Lee EY et al. (2015), Distinct action of the α-glucosidase inhibitor ...

XB-ART-49998

J Endocrinol 2015 Mar 01;2243:205-14. doi: 10.1530/JOE-14-0555.

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Distinct action of the α-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion.

Lee EY , Kaneko S , Jutabha P , Zhang X , Seino S , Jomori T , Anzai N , Miki T .

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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.

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Species referenced: Xenopus laevis
Genes referenced: camk2a gcg kcnj11 slc2a2 slc5a1.2

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	Figure 1. Physiological relevance of SGLT1, GLUT2, and KATP channel in glucose-induced GLP1 secretion in the early phase. Blood glucose (A) and plasma GLP1 concentrations (B) in portal vein at 5 min after intraduodenal administration of glucose (or vehicle) are shown. Glucose was co-administrated with or without phlorizin (500 mg/kg) or phloretin (500 mg/kg) to WT mice (A and B). Blood glucose (C) and plasma GLP1 concentrations (D) in portal vein of Kir6.2-deficient mice at 5 min after intraduodenal glucose administration are also shown. Data are expressed as mean±s.e.m. P<0.05 and **P<0.001.
	Figure 2. Physiological relevance of SGLT1 and GLUT2 in GLP1 secretion by maltose plus miglitol in the late phase. Blood glucose (A and C) and plasma GLP1 concentrations (B and D) in the portal vein of awake, WT mice at 30 min are shown. Data after oral administration of glucose, maltose, or vehicle (A, B, C, and D) or of maltose plus miglitol with or without either phlorizin or phloretin (C and D) are shown. Blood glucose (E) and plasma GLP1 concentrations (F) in portal vein of Kir6.2 −/− mice at 30 min after oral administration of maltose plus miglitol are shown. Effect of different doses (250, 125, and 50 mg/kg) of phlorizin on glucose-induced GLP1 secretion is shown (G and H). Data are expressed as mean±s.e.m. P<0.05, P<0.01, and **P<0.001.
	Figure 3. Comparison between miglitol and acarbose of GLP1 secretion induced by maltose. Blood glucose (A) and plasma GLP1 concentrations (B) in the portal vein at 30 min after oral administration of miglitol, acarbose, maltose plus miglitol, or maltose plus acarbose are shown. Data are expressed as mean±s.e.m. P<0.05, P<0.01 and **P<0.001.
	Figure 4. Electrophysiological recording of Xenopus laevis oocytes expressing hSGLT3. (A, B, C, and D) (A) I–V relationship of the oocytes expressing hSGLT3 in the presence (solid line) or absence (dashed line) of miglitol. (B) A representative recording of whole-cell current under voltage clamp mode in an oocyte expressing hSGLT3 in the absence (left) or presence (right) of Na+ in the buffer. ‘Gluc.’ denotes glucose. (C) A representative recording of the membrane potentials under current clamp mode in an oocyte expressing hSGLT3 in response to glucose and/or miglitol. The SGLT3 agonist α-methyl-d-glucopyranoside (αMDG) was used as a positive control for SGLT3-dependent depolarization. ‘Gluc.’ denotes glucose. (E) The current changes by several stimuli (n=4 for each). Data are expressed as mean±s.e.m. P<0.05 and *P<0.01 (compared with the base line).
	Figure 5. Activation of CaMK2 of duodenal enteroendocrine cells. (A, B, C, D, and E) Immunohistochemistry of phospho-CaMK2 (green) and 5-HT (red) of duodenum is shown. (A) Oral vehicle administration. (B) Intraduodenal glucose administration. (C) Oral maltose plus miglitol administration. (D) Oral miglitol administration. (E) Oral acarbose administration. (F) Intraperitoneal glucose administration. Insets denote the cells indicated by yellow arrows at a higher magnification. White arrows indicate immunopositive cells. (A, B, C, D, and E) Images of phospho-CaMK2 (left), 5-HT (middle), and their superposition (phospho-CaMK2, 5-HT, and DAPI). Bars indicate 50 μm.
	Figure 6. Involvement of parasympathetic nerves in GLP1 secretion. Blood glucose (A) and plasma GLP1 concentrations (B) in the portal vein at 30 min after oral administration of maltose plus miglitol with or without atropine pretreatment are shown. Data are expressed as mean±s.e.m. P<0.05, P<0.01, and **P<0.001.

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	Figure 1. Physiological relevance of SGLT1, GLUT2, and KATP channel in glucose-induced GLP1 secretion in the early phase. Blood glucose (A) and plasma GLP1 concentrations (B) in portal vein at 5 min after intraduodenal administration of glucose (or vehicle) are shown. Glucose was co-administrated with or without phlorizin (500 mg/kg) or phloretin (500 mg/kg) to WT mice (A and B). Blood glucose (C) and plasma GLP1 concentrations (D) in portal vein of Kir6.2-deficient mice at 5 min after intraduodenal glucose administration are also shown. Data are expressed as mean±s.e.m. P<0.05 and **P<0.001.
	Figure 2. Physiological relevance of SGLT1 and GLUT2 in GLP1 secretion by maltose plus miglitol in the late phase. Blood glucose (A and C) and plasma GLP1 concentrations (B and D) in the portal vein of awake, WT mice at 30 min are shown. Data after oral administration of glucose, maltose, or vehicle (A, B, C, and D) or of maltose plus miglitol with or without either phlorizin or phloretin (C and D) are shown. Blood glucose (E) and plasma GLP1 concentrations (F) in portal vein of Kir6.2 −/− mice at 30 min after oral administration of maltose plus miglitol are shown. Effect of different doses (250, 125, and 50 mg/kg) of phlorizin on glucose-induced GLP1 secretion is shown (G and H). Data are expressed as mean±s.e.m. P<0.05, P<0.01, and **P<0.001.
	Figure 3. Comparison between miglitol and acarbose of GLP1 secretion induced by maltose. Blood glucose (A) and plasma GLP1 concentrations (B) in the portal vein at 30 min after oral administration of miglitol, acarbose, maltose plus miglitol, or maltose plus acarbose are shown. Data are expressed as mean±s.e.m. P<0.05, P<0.01 and **P<0.001.
	Figure 4. Electrophysiological recording of Xenopus laevis oocytes expressing hSGLT3. (A, B, C, and D) (A) I–V relationship of the oocytes expressing hSGLT3 in the presence (solid line) or absence (dashed line) of miglitol. (B) A representative recording of whole-cell current under voltage clamp mode in an oocyte expressing hSGLT3 in the absence (left) or presence (right) of Na+ in the buffer. ‘Gluc.’ denotes glucose. (C) A representative recording of the membrane potentials under current clamp mode in an oocyte expressing hSGLT3 in response to glucose and/or miglitol. The SGLT3 agonist α-methyl-d-glucopyranoside (αMDG) was used as a positive control for SGLT3-dependent depolarization. ‘Gluc.’ denotes glucose. (E) The current changes by several stimuli (n=4 for each). Data are expressed as mean±s.e.m. P<0.05 and *P<0.01 (compared with the base line).
	Figure 5. Activation of CaMK2 of duodenal enteroendocrine cells. (A, B, C, D, and E) Immunohistochemistry of phospho-CaMK2 (green) and 5-HT (red) of duodenum is shown. (A) Oral vehicle administration. (B) Intraduodenal glucose administration. (C) Oral maltose plus miglitol administration. (D) Oral miglitol administration. (E) Oral acarbose administration. (F) Intraperitoneal glucose administration. Insets denote the cells indicated by yellow arrows at a higher magnification. White arrows indicate immunopositive cells. (A, B, C, D, and E) Images of phospho-CaMK2 (left), 5-HT (middle), and their superposition (phospho-CaMK2, 5-HT, and DAPI). Bars indicate 50 μm.
	Figure 6. Involvement of parasympathetic nerves in GLP1 secretion. Blood glucose (A) and plasma GLP1 concentrations (B) in the portal vein at 30 min after oral administration of maltose plus miglitol with or without atropine pretreatment are shown. Data are expressed as mean±s.e.m. P<0.05, P<0.01, and **P<0.001.