Na+/H+ exchanger 3 blockade ameliorates type 2 diabetes mellitus via inhibition of sodium-glucose co-transporter 1-mediated glucose absorption in the small intestine
Publication in refereed journal


Times Cited
Altmetrics Information
.

Other information
AbstractAim:
To elucidate the role of Na+/H+ exchanger 3 (NHE3) in sodium-glucose co-transporter 1 (SGLT1)-mediated small intestinal brush border membrane (BBM) glucose absorption and its functional implications in type 2 diabetes mellitus (T2DM).
Materials and Methods:
Human jejunal samples were obtained from patients undergoing gastrectomy. 14C-glucose absorption was measured by liquid scintillation counting. NHE3 expression was suppressed by siRNA-mediated knockdown or augmented in Caco2 cells. Glucose and insulin tolerance in db/db and m+/db mice was assessed with oral and intraperitoneal glucose tolerance tests, and an intraperitoneal insulin tolerance test. Insulin resistance and β-cell function were assessed using homeostatic model assessment of insulin resistance and β-cell function.
Results:
NHE3 expression was upregulated in db/db mouse jejunal BBM and high-glucose-treated Caco2 cells. NHE3 blockade impaired SGLT1-mediated glucose absorption in human jejunum, m+/db and db/db mouse jejunums, and Caco2 cells, via serum/glucocorticoid-regulated kinase 1 (SGK1). NHE3 knockdown suppressed SGLT1-mediated glucose uptake and reduced mRNA and protein levels of SGK1 and SGLT1, which were conversely enhanced by NHE3 overexpression. Chronic S3226 treatment diminished postprandial glucose levels and ameliorated glucose intolerance in db/db mice.
Conclusion:
NHE3 is essential in the modulation of small intestinal BBM glucose absorption. Our findings provide a rationale for future possible clinical application of NHE3 for treatment of T2DM through reducing intestinal glucose uptake and counteracting postprandial hyperglycaemia.
All Author(s) ListLeo Ka Yu CHAN, Yi WANG, Enders Kwok Wai NG, Po Sing LEUNG
Journal nameDiabetes, Obesity and Metabolism
Year2018
Month3
Volume Number20
Issue Number3
PublisherWILEY
Pages709 - 717
ISSN1462-8902
LanguagesEnglish-United Kingdom
Keywordsdiabetes,glucose intolerance,NHE3 inhibitor,postprandial hyperglycaemia
Web of Science Subject CategoriesEndocrinology & Metabolism;Endocrinology & Metabolism

Last updated on 2020-05-04 at 01:30