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      Effects of Miglitol, Acarbose, and Sitagliptin on Plasma Insulin and Gut Peptides in Type 2 Diabetes Mellitus: A Crossover Study

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          Abstract

          Introduction

          Both dipeptidyl peptidase-4 inhibitors and α-glucosidase inhibitors (α-GI) have been reported to change the incretin and insulin secretion. To examine the effects of acarbose, miglitol, and sitagliptin on glucose metabolism and secretion of gut peptides, we conducted a crossover study in patients with type 2 diabetes mellitus (T2DM).

          Methods

          Eleven Japanese patients with T2DM underwent four meal tolerance tests with single administration of acarbose, miglitol, sitagliptin, or nothing. Fasting and postprandial plasma levels of glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), ghrelin, and des-acyl ghrelin were measured.

          Results

          Early-phase insulin secretion was reduced following acarbose and miglitol, and the areas under the curve (AUC) of insulin at 180 min following acarbose and miglitol were significantly lower than sitagliptin. AUC of plasma glucose at 180 min after acarbose, miglitol, and sitagliptin tended to be lower than in controls, and plasma glucose levels at 30–60 min following miglitol were significantly lower than in controls. Plasma glucagon, ghrelin, and des-acyl ghrelin levels did not differ among the four conditions. Postprandial plasma active GLP-1 levels and AUC of GLP-1 increased significantly in both the sitagliptin and miglitol groups compared to control. Postprandial plasma total GIP levels increased following sitagliptin but decreased after acarbose and miglitol. Changes in incretin levels tended to be greater with miglitol than acarbose.

          Conclusion

          These results showed that sitagliptin and α-GIs, miglitol more so than acarbose, improved hyperglycemia in patients with T2DM after single administration, and had different effects on insulin and incretin secretion.

          Trial registration: UMIN-CTR number, UMIN000009981.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s13300-015-0113-3) contains supplementary material, which is available to authorized users.

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          Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes.

          C Deacon, Alese Wagner, B Dietrich … (2006)
          In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin. This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study. The study was conducted at six investigational sites. The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents. Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo. Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics. Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events. In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nm or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.
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            Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia.

            Christopher W. Schmidt, C Deacon, N Siepmann … (2003)
            In the isolated perfused pancreas, gastric inhibitory polypeptide (GIP) has been shown to enhance glucagon secretion at basal glucose concentrations, but in healthy humans no glucagonotropic effect of GIP has yet been reported. Therefore, we studied the effect of GIP on glucagon secretion under normoglycaemic conditions. Ten healthy subjects (9 men, 1 woman; age 33+/-11; BMI 26.8+/-2.2 kg/m(2)) received three different doses of intravenous GIP (7, 20, and 60 pmol/kg body weight) and placebo. Venous blood samples were drawn over 30 min for glucagon and GIP concentrations (specific radioimmunoassays). In addition, 31 healthy subjects (16 men, 15 women; 42+/-11 years; BMI 24.4+/-2.7 kg/m(2)) were studied with 20 pmol GIP/kg. Statistics were done with RM-ANOVA and Duncan's post hoc tests. Gastric inhibitory polypeptide dose-dependently stimulated glucagon secretion ( p=0.019) with a maximal increment after 10 min. Incremental glucagon concentrations (Delta(10-0 min)) were 0.1+/-0.7, 1.4+/-0.5, 2.4+/-0.5, and 3.4+/-0.8 pmol/l (for placebo and for 7, 20, and 60 pmol GIP/kg, respectively; p=0.017). After the injection of 20 pmol GIP/kg b.w. in 31 healthy subjects, glucagon concentrations increased over the baseline from 7.5+/-0.5 to 9.3+/-0.7 pmol/l ( p=0.0082). Glucagon secretion is dose-dependently stimulated by GIP at basal glucose concentrations. The absence of a glucagonotropic GIP effect in previous studies could be due to the hyperglycaemic conditions used in these experiments. Our results underline differences between GIP and the glucagonostatic incretin GLP-1.
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              Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1.

              E M Migoya, R. Bergeron, J. Miller … (2010)
              The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.
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                Author and article information

                Contributors
                Hiroaki Ueno:
                ORCID: http://orcid.org/0000-0003-4947-594X
                intron@med.miyazaki-u.ac.jp
                Masamitsu Nakazato: nakazato@med.miyazaki-u.ac.jp
                Journal
                Journal ID (nlm-ta): Diabetes Ther
                Journal ID (iso-abbrev): Diabetes Ther
                Title: Diabetes Therapy
                Publisher: Springer Healthcare (Cheshire )
                ISSN (Print): 1869-6953
                ISSN (Electronic): 1869-6961
                Publication date (Electronic): 9 June 2015
                Publication date PMC-release: 9 June 2015
                Publication date (Print): June 2015
                Volume: 6
                Issue: 2
                Pages: 187-196
                Affiliations
                [ ]Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
                [ ]Department of Endocrinology and Metabolism, The Affiliated Zhongshan Hospital of Dalian University, Dalian, China
                Author information
                http://orcid.org/0000-0003-4947-594X
                Article
                Publisher ID: 113
                DOI: 10.1007/s13300-015-0113-3
                PMC ID: 4478179
                PubMed ID: 26055217
                SO-VID: 9214b024-26ff-4a78-939f-38da59e8723a
                Copyright © © The Author(s) 2015
                History
                Date received : 2 May 2015
                Categories
                Subject: Original Research
                Custom metadata
                issue-copyright-statement © Springer Healthcare 2015

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: acarbose,glucagon-like peptide-1,glucose-dependent insulinotropic polypeptide,insulin,japanese patients,miglitol,sitagliptin,type 2 diabetes mellitus
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: acarbose, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, insulin, japanese patients, miglitol, sitagliptin, type 2 diabetes mellitus

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