Imino Sugars Are Potent Agonists of the Human Glucose Sensor SGLT3

Abstract

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 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 M). 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.

Bridging the gap between structure and kinetics of human SGLT1

“…The large increase in K 0.5 ␣MDG with mutations of sugar coordinating residues (Table 2) is in agreement with the loss in sugar affinity when the equatorial hydroxyl group at C2 or C3 in the pyranose ring is removed (47). When the hydrogen bonds are absent, as in the case of 2-deoxy-D-glucose and 3-deoxy-Dglucose, large (ϾϾ200-fold) reductions in apparent affinity for sugar have been reported for hSGLT1 (44).…”

Identification of phlorizin binding domains in sodium-glucose cotransporter family: SGLT1 as a unique model system

“…In the presence of D-glucose, hSGLT3 depolarizes the membrane potential because of an uncoupled inward Na þ current [25] indicating its role as a glucose-stimulated Na þ transporter. Transport studies in the presence of alpha methyl D-glucose (AMG) indicates that SGLT3 is weakly inhibited by Pz (Ki~120 mM [33], Table 1). …”

Functional characterization of mouse sodium/glucose transporter type 3b

“…Despite 70% amino acid identity between human SGLT3 and human SGLT1, they present different selectivity for sugars that activate them (23). mSGLT3b has 76% amino acid identity with human SGLT3 and 72% with mouse SGLT1.…”