XB-ART-49998J Endocrinol March 1, 2015; 224 (3): 205-14.
Distinct action of the α-glucosidase inhibitor miglitol on SGLT3, enteroendocrine cells, and GLP1 secretion.
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.
PubMed ID: 25486965
PMC ID: PMC4324305
Article link: J Endocrinol
Genes referenced: camk2a gcg kcnj11 slc2a2 slc5a1.2
Article Images: [+] show captions
|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.|