From the Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California 92093 and the Veterans Affairs San Diego Healthcare System, San Diego, California 92161
Regulation of glucose metabolism is a key aspect
of metabolic homeostasis, and insulin is the dominant hormone
influencing this regulatory system. One of the major effects of insulin
is to enhance overall glucose disposal, and this is achieved by
stimulation of glucose uptake into target tissues. In mammalian systems
there are currently five distinct hexose transport proteins that have been identified, each derived from a separate gene. The mammalian glucose transporters are quite similar in sequence and overall structure but are unique in their tissue distribution. One of them,
GLUT4 or the insulin-sensitive glucose transporter, is uniquely expressed in skeletal muscle, cardiac muscle, and adipose tissue. Insulin stimulates glucose transport into these tissues by causing the
recruitment, or translocation, of GLUT4 proteins from an intracellular vesicular compartment to the plasma membrane. Once GLUT4 recruitment occurs, the transporter inserts into the plasma membrane, allowing uptake of glucose into the cell. However, tissue-specific expression of
GLUT4 is not the only factor conferring insulin-stimulated glucose
transport into these tissues because heterologous expression of GLUT4
in other tissues by various transfection strategies does not confer
insulin-stimulated GLUT4 translocation to non-muscle, non-adipocyte
cells. Therefore, it follows that additional factors in muscle and
adipose tissue, related to insulin signaling or vesicle trafficking,
must exist. Thus, the genetic program endowing the cell with the
ability to exhibit insulin-stimulated GLUT4 translocation is complex
and most likely involves a number of specific components. Skeletal
muscle accounts for the bulk of insulin-stimulated glucose disposal
in vivo (70-80%), with adipose tissue and other organs
playing a lesser role. In this way, insulin stimulation of GLUT4
translocation in muscle and, to a lesser extent, adipose tissue becomes
the key biologic event regulating overall in vivo glucose
disposal in the normal state.
In addition to the importance of insulin-stimulated glucose transport
in normal physiology, this process is of heightened importance because
of its critical role in human pathophysiologic states such as insulin
resistance and Type 2 diabetes. For example, in patients with Type 2 diabetes, decreased insulin-stimulated glucose disposal is a major
metabolic defect, and evidence exists to indicate that it is the
earliest abnormality that can be detected in this condition. Because
under most conditions that prevail in vivo glucose transport
is rate-limiting for glucose disposal and because insulin-induced GLUT4
translocation is the way insulin stimulates glucose transport,
understanding the mechanisms of this process will be key to our
understanding of this important human disease.
Although incompletely understood, the signaling events that lead to
GLUT4 translocation have been the subject of intense investigation. The
first article of this minireview series entitled "Signaling Mechanisms That Regulate Glucose Transport" by Michael P. Czech and
Silvia Corvera summarizes this complex and interesting field. This
chapter points out what is known about the molecular and cellular
events leading to insulin-stimulated glucose transport and also
highlights the important questions for future investigation. In
integrating the complex information already available, this review
points out that insulin simulates the GLUT4 translocation pathway by
interacting at multiple points that involve targeting of effector
proteins to their proper subcellular location, as well as protein
activation (or deactivation) events. This review also expands the
complexity of GLUT4 translocation regulation by pointing out that
insulin engages multiple signaling pathways and that there are other
stimulants (e.g. exercise, osmotic shock, and other
agonists), which can mediate GLUT4 translocation.
GLUT4 proteins translocate from intracellular vesicular pools to the
plasma membrane by a process of targeted exocytosis and then return to
the intracellular environment via endocytotic events. The amount of
GLUT4 that is distributed between the intracellular and cell surface
compartments represents the balance between the rates of exocytosis and
endocytosis. The specialized compartments through which the GLUT4
proteins traverse represent a specific functional aspect of the general
cell biologic system of vesicular trafficking, cargo movement, and
protein targeting. With respect to the itinerary of GLUT4 proteins,
once the insulin signal arrives at its proper intracellular locus, it
must productively engage the intracellular vesicular trafficking
machinery. This involves a complex, and expanding, list of proteins,
specialized vesicular compartments and sub-compartments, and regulatory
events. The second minireview in the series entitled "Molecular Basis
of Insulin-stimulated GLUT4 Vesicle Trafficking: Location! Location!
Location!" by Jeffrey E. Pessin and colleagues examines this fast
moving area. This minireview highlights what is known about the
endocytotic and exocytotic events involved in GLUT4 trafficking.
Although both are subject to insulin regulation, the major effect of
insulin is on exocytosis. The two dominant theories of GLUT4 exocytosis are reviewed. One involves a specialized GLUT4 vesicular compartment that is segregated within the cell in the basal state because of a
retention receptor mechanism and is released upon insulin stimulation,
allowing the GLUT4 vesicles to enter the constitutively cycling
vesicular pathway. The other involves a system analogous to synaptic
vesicle movement, in which insulin may regulate the specific
interactions between v- and t-SNARE protein complexes.
The use of transgenic and knock-out mice has been a powerful tool to
push forward our understanding of a number of biological processes, and
several investigators have applied these approaches to elucidate
important aspects of the biology of GLUT4 and insulin signaling. The
final article in this minireview series is entitled "GLUT4 Gene
Regulation and Manipulation" by Maureen Charron and colleagues, whose
laboratory has generated some of the most important insights in this
area. This article reviews what is known about in vivo
physiologic regulation of GLUT4 gene expression in adipose tissue and
muscle and then moves to the molecular level for a discussion of
cis-acting regulatory elements and what is known about transcription
factors that interact with these regulatory domains. Finally, this
minireview summarizes what we have learned from transgenic and
knock-out technology of the GLUT4 gene, particularly with respect to
the role of GLUT4 expression in insulin resistance and diabetes.
Given the importance of insulin-stimulated GLUT4 translocation for both
normal human physiology and human disease, it is clear that a detailed
understanding of the events that underlie this process could have major
implications, not only for our knowledge about glucose homeostasis but
also for the development of new treatment strategies and therapeutics
for Type 2 diabetes.
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* This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999.