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This Article Full Text (PDF) All Versions of this Article: 297/6/E1358    most recent ajpendo.00412.2009v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Moriya, R. Articles by Seo, T. PubMed PubMed Citation Articles by Moriya, R. Articles by Seo, T.

RESEARCH ARTICLE

Sodium glucose co-transporter 1 (SGLT1) mediates glucose-induced incretin secretion in mice in vivo

¹Banyu Pharmaceuticals ²Merck & Co. Inc

Submitted 29 June 2009 ; revised 2 October 2009 ; accepted in final form 2 October 2009

Glucose ingestion stimulates the secretion of the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Despite the critical role of incretins in glucose homeostasis, the mechanism of glucose induced incretin secretion has not been established. We investigated the underlying mechanism of glucose-induced incretin secretion in vivo in mice. Injection of glucose at 1 g/kg into the upper intestine significantly increased plasma GIP and GLP-1 levels, whereas injection of glucose into the colon did not increase GIP and GLP-1 levels. This finding indicates that the glucose sensor for glucose-induced incretin secretion is in the upper intestine. Co-administration of a sodium-glucose cotransporter-1 (SGLT1) inhibitor, phloridzin, with glucose into the upper intestine blocked glucose absorption and glucose-induced incretin secretion. Alpha-methyl-d-glucopyranoside (MDG), an SGLT1 substrate that is a non-metabolizable sugar, significantly increased plasma GIP and GLP-1 levels, whereas phloridzin blocked these increases, indicating that concomitant transport of sodium ions and glucose (substrate) via SGLT1 itself triggers incretin secretion without the need for subsequent glucose metabolism. Interestingly, oral administration of MDG significantly increased plasma GIP, GLP-1, and insulin levels and reduced blood glucose levels during an intraperitoneal glucose tolerance test. Furthermore, chronic MDG treatment in drinking water (3%) for 13 days reduced blood glucose levels after 2 hours fast and in an oral glucose tolerance test in diabetic db/db mice. Our findings indicate that SGLT1 serves as the intestinal glucose sensor for glucose-induced incretin secretion and that a non-calorigenic SGLT1 substrate ameliorates hyperglycemia by stimulating incretin secretion.

glucose-dependent insulinotropic peptide (GIP); glucagon-like peptide-1 (GLP-1); Sodium glucose co-transporter