Imino sugars are potent agonists of the human glucose sensor SGLT3 Article

Voss, AA, Díez-Sampedro, A, Hirayama, BA et al. (2007). Imino sugars are potent agonists of the human glucose sensor SGLT3 . 71(2), 628-634. 10.1124/mol.106.030288

cited authors

  • Voss, AA; Díez-Sampedro, A; Hirayama, BA; Loo, DDF; Wright, EM

authors

abstract

  • Imino sugars are used to treat type 2 diabetes mellitus [miglitol (Glyset)] and lysosomal storage disorders [miglustat (Zavesca)] based on the inhibition of α-glucosidases and glucosyltransferases. In this substrate specificity study, we examined the interactions of imino sugars with a novel human glucose sensor, sodium/glucose cotransporter type 3 (hSGLT3), using expression in Xenopus laevis oocytes and electrophysiology. The results for hSGLT3 are compared with those for α-glucosidases and human SGLT type 1 (hSGLT1), a well characterized sodium/glucose cotransporter of the SGLT family. In general, substrates have lower apparent affinities (K0.5) for hSGLT3 than hSGLT1 (D-glucose, α-methyl-D-glucose, 1-deoxy-D-glucose, and 4-deoxy-4-fluoro-D-glucose exhibit K0.5 values of 19, 21, 43, and 17 mM, respectively, for hSGLT3, and 0.5, 0.7, 10, and 0.07 mM, respectively, for hSGLT1). However, specificity of hSGLT3 binding is greater (D-galactose and 4-deoxy-4-fluoro-D-galactose are not hSGLT3 substrates, but have hSGLT1 K 0.5 values of 0.6 and 1.3 mM). An important deviation from this trend is potent hSGLT3 activation by the imino sugars 1-deoxynojirimycin (DNJ), N-hydroxylethyl-1-deoxynojirimycin (miglitol), N-butyl-1-deoxynojirimycin (miglustat), N-ethyl-1-deoxynojirimycin, and 1-deoxynojirimycin-1-sulfonic acid, with K0.5 values of 0.5 to 9 μM. The diastereomer 1-deoxygalactonojirimycin activates hSGT3 with a K0.5 value of 11 mM, a 3000-fold less potent interaction than is observed for DNJ (4 μM). These imino sugar binding characteristics are similar to those for α-glucosidases, but there are no interactions with hSGLT1. This work provides insights into hSGLT3 and -1 substrate binding interactions, establishes a pharmacological profile to study endogenous hSGLT3, and may have important ramifications for the clinical application of imino sugars. Copyright © 2007 The American Society for Pharmacology and Experimental Therapeutics.

publication date

  • February 1, 2007

Digital Object Identifier (DOI)

start page

  • 628

end page

  • 634

volume

  • 71

issue

  • 2