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Imino Sugars Are Potent Agonists of the Human Glucose Sensor SGLT3

Department of Physiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

Imino sugars are used to treat type 2 diabetes mellitus [miglitol (Glyset)] and lysosomal storage disorders [miglustat (Zavesca)] based on the inhibition of -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 -glucosidases and human SGLT type 1 (hSGLT1), a well characterized sodium/glucose cotransporter of the SGLT family. In general, substrates have lower apparent affinities (K_0.5) for hSGLT3 than hSGLT1 (D-glucose, -methyl-D-glucose, 1-deoxy-D-glucose, and 4-deoxy-4-fluoro-D-glucose exhibit K_0.5 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 K_0.5 values of 0.5 to 9 µM. The diastereomer 1-deoxygalactonojirimycin activates hSGT3 with a K_0.5 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 -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.

Address correspondence to: Andrew A. Voss, David Geffen School of Medicine at UCLA, Department of Physiology, 10833 Le Conte Avenue, 53-263 Center for Health Sciences, Los Angeles, CA 90095-1751. E-mail avoss{at}mednet.ucla.edu

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