Endocrine Journal 2011, 58 (10), 869-877 ORIGINAL Effects of miglitol in combination with intensive insulin 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 carbohydrate 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, type 2 diabetes 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 carbohydrates Table 1 Clinical characteristics of T1DM subjects enrolled in the (such as disaccharides, oligosaccharides, and poly- study. saccharides) into monosaccharides, 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 tablet immediately before meals