Imino sugars are potent agonists of the human glucose sensor SGLT3

Imino sugars are used to treat type 2 diabetes mellitus [ miglitol ( Glyset)] and lysosomal storage disorders [ miglustat ( Zavesca)] based on the inhibition of alpha-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 alpha-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, alpha- 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 mu M. 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 mu M). These imino sugar binding characteristics are similar to those for alpha-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.