Insulin-stimulated Glucose Transport Minireview Series (1999)

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 disposalin 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 vivophysiologic 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. 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 disposalin 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 vivophysiologic 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.