Am J Physiol Cell Physiol 302: C1071–C1072, 2012;
doi:10.1152/ajpcell.00054.2012.
Editorial Focus
SGLT and GLUT: are they teammates? Focus on “Mouse SGLT3a generates
proton-activated currents but does not transport sugar”
Thomas W. Balon
Diabetes Research Unit, Section of Endocrinology, Department of Medicine, Boston University Medical Center,
Boston, Massachusetts
Address for reprint requests and other correspondence: T. W. Balon, Diabetes
and Metabolism Research Unit, BUMC, 650 Albany St., 8th Floor, Rm. 820,
Boston, MA 02118 (e-mail: [email protected]).
The other major type of hexose transporter is the SGLT or
sodium-glucose transporters (gene family SLC5). Their roles
include the active transport of sugars and other moieties against
a concentration gradient. At least six different isoforms of
SGLT exist in humans, with their distribution, subtypes, and
function differing among species (14). SGLT1 and SGLT2
have been the focus of numerous investigations, yet SGLT3,
which is expressed in tissues including skeletal muscle and
small intestine of humans, remained an understudied yet provocative candidate for investigation (Fig. 1). While SGLT3
may be a functional hexose transporter in the pig, DíezSampedro and colleagues (4) used a Xenopus laevis oocyte
expression system and suggested that the human SGLT3 is a
nonfunctional hexose transporter but served as a glucose sensor. However, in both the rat and the mouse, there are two
different genes that code for two different SGLT3s, SGLT3a
and SGLT3b. Subsequently, another study from the DíezSampedro lab determined that mouse SGLT3b is a functional
glucose transporter (1). In this issue of American Journal of
Physiology-Cell Physiology, a subsequent study by Barcelona,
Menegas, and Díez-Sampedro (2) demonstrates that the mouse
SGLT3a is similar to the human SGLT3 in that it does not
transport glucose as measured by the transport of ␣-methyl-Dglucose in oocytes expressing mouse SGLT3a but instead, that
it generates proton-activated currents in a pH-dependent manner. This study has given a greater understanding to both the
redundancy yet uniqueness of the mouse SGLT3 protein.
While the role of the SGLT3 isoforms has been further
defined using well-accepted models and standard techniques in
this and prior studies by the authors (1, 2, 4), its relative physiological relevance remains obscure and serves as an impetus
for further research. It remains to be confirmed whether SGLT3 is
Fig. 1. Shown is a schematic model for sodium-glucose transporter (SGLT) and glucose
transporter (GLUT) isoforms representing
different roles in skeletal muscle. The transporter at left depicts SGLT3 as originally
hypothesized as a glucose sensor and nonfunctional hexose (HEX) transporter. The
second from left and middle transporters are
the different isoforms of SGLT3 transporters
in rat and mouse skeletal muscle showing
either a functional hexose transporter or a
glucose sensor. The signals regulating the
SGLT3 isoforms remain in large part unknown. The two rightmost figures represent
different GLUT4 transporters, which are recruited in response to insulin or exercise,
which may act through nitric oxide. The dark
dashed arrows represent multiple signaling
intermediates integral to each signaling pathways. The light, dashed doubled-headed arrow between different transporters represents
possible cross talk among different isoforms.
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C1071
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MORE THAN 25 YEARS AGO, it was hypothesized that a specific
enzyme, glucokinase, acted as a “glucose sensor” in pancreatic
␤-cells (9). However, after the discovery of different glucose
transporter proteins in the mid- to late-1980s, the hypothesis proposed by several groups evolved to include a transporter molecule, GLUT2, as part of a glucose sensing mechanism (10, 13).
GLUT is one type of transporter protein (gene family
SLC2A) that has no less than 14 distinctive isoforms, whose
primary role appears to aid in facilitative diffusion of different
hexoses or polyol across cell membranes (12). A classification
of the different GLUT proteins was proposed by Joost and
associates (8) based on their tissue distribution, hormonal
regulation, lack of a glycosylation site, and other properties.
With the identification of different isoforms of GLUT,
further research revealed more specific and exact conclusions
and relevance of the GLUT proteins. For example, while both
insulin and acute exercise cause an increase in glucose uptake
by skeletal muscle, it was proposed that insulin and exercise
worked through different mechanisms or pathways, based on
their additive effects in stimulating glucose uptake (15). A
series of landmark studies by David James and colleagues (6,
7) identified a 47 kDa protein as the insulin-responsive GLUT,
thus establishing a foundation for others to determine that
different pools of GLUT4 were selectively recruited by different stimuli (3, 5). Furthermore, not only were different signaling pathways identified (11) in relationship to the recruitment
of GLUT4 by different stimuli, but its abundance, translocation
dynamics, and relevance to disease states were further defined.
Editorial Focus
C1072
a functional hexose transporter in more traditional skeletal
muscle preparations or intact mammals. Likewise, it is unknown whether different physiological states, such as acute
hypoglycemia, aging, dietary manipulation, acute muscle contraction, or certain pathologies, such as diabetes or metabolic
syndrome, alter SGLT3 function, protein, or gene expression,
recruitment, signaling, or trafficking. Similarly, since certain
SGLTs and GLUTs are expressed in the same tissue, the
possibility of cross talk between the molecules remains plausible but undetermined. Hopefully, future research will provide
answers to these and other questions, which may lead to better
therapeutic modalities.
5.
6.
7.
8.
DISCLOSURES
AUTHOR CONTRIBUTIONS
9.
10.
T.W.B. drafted the manuscript.
11.
REFERENCES
1. Aljure O, Diez-Sampedro A. Functional characterization of mouse sodium/glucose transporter type 3b. Am J Physiol Cell Physiol 299: C58 –
C65, 2010.
2. Barcelona S, Menegaz D, Díez-Sampedro A. Mouse SGLT3a generates
proton-activated currents but does not transport sugar. Am J Physiol Cell
Physiol (February 1, 2012). doi:10.1152/ajpcell.00436.2011.
3. Coderre L, Kandror KV, Vallega G, Pilch PF. Identification and
characterization of an exercise-sensitive pool of glucose transporters in
skeletal muscle. J Biol Chem 270: 27584 –27588, 1995.
4. Diez-Sampedro A, Hirayama BA, Osswald C, Gorboulev V, Baumgarten K, Volk C, Wright EM, Koepsell H. A glucose sensor hiding in
12.
13.
14.
15.
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No conflicts of interest, financial or otherwise, are declared by the author.
a family of transporters. Proc Natl Acad Sci USA 100: 11753–11758,
2003.
Douen AG, Ramlal T, Rastogi S, Bilan PJ, Cartee GD, Vranic M,
Holloszy JO, Klip A. Exercise induces recruitment of the “insulinresponsive glucose transporter”. Evidence for distinct intracellular insulinand exercise-recruitable transporter pools in skeletal muscle. J Biol Chem
265: 13427–13430, 1990.
James DE, Brown R, Navarro J, Pilch PF. Insulin-regulatable tissues
express a unique insulin-sensitive glucose transport protein. Nature 333:
183–185, 1988.
James DE, Strube M, Mueckler M. Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature 338: 83–87,
1989.
Joost HG, Bell GI, Best JD, Birnbaum MJ, Charron MJ, Chen YT,
Doege H, James DE, Lodish HF, Moley KH, Moley JF, Mueckler M,
Rogers S, Schurmann A, Seino S, Thorens B. Nomenclature of the
GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol
Endocrinol Metab 282: E974 –E976, 2002.
Meglasson MD, Matschinsky FM. New perspectives on pancreatic islet
glucokinase. Am J Physiol Endocrinol Metab 246: E1–E13, 1984.
Orci L, Thorens B, Ravazzola M, Lodish HF. Localization of the
pancreatic beta cell glucose transporter to specific plasma membrane
domains. Science 245: 295–297, 1989.
Roberts CK, Barnard RJ, Scheck SH, Balon TW. Exercise-stimulated
glucose transport in skeletal muscle is nitric oxide dependent. Am J
Physiol Endocrinol Metab 273: E220 –E225, 1997.
Thorens B, Mueckler M. Glucose transporters in the 21st Century. Am J
Physiol Endocrinol Metab 298: E141–E1451, 2010.
Thorens B, Sarkar HK, Kaback HR, Lodish HF. Cloning and functional expression in bacteria of a novel glucose transporter present in liver,
intestine, kidney, and beta-pancreatic islet cells. Cell 55: 281–290, 1988.
Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose
transporters. Physiol Rev 91: 733–794, 2011.
Zorzano A, Balon TW, Goodman MN, Ruderman NB. Additive effects
of prior exercise and insulin on glucose and AIB uptake by rat muscle. Am
J Physiol Endocrinol Metab 251: E21–E26, 1986.