title: Distinct action of the α-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion.
abstract: Oral ingestion of carbohydrate triggers glucagon-like peptide 1 (GLP1) secretion, but the molecular mechanism remains elusive. By measuring GLP1 concentrations in murine portal vein, we found that the ATP-sensitive K(+) (KATP) channel is not essential for glucose-induced GLP1 secretion from enteroendocrine L cells, while the sodium-glucose co-transporter 1 (SGLT1) is required, at least in the early phase (5 min) of secretion. By contrast, co-administration of the α-glucosidase inhibitor (α-GI) miglitol plus maltose evoked late-phase secretion in a glucose transporter 2-dependent manner. We found that GLP1 secretion induced by miglitol plus maltose was significantly higher than that by another α-GI, acarbose, plus maltose, despite the fact that acarbose inhibits maltase more potently than miglitol. As miglitol activates SGLT3, we compared the effects of miglitol on GLP1 secretion with those of acarbose, which failed to depolarize the Xenopus laevis oocytes expressing human SGLT3. Oral administration of miglitol activated duodenal enterochromaffin (EC) cells as assessed by immunostaining of phosphorylated calcium-calmodulin kinase 2 (phospho-CaMK2). In contrast, acarbose activated much fewer enteroendocrine cells, having only modest phospho-CaMK2 immunoreactivity. Single administration of miglitol triggered no GLP1 secretion, and GLP1 secretion by miglitol plus maltose was significantly attenuated by atropine pretreatment, suggesting regulation via vagal nerve. Thus, while α-GIs generally delay carbohydrate absorption and potentiate GLP1 secretion, miglitol also activates duodenal EC cells, possibly via SGLT3, and potentiates GLP1 secretion through the parasympathetic nervous system.
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Jomori
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
authors.affiliation: Department of Medical PhysiologyGraduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanDepartment of Molecular PharmacologyGraduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, JapanDepartment of Pharmacology and ToxicologyDokkyo Medical University School of Medicine, Tochigi 321-0293, JapanDivision of Molecular and Metabolic MedicineKobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, JapanDrug Development CenterSanwa Kagaku Kenkyusho Co., Ltd, 35 Higashisotobori-cho, Higashi-ku, Nagoya 461-8631, Japan tmiki@faculty.chiba-u.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D020909:Acarbose / Q000494:pharmacology; D000818:Animals; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000502:physiology; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051247:Sodium-Glucose Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1 / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D051273:Glucose Transporter Type 2; D065089:Glycoside Hydrolase Inhibitors; C495682:Slc2a2 protein, mouse; C495675:Slc5a1 protein, mouse; C490297:Slc5a4b protein, mouse; D051247:Sodium-Glucose Transport Proteins; D051269:Sodium-Glucose Transporter 1; C045621:miglitol; D017485:1-Deoxynojirimycin; D052216:Glucagon-Like Peptide 1; D020909:Acarbose
keywords: GLP1 secretion; L cell; SGLT3; miglitol