Functional characterization of the human facilitative glucose transporter 12 (GLUT12) by electrophysiological methods

Abstract

GLUT12 is a member of the facilitative family of glucose transporters. The goal of this study was to characterize the functional properties of GLUT12, expressed in Xenopus laevis oocytes, using radiotracer and electrophysiological methods. Our results showed that GLUT12 is a facilitative sugar transporter with substrate selectivity: d-glucose ≥ α-methyl-d-glucopyranoside (α-MG) > 2-deoxy-d-glucose(2-DOG) > d-fructose = d-galactose. α-MG is a characteristic substrate of the Na(+)/glucose (SGLT) family and has not been shown to be a substrate of any of the GLUTs. In the absence of sugar, (22)Na(+) was transported through GLUT12 at a higher rate (40%) than noninjected oocytes, indicating that there is a Na(+) leak through GLUT12. Genistein, an inhibitor of GLUT1, also inhibited sugar uptake by GLUT12. Glucose uptake was increased by the PKA activator 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) but not by the PKC activator phorbol-12-myristate-13-acetate (PMA). In high K(+) concentrations, glucose uptake was blocked. Addition of glucose to the external solution induced an inward current with a reversal potential of approximately -15 mV and was blocked by Cl(-) channel blockers, indicating the current was carried by Cl(-) ions. The sugar-activated Cl(-) currents were unaffected by genistein. In high external K(+) concentrations, sugar-activated Cl(-) currents were also blocked, indicating that GLUT12 activity is voltage dependent. Furthermore, glucose-induced current was increased by the PKA activator 8-Br-cAMP but not by the PKC activator PMA. These new features of GLUT12 are very different from those described for other GLUTs, indicating that GLUT12 must have a specific physiological role within glucose homeostasis, still to be discovered.

Transendothelial glucose transport is not restricted by extracellular hyperglycaemia

“…Here we have found HUVEC GLUT transporter mRNA expression qualitatively and quantitatively similar to that in other endothelial cells from capillaries (HDMEC), veins (SVEC) and arteries (HAoEC). The notable exception was very high expression of GLUT12 detected in HDMEC, suggesting a microcirculation-specific function possibly related to the reported GLUT12 insulin responsiveness [55] or distinct physiological characteristics [30,56]. The relative protein levels of two of the most abundant transporters, GLUT1 and GLUT3, correlated well with the mRNA expression, and both transporters were glycosylated in all cells examined.…”

Avian and Mammalian Facilitative Glucose Transporters

“…GLUT12 can facilitate transport of a variety of hexoses [68]. Human GLUT12 is expressed in skeletal muscle, heart and prostate, with lower mRNA expression in the brain, placenta and kidneys [69].…”

SGLT2 Inhibitors: Glucotoxicity and Tumorigenesis Downstream the Renal Proximal Tubule?

“…Recent studies have proposed GLUT12 to be a major glucose transporter involved in the metabolism of cancer cells (Pujol‐Gimenez et al, ). GLUT12 functions as a versatile transporter for a wide diversity of hexoses and works as a Na+ or H+/glucose symporter, with electrogenic properties possibly activated by an osmotic mechanism (Pujol‐Gimenez et al, ). Moreover, GLUT12 is also proposed to translocate to the plasma membrane in response to different stimuli through activation of mTOR (Wilson‐O'Brien et al, ) and PI3K (Stuart et al, ) pathways, both of which play a key role in pathological glycogen accumulation and tumorigenesis in renal distal tubules of human and rat (Ribback et al, ).…”