalu- healthy subjects, and the administration of vildaglip- ate the gastric emptying or the appetite changes; how- tin for ten days also did not change the post-prandial ever, the observed changes in the PYY, CKK, ghrelin, active ghrelin levels in patients with type 2 diabetes and obestatin levels after combination therapy suggest [27, 32, 33]. The plasma ghrelin level after combina- that this combination therapy did not have any effects tion therapy has not been previously reported. In the on body weight or appetite, as previously described present study, the AUC of the active ghrelin level in [33, 34]. We plan to evaluate the effects of miglitol and the M+V group tended to be higher than that in the C vildagliptin on body weight and appetite over a longer group, although the difference was not statistically sig- treatment period in the future. nificant. If we had measured the plasma ghrelin levels The present study had several limitations. First, the at 180 min, a lower ghrelin concentration at 180 min number of subjects was relatively small, the drugs were and a tendency toward a decreased ghrelin concentra- administered only to healthy subjects, and only the total tion at 60 to 180 min in the M and M+V groups might PYY level was measured. Therefore, larger-scale stud- have been observed, as described previously [24]. The ies in which the test drugs are administered to patients plasma obestatin level after the administration of migli- with type 2 diabetes are needed in the future. In the tol, vildagliptin, or a combination also has not been pre- future, we would also like to measure the levels of viously reported. In this study, the plasma obestatin PYY1-36 and PYY3-36 after combination therapy so as level at 30 min was higher in the M+V group than in to determine their precise hormonal effects on appetite. the C group; however, the AUCs of the M, V, and M+V In conclusion, the results of our study suggested that groups were not significantly different from that of the C combination therapy with miglitol and vildagliptin did group. No significant differences in the ghrelin/obesta- not have any effect on appetite regulation hormones, tin levels were observed among the four groups. such as total PYY, CCK, active ghrelin, and obestatin, We hypothesized that combination therapy with compared with the levels in the control group. the drugs used in this study would increase the active GLP-1 levels and decrease the total GIP levels, com- Acknowledgements pared with monotherapy, based on our previous results [10, 11]. Therefore, with regard to the hormones that This work was supported in part by Grants-in-Aid for are secreted by the intestine in response to the admin- Scientific Research (B) 19390251 and (B) 21390282 istration of αGIs and DPP-4 inhibitors, the changes in from the Ministry of Education, Culture, Sports, Science GLP-1 and GIP were expected to favor body weight and Technology (MEXT) of Japan, a Medical Award reduction or the suppression of appetite. Concerning from the Japan Medical Association, Diabetes Masters body weight changes, we recently reported that a slight Conference, and the Suzuken Memorial Foundation. reduction in body weight from the baseline value was seen after 3 months of combination therapy with αGI Disclosure (three times a day) and alogliptin [34]; however, no significant reduction in BMI was seen after the com- The authors have no direct conficts of interest that bined administration of voglibose (three times a day) are relevant to the content of this manuscript.

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