Endocrine Journal 2011, 58 (10), 869-877

Or i g i n a l Effects of miglitol in combination with intensive therapy on blood glucose control with special reference to incretin responses in type 1 diabetes mellitus

Etsuko Nagai1), Tomoyuki Katsuno1), Jun-ichiro Miyagawa1), Kosuke Konishi1), Masayuki Miuchi1), Fumihiro Ochi1), Yoshiki Kusunoki1), Masaru Tokuda1), Kazuki Murai1), Tomoya Hamaguchi2) and Mitsuyoshi Namba1)

1)Division of Diabetes and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan 2)Division of Innovative Diabetes Treatment, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan

Abstract. To determine whether miglitol administration improves glycemic control and reduces the frequency of hypoglycemia in type 1 diabetes mellitus (T1DM) patients treated with intensive insulin therapy, we analyzed the effect of miglitol on daily insulin doses, body weight, hypoglycemia, and incretin hormone responses during meal tolerance tests (MTT). Eleven T1DM subjects (21-77 years) undergoing intensive insulin therapy, took 25 mg (weeks 0-4) and 50 mg miglitol (weeks 4-12) thrice daily, immediately before meals. At weeks 0 and 12, 9 of 11 subjects underwent MTT. In present study, mean HbA1c, glycoalbumin, and 1,5-anhydroglucitol levels were significantly improved. The blood glucose level 1 h after dinner was significantly lower at week 12 than at week 0 (p = 0.008). From week 0 to 12, there was a significant decrease in the body mass index (BMI;p = 0.0051), frequency of preprandial hypoglycemic events (p = 0.012), and daily bolus insulin dosage (p = 0.018). The change in active glucagon-like peptide-1 (GLP-1) at 120 min significantly increased at week 12 (p = 0.015). The change in total glucose-dependent insulinotropic peptide (GIP) significantly decreased in the MTT at week 12. These results demonstrate that addition of miglitol on intensive insulin therapy in T1DM patients has beneficial effects on reducing BMI, bolus and total insulin dosage, and frequency of preprandial hypoglycemic events. MTT findings suggest that this combination therapy improves blood glucose control by delaying absorption and modifying the responses of incretins, GIP, and GLP-1.

Key words: Glucagon-like peptide-1 (GLP-1), Glucose-dependent insulinotropic peptide (GIP), Glucagon, Alpha- glucosidase inhibitor

The therapeutic goals of intervention in levels, slowed the onset and progression of microvas- patients with T1DM are to achieve normoglycemia cular complications and cardiovascular events caused and to reduce the risks of microvascular complica- by diabetes [1-3]. However, improving postprandial tions and cardiovascular events. The Diabetes Control blood glucose and obtaining target HbA1c levels with- and Complications Trial and the follow-up study, out significant hypoglycemia in patients with T1DM called Epidemiology of Diabetes Interventions and is a very difficult challenge for medical practitioners. Complications, showed that early regulation of blood Although combination therapy of ultra-rapid acting glucose levels in T1DM, as close as possible to normal insulin and long-acting insulin, namely intensive insu-

Submitted Apr. 18, 2011; Accepted Jul. 27, 2011 as K11E-129 pressure; GA, glycoalbumin; GIP, glucose-dependent insulinotropic Released online in J-STAGE as advance publication Aug.26, 2011 peptide; GLP-1, glucagon-like peptide-1; HbA1c, glycated Correspondence to: Etsuko Nagai, M.D., Division of Diabetes and hemoglobin; HDL-C, high-density lipoprotein cholesterol; IRG, Metabolism, Department of Internal Medicine, Hyogo College of immunoreactive glucagons; JDS, Japanese standard measurement Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, method; LDL-C, low-density lipoprotein cholesterol; MTT, meal Japan. E-mail: [email protected] tolerance tests; NGSP, National Glycohemoglobin Standardization Program; SBP, systolic blood pressure; SMBG, self-monitoring of List of Abbreviations: 1,5-AG, 1,5-anhydroglucitol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; BMI, blood glucose; TC, total cholesterol; TG, triglyceride; T1DM, type body mass index; CPR, C-peptide reactivity; DBP, diastolic blood 1 diabetes mellitus; T2DM, mellitus

©The Japan Endocrine Society 870 Nagai et al. lin therapy, is the current strategy of choice for treat- study, fulfilled all of the following inclusion criteria: ment of T1DM, it is still difficult to minimize daily 1. Patients had to be 20–80 years of age, should have fluctuations of blood glucose levels. had T1DM for at least 6 months, and should have been Since about half of the daily endogenous insulin is treated with intensive insulin therapy (i.e., at least 4 released in response to the consumption of meals, and the insulin injections per day). remaining half is basally secreted, 50% of the daily insu- 2. The ad lib CPR measured before the study was <0.5 lin should be given as a basal supplement and the other ng/mL. 50% should be administered preprandially in T1DM 3. All patients had an HbA1c level of 6.4–8.9% (NGSP), patients having a westernized life style [4]. However, and a BMI of <30 kg/m2 at week 0. about 30–40% of daily insulin is usually given as a basal The exclusion criteria were any major illness or endo- supplement and the other 60–70% is given preprandi- crinological, cardiac, renal, gastrointestinal or severe ally to Japanese T1DM patients [5]. The difference of hepatic disorder, and severe neuropathy (associated the ratio of basal/bolus insulin supplementation between with autonomic neuropathy) or severe retinopathy T1DM in Japan and westernized countries might be (preproliferative retinopathy or more severe stages); dependent on the difference of whole body insulin resis- in addition, pregnant or lactating females, and females tance and hepatic insulin resistance between T1DM in not using adequate contraception were excluded. The Japan and westernized countries. The difference of the characteristics of the subjects are shown in Table 1. The percentage of carbohydrate intake at each meal might study protocol was approved by the Ethics Committee also affect on the difference of the ratio of basal/bolus of Hyogo College of Medicine, and written informed insulin supplementation as well. consent was provided in accordance with the ethical Miglitol, an α-glucosidase inhibitor, has been pri- principles stated in the Declaration of Helsinki. marily used in patients with T2DM for establishing bet- ter glycemic control by preventing postprandial hyper- glycemia via inhibition of digestion of Table 1 Clinical characteristics of T1DM subjects enrolled in the (such as disaccharides, oligosaccharides, and poly- study. saccharides) into , particularly in the Number of patients 11 upper small intestine. After oral administration, migli- Gender 4 males / 7 females tol is rapidly and completely absorbed in the upper Age (years old) 50.5 ± 19.0 BMI (kg/m2) 20.8 ± 2.1 small intestine, but other types of α-glucosidase inhibi- Duration of diabetes (years) 9.7 ± 7.4 tors are poorly absorbed there [6]. In T2DM patients HbA1c (%) (NGSP) 7.4 ± 0.6 treated with insulin therapy, combination therapy of Total insulin dose (units/day) 36.2 ± 15.4 insulin and miglitol was effective for regulating post- Ad lib C peptide (ng/mL) 0.15 ± 0.20 prandial glucose and improving glycemic control [7]. SBP (mmHg) 113 ± 15 In this study, we added miglitol on intensive insulin DBP (mmHg) 68 ± 7 therapy in T1DM patients and investigated the efficacy of LDL-C (mg/dL) 96 ± 28 HDL-C (mg/dL) 68 ± 22 miglitol by examining blood glucose levels, daily insu- TG (mg/dL) 62 ± 30 lin doses, body weight changes, and frequency of hypo- TC (mg/dL) 190 ± 41 glycemia. In addition, we analyzed changes in incretin Diabetic Complications hormone responses by addition of miglitol on intensive Retinopathy 1 (SDR) insulin therapy in T1DM patients during MTT. Neuropathy 5 Nephropathy 0 Subjects and Methods Data are means ± SD. Eight subjects had GAD-antibodies, and the rest 3 subjects were diagnosed as T1DM due to their clinical features with acute onset. Five subjects had mild neuropathy; Subjects Achilles tendon reflexes were only slightly decreased. T1DM, We recruited 11 outpatients with T1DM who had type 1 diabetes mellitus; BMI indicates body mass index; NGSP, been regularly attending our Division of Diabetes and National Glycohemoglobin Standardization Program; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-C, low- Metabolism, Department of Internal Medicine, Hyogo density lipoprotein cholesterol; HDL-C, high-density lipoprotein College of Medicine. Each participant, who had pro- cholesterol; TG, triglyceride; TC, total cholesterol; SDR, simple vided written informed consent before the start of the diabetic retinopathy Miglitol and intensive insulin therapy 871

Fig. 1 Study design. Test meal (460 kcal, 56.5 g carbohydrate, 18 g protein, 18 g fat)

Study design and methods meal, and at bedtime), at least once a week. All SMBG As shown in Fig. 1, this study consisted of a 4- to data, as well as all occurrences of hypoglycemia, when 8-week observation period and a 12-week treatment they became aware of symptoms of hypoglycemia or period. From week 0 to 4 of the treatment period, when blood glucose levels fell below 60 mg/dL were enrolled subjects were instructed to take a 25 mg self-recorded in a diary. In addition, a questionnaire miglitol immediately before meals 3 times daily. regarding appetite, nausea, abdominal bloating, and From week 4 to 12, they were instructed to take a 50 diarrhea was administered during medical interviews mg miglitol tablet immediately before meals 3 times at weeks 0, 4, 8, and 12. daily. Throughout the observation and treatment peri- ods, patients were instructed to follow the same diet and Meal tolerance test (MTT) exercise regimen as they did before the study. Changes Of the 11 patients, 9 who agreed to participate in in the type of insulin or drugs were prohibited; how- MTT were instructed to take test meals (JANEF ever, the dosage of insulin could be adjusted to achieve E460F18® Kewpie Corporation, Tokyo, Japan, 460 target blood glucose (; preprandial; 70 - 120 mg/dl, 2hr kcal 56.5 g carbohydrate, 18 g protein, and 18 g fat) postprandial; 120 – 160 mg/dl). Ad-lib C-peptide was in the overnight fasting state as breakfast for MTT at measured by lumipulse presto C-peptide (Fujirebio week 0 and 12. At week 12, patients were instructed Inc, Tokyo, Japan). The levels of HbA1c, GA, 1,5-AG, to take 50 mg of miglitol immediately before start- body weight, AST, ALT and blood pressure (SBP and ing the test. For active GLP-1 and total GIP analyses, DBP) were measured at weeks 0, 4, 8, and 12. The lev- catheters were placed in cubital veins and blood sam- els of LDL-C, HDL-C, TG and TC were measured in ples were withdrawn directly into EDTA-2Na coated fasting state at weeks 0 and 12. The HbA1c value (%) blood collection tubes (1.25 mg/mL blood) contain- in the present study is shown as the NGSP equivalent ing aprotinin and an inhibitor of DPP-4 (10 μL/mL of value (%) calculated on the basis of the following for- blood; Linco Research Inc., MO, USA) before the start mula [8]: HbA1c (NGSP) (%) = HbA1c (JDS) (%) + 0.4 of MTT and 30, 60 and 120 min after ingestion. The (%). All levels of HbA1c in this study are expressed as levels of plasma glucose, IRG, total GIP, and active NGSP equivalent values. The urinary albumin excre- GLP-1 were measured in each sample. Plasma glucose tion rate was measured at weeks 0 and 12. Throughout concentrations were measured immediately by the glu- the study period, measurements of blood glucose lev- cose oxidase method. Plasma levels of glucagon were els were performed through SMBG before each meal 3 measured by the radioimmunoassay method, using times a day, and 1 or 2 h after each meal, i.e., 6 mea- the Glucagon kit Daiichi-II (TFB Corp., CA, USA) at surements per day to titrate the insulin regimen. All Cosmic Corp. (Tokyo, Japan). Plasma levels of active subjects were additionally instructed to perform SMBG GLP-1 were measured by the ELISA method, using the 10 times daily (before every meal, 1 and 2 h after every GLP-1 Active ELISA kit (Millipore Corp., MA, USA) 872 Nagai et al. at Cosmic Corp. (Tokyo, Japan) according to the manu- Results facturer’s instruction. Plasma levels of total GIP were also measured by the ELISA method, using the Human HbA1c, GA, and 1,5-AG levels GIP (total) ELISA kit (Millipore Corp.) at Cosmic Serial changes in parameters from week 0 to 12 are Corp. (Tokyo, Japan). The study was performed from shown in Table 2. The mean HbA1c level before treat- March 2009 to March 2010. ment was 7.4%, and it decreased significantly to 7.0% at week 4 (p = 0.011), 7.0% at week 8 (p = 0.013), and Statistical analysis 6.9% at week 12 (p = 0.0099). The GA level decreased The results of statistical analysis are shown as the significantly from 23.6% at week 0 to 21.7% at week mean ± standard deviation (SD) unless otherwise spec- 12 (p = 0.0208). The level of 1,5-AG was significantly ified. Analyses of efficacy were carried out at each improved from 5.3 μg/mL at week 0 to 8.0 μg/mL at timepoint with Wilcoxon signed rank test against week 4 (p = 0.021) and 8.1 μg/mL at week 12 (p = the baseline. Comparisons of time curves during the 0.013). MTT were analyzed by two-way repeated measures ANOVA, followed by Wilcoxon singned rank test at BMI and hypoglycemic events each time measurement value. A P value of less than The BMI decreased significantly from 20.8 kg/m2 at 0.05 was considered to indicate statistically significant week 0 to 20.4 kg/m2 at week 4 (p = 0.0077), 20.5 kg/ differences. m2 at week 8 (p = 0.0093), and to 20.4 kg/m2 at week 12 (p = 0.0051). The frequency of weekly hypoglyce-

Table 2 Changes in parameters for blood glucose control from Week 0 to 12. p value p value p value Week 0 Week 4 (vs. week 0) Week 8 (vs. week 0) Week 12 (vs. week 0)

HbA1c (%) 7.4±0.6 7.0±0.6 0.011 7.0±0.6 0.013 6.9±0.5 0.0099 GA (%) 23.6±3.3 22.9±3.7 N.S. 22.4±2.8 N.S. 21.7±3.3 0.0208 1,5 AG (μg/mL) 5.3±4.2 8.0±4.4 0.021 8.4±4.4 N.S. 8.1±3.9 0.013 BMI (kg/m2) 20.8±2.1 20.4±2.1 0.0077 20.5±2.0 0.0093 20.4±2.0 0.0051 Hypoglycemia (times/week) 0 a.m. to 5 a.m. 0.01±0.03 0.06±0.2 N.S. 0.01±0.04 N.S. 0.04±0.09 N.S. 5 a.m. to breakfast 0.3±0.6 0.3±0.6 N.S. 0.4±0.8 N.S. 0.2±0.6 N.S. before lunch and dinner 1.0±1.2 0.9±1.2 N.S. 0.6±0.2 N.S. 0.3±0.6 0.012 after meals 0.5±0.5 0.8±0.7 N.S. 0.8±0.8 N.S. 0.6±0.5 N.S. Total insulin (unit/day) 36.2±15.0 35.6±15.2 0.028 33.9±13.5 0.012 33.8±13.4 0.012 Basal insulin (unit/day) 12.0±4.9 12.0±4.9 N.S. 11.8±5.1 N.S. 11.7±5.2 N.S. Bolus insulin (unit/day) 24.2±12.6 23.8±12.8 0.043 22.3±11.4 0.018 22.3±11.5 0.018 SBP (mmHg) 113±15 117±15 N.S. 117±14 N.S. 113±14 N.S. DBP (mmHg) 68±7 70±7 N.S. 68±7 N.S. 70±7 N.S. LDL-C (mg/dL) 100±28 ---- 95±33 N.S. HDL-C (mgdL) 68±22 ---- 72±29 N.S. TG (mg/dL) 62±30 ---- 62±30 N.S. TC (mg/dL) 190±41 ---- 192±56 N.S. AST (U/L) 22.2±7.0 22.3±8.4 N.S. 22.6±5.1 N.S. 22.5±5.1 N.S. ALT (U/L) 20.0±8.5 21.7±10.6 N.S. 24.6±6.9 N.S. 23.5±7.4 N.S. Urinary albumin excretion rate ---- 15.7±33.4 N.S. (μg/g.creatinine) 7.3±8.3 Data are expressed as mean±SD. Changes in parameters for blood glucose control from Week 0 to 12. HbA1c: hemoglobin A1c; GA: glycoalbumin; 1,5-AG: 1,5-anhydroglucitol; BMI: Body mass index; NGSP, National Glycohemoglobin Standardization Program; SBP, systolic blood pressure; DBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol; AST,aspartate aminotransferase; ALT, alanine aminotransferase; N.S., not significant Miglitol and intensive insulin therapy 873

Fig. 2 The daily profiles of blood glucose levels measured with self-monitoring of blood glucose (10 times/day). Data are means ± SD. Asterisks denote significant differences (Wilcoxon signed rank t-test) between values at 0 week and week 12. **: p < 0.01

mic events before lunch and dinner markedly and sig- 2. Compared to week 0, at week 12 the blood glucose nificantly decreased from 1.0 at week 0 to 0.3 at week levels after meals tended to be lower and the blood glu- 12 (p = 0.012). cose level 1 h after dinner was significantly lower (p = 0.008). Dosage of insulin (total, basal, and bolus) The mean total daily insulin dosage decreased from Results of the questionnaire survey 36.2 units at week 0 to 35.6 units at week 4 (p = 0.028), No substantial change was found in appetite, nausea, 33.9 units at week 8 (p = 0.012), and to 33.8 units at bloating sensation in the abdomen, constipation, and week 12 (p = 0.012). While the daily basal insulin dos- diarrhea in weeks 0, 4, 8, and 12. age was not changed, the daily bolus insulin dosage decreased from 24.2 units at week 0, to 23.8 units at Plasma glucose and incretin levels in MTT at weeks week 4 (p = 0.043), 22.3 units at week 8 (p = 0.018), 0 and 12 and to 22.3 units at week 12 (p = 0.018). The changes in plasma glucose, active GLP-1, total GIP and IRG during MTT from week 0 to 12 are shown Blood Pressure (SBP and DBP), LDL-C, HDL-C, TG in Figs. 3A-D. While the mean plasma glucose levels and TC at 0 min at weeks 0 and 12 were almost similar, those There were no significant changes in SBP and DBP at 60, and 120 min were significantly decreased from at week 4, 8, and 12 in comparison with week 0. There 251.9 mg/dL to 133.0 mg/dL (p = 0.0077) and from were also no significant changes in LDL-C, HDL-C, 231.3 mg/dL to 149.9 mg/dL (p = 0.021), respectively TG and TC between weeks 0 and 12. (Fig. 3A). Fig. 3B demonstrates that the change in active GLP-1 at 120 min at week 12 significantly increased AST, ALT, and urinary albumin excretion rate from 1.9 pmol/L to 6.8 pmol/L (p = 0.015). The change There were no significant changes in AST and ALT in total GIP at week 12 significantly decreased from at week 4, 8, and 12 in comparison with week 0. There 587.7 pg/mL to 233.2 pg/mL (p = 0.011) at 30 min, was also no significant change in the albumin excretion from 551.8 pg/mL to 189.6 pg/mL (p = 0.0077) at 60 rate between weeks 0 and 12. min, and from 251.4 pg/mL to 128.2 pg/mL (p = 0.038) at 120 min (Fig. 3C). However, there was no signifi- Daily profile with SMBG at weeks 0 and 12 cant difference of the change in IRG between weeks 0 The SMBG data (10 times/day) are shown in Fig. and 12 (Fig. 3D). 874 Nagai et al.

Fig. 3 A Plasma glucose level after meal tolerance test from Week 0 to 12. Data are means ± SD. **: p < 0.01, *: p < 0.05 vs before treatment with miglitol. B Changes in active GLP-1 level after meal tolerance test from Week 0 to 12. Data are means ± SD. *: p < 0.05 vs before treatment with miglitol. C Changes in total GIP level after meal tolerance test from Week 0 to 12. Data are means ± SD. **: p < 0.01, *: p < 0.05 vs before treatment with miglitol. D Changes in glucagon level after meal tolerance test from Week 0 to 12. Data are means ± SD.

Discussion study (weeks 4 and 8), as shown in Table 2. Since the dose of bolus insulin was titrated, hypoglycemic events The combination of insulin therapy and miglitol before lunch and dinner at week 12 were significantly treatment has been previously reported to improve reduced. Even though patients used less bolus insu- postprandial in T1DM patients [9, 10] lin in this study, we achieved an improvement in blood and to enable decreased dosages of insulin [11], how- glucose levels after meals when we compare the results ever the insulin regimen in those reports were evi- of SMBG at weeks 0 and 12 (Figure 2). In the SMBG dently different from the standard regimen in inten- record by the subjects in their ordinary daily lives, we sive insulin therapy involving ultra-rapid acting insulin were able to measure a significant suppression in post- preparations, which are currently available in T1DM prandial blood glucose levels only at 1 h after dinner, patients. The present study clearly shows that addition since the carbohydrate intake is relatively high at din- of miglitol, an alpha-glucosidase inhibitor, on intensive ner in Japanese T1DM patients and the effect of alpha– insulin therapy in T1DM patients has beneficial effects glucosidase inhibitors would be most evident. Since on improving HbA1c, GA, and 1,5-AG levels and on combination therapy of miglitol and insulin reduced reducing BMI, bolus and total insulin dosage, and fre- glucose fluctuations throughout the day in this study, quency of preprandial hypoglycemic events. we speculate that this therapy could slow the onset and One of the objectives of the combined administra- progression of microvascular complications and car- tion of miglitol in T1DM patients treated with insu- diovascular events in T1DM patients. lin is to obtain target HbA1c without significant hypo- Kubo et al. have shown that addition of miglitol on glycemia and to improve postprandial hyperglycemia. intensive insulin therapy in T1DM patients resulted in Although it was not significant, the frequency of hypo- an improvement of postprandial hyperglycemia with a glycemia after meals increased at the beginning of the reduction of insulin dosage [12]. However, they could Miglitol and intensive insulin therapy 875 not identify the precise mechanism of the improvement bers in T1DM patients [21]. In addition, it is possible of blood glucose control in relation to the response of that the miglitol-induced increase of GLP-1 secretion incretin hormones. The changes of GLP-1 and GIP con- in this study did not achieve sufficient concentrations centrations in healthy subjects or T2DM patients who to inhibit glucagon secretion. Another hypothesis to take miglitol have been examined in several studies. account for the increased glucagon response in the Arakawa et al. and Aoki et al. studied subjects without present study is the difference of plasma glucose levels diabetes and showed that miglitol increased the plasma in MTT. As shown in Figure 3A, compared to the glu- GLP-1 levels after meals [13, 14]. In T2DM patients, cose level measured at week 0, the mean glucose level Lee et al. demonstrated that miglitol induced an at week 12 after meal ingestion was significantly sup- enhanced and prolonged GLP-1 release after ingesting pressed. Further study is necessary to clarify the reason an ordinary meal [15], and Narita et al. demonstrated why glucagon was not suppressed in relation to both that miglitol induced prolonged and enhanced GLP-1 incretins after addition of miglitol on T1DM patients. and reduced GIP responses after ingestion of a mixed Since glucagon level at MTT in this study was not sup- meal by Japanese T2DM patients [16]. However, the pressed, we cannot demonstrate that GLP-1 elevation effect of combination therapy of miglitol and insulin on affected on the improvement of glycemic control in secretion of incretin in T1DM patients who have been this study. GLP-1 may have contributed to the better treated with intensive insulin therapy is a novel finding glycemic control by mild appetite loss which was not of this study. apparent at the questionnaire test , however, the under- This is the first report of miglitol–insulin -combi lying mechanism in relation to GLP-1 response after nation therapy analyzing the modification of incretin addition of miglitol in this study is still unclear. responses in T1DM patients undergoing MTT. And further, since miglitol suppressed the steep post- In the present study, at week 12, the active GLP-1 prandial elevation of plasma glucose, the dose of bolus at 120 min significantly increased, and the total GIP insulin could be decreased remarkably. By decreasing significantly decreased, as shown in Figure 3B and C. bolus insulin doses, a reduction of preprandial hypo- Our investigation of incretin hormone levels before glycemic events and body weight was achieved, and and after MTT showed that combination therapy of vice versa. miglitol and insulin in T1DM patients not only delays Another possible mechanism underlying the benefi- the absorption of carbohydrates, but also significantly cial effect of combination therapy could be the modifi- decreases the secretion of GIP and increases the secre- cation of the responses of GIP. The BMI of the subjects tion of GLP-1. Because miglitol has the potential to significantly decreased over the course of the study, as decrease the absorption of carbohydrates at the upper shown in Table 2. The reduction in body weight could small intestine and increase the absorption at the lower be due to the decrease of the GIP level. Yamada et al. small intestine, the GIP secreted from K cells, primar- demonstrated that GIP has not only an insulinotropic ily in the proximal small intestine, was decreased. In role, but also physiological roles on fat accumulation contrast, the level of GLP-1 secreted from L cells, pri- into adipose tissues; they proposed a new acronym, marily in the distal portion of the small intestine, was GIP (gut-derived nutrient-intake peptide) [22]. As GIP increased throughout MTT. decreased significantly in this co-administration study To clarify the mechanism of achieving better glyce- of miglitol, we think that body weight loss could occur mic control in T1DM patients undergoing miglitol and by a decrease of fat accumulation into adipose tissue. intensive insulin combination therapy, we measured Consquently, a reduction in BMI has the potential to IRG in MTT. We expected that the secretion of gluca- reduce the requirements for bolus insulin doses and the gon might be suppressed in MTT, because both GLP-1 frequency of hypoglycemic events. and GLP-1 receptor agonists suppress glucagon secre- Since the study was analyzed based on the relatively tion during euglycemia in healthy subjects [17-20]. small number of patients, we also need further inves- Although active GLP-1 significantly increased in MTT tigation of a large number of T1DM patients to eluci- at week 12, we could not find any significant differ- date the relationship between improved blood glucose ence in IRG between week 0 and 12. This could be due control and the response of incretin after the addition to severely impaired function of alpha cells in T1DM; of miglitol. although the alpha cells are still present in normal num- 876 Nagai et al.

Conclusions tion of the responses of incretins, GIP and GLP-1.

The present study showed that addition of miglitol Acknowledgment on intensive insulin therapy in T1DM patients has ben- eficial effects on the stabilization of glycemic control This work was supported in part by a grant-in-aid and reduction of BMI, bolus and total insulin dosage, (Grant No. 20591075) to Jun-ichiro Miyagawa from and frequency of preprandial hypoglycemic events. the Ministry of Education, Science, Sports and Culture By combining miglitol with insulin, the fluctuation in of Japan. daily profiles of blood glucose levels in T1DM could be minimized. Disclosure Statement Furthermore, our MTT results suggest that combina- tion therapy of miglitol and insulin in T1DM patients The authors declare that there is no conflict of inter- improves their blood glucose control via not only a est associated with this manuscript. delay in carbohydrate absorption but also the modifica-

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