Comprehensive Physiology Wiley Online Library

Regulation of Glucose Transporters by Insulin and Exercise: Cellular Effects and Implications for Diabetes

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Properties of the Glucose Transporter Families
1.1 The GLUT Family
2 Acute Regulation of Glucose Transporters by Insulin‐Responsive Tissues
2.1 The Glucose Transporter Recruitment Hypothesis
2.2 Insulin‐Responsive Glucose Transporters
2.3 Testing and Verification of the Recruitment Hypothesis
3 Biochemical Characteristics of The Glut‐4‐Containing Organelle
3.1 Resident Proteins
3.2 Proteins Involved in Vesicle Docking and Fusion
3.3 Low‐Molecular‐Weight G Proteins
4 Insulin Signals Involved in The Mobilization of Glucose Transporters
4.1 Testing the Participation of a Signaling Pathway
5 Effects of Prolonged Exposure to Insulin on the Glucose Transporters
6 Regulation of Glucose Transporters by Exercise
6.1 Effects of Exercise In Vivo: Roles of Hypoxia, Blood Flow, and Muscle Fiber Composition
6.2 Glucose Transporters in Exercised Muscles
6.3 Signaling Mechanism of Contraction‐Induced Glucose Transport
7 Glucose Transporters in Diabetes
7.1 Glucose Transporters in Insulin‐Dependent Diabetes Mellitus
7.2 Glucose Transporters in Obesity and Non‐Insulin‐Dependent Diabetes Mellitus
7.3 Proposed Mechanisms Leading to Impaired GLUT‐4 Translocation in Diabetes
7.4 GLUT‐4 Translocation Defect: Primary or Acquired?
7.5 Effects of Antidiabetic Drugs on Glucose Transporters
8 Lessons from the Manipulation of Glucose‐Transporter Expression by Transgenic Mouse Approaches and Natural Mutations
8.1 GLUT‐1 Overexpression in Muscle
8.2 GLUT‐4 Overexpression in Tissues of Natural Expression
8.3 Selective Overexpression of GLUT‐4 in Muscle
8.4 GLUT‐4 Overexpression in Fat
8.5 GLUT‐4 Ablation
8.6 A Naturally Occurring Genetic Abnormality in GLUT‐1 Expression
9 Concluding Remarks
Figure 1. Figure 1.

Tissue distribution of members of the glucose transporter (GLUT) and sodium‐dependent glucose co‐transporter (SGT) families. The distribution of the glucose transporters of the GLUT and SGT families is highlighted, with emphasis on tissues relevant to the maintenance of glucose homeostasis. Within any tissue, the most abundant glucose transporter is listed in larger type. See text for more information on each GLUT isoform. RBC, red blood cell; WBC, white blood cell.

Figure 2. Figure 2.

Orientation of the glucose transporter (GLUT) in the plasma membrane. Schematic representation of a generic GLUT, showing 12 transmembrane domains (M1 to M12). Amino acids that are identical for the human GLUT‐1 through GLUT‐5 proteins are indicated by single‐letter abbreviations. Chemically similar residues (D, E; Y, W, F; I, L, V, M; K, R; N, Q; S, T) are denoted by black circles. The amino‐and carboxy‐terminal domains as well as the exofacial loop between M1 and M2 differ in sequence and size among transporter isoforms.

(Reproduced with permission from ref. : Gould, G. W., and G. I. Bell, Trends Biochem. Sci. 15: 18–23, 1990, Elsevier Science Publishers, Ltd.).
Figure 3. Figure 3.

The glucose transporter translocation hypothesis. Insulin‐responsive fat and muscle tissues contain intracellular stores of glucose transporter proteins. Upon binding of insulin to its receptor, signals which lead to the mobilization of stored glucose transporters to the plasma membrane are generated. Insertion of glucose transporter molecules into the cell surface allows for increased glucose influx into the cell.

Figure 4. Figure 4.

Process for isolation of glucose transporter 4 (GLUT‐4)‐containing vesicles. Polymer beads containing a magnetizable core are covalently linked to antibodies that recognize the heavy chain of anti‐GLUT‐4 antibodies (α‐GLUT‐4). Isolated intracellular membranes from fat or muscle cells expose the cytosolic C‐terminal end of the GLUT‐4 protein to the solution, making it accessible for recognition by α‐GLUT‐4. A magnet is used to pull the loaded beads out of the suspension, thereby separating the GLUT‐4‐containing vesicles from all other membranes.

Figure 5. Figure 5.

Soluble N‐ethyimaleimide‐sensitive factor attachment protein (SNAP) receptors (SNAREs) mediating vesicle binding to target membranes in neuronal and insulin‐responsive cells. A: Binding of the vesicular SNAREs vesicle‐associated membrane protein 1 (VAMP‐1) and VAMP‐2 of synaptic vesicles with the target SNAREs syntaxin‐1 and SNAP‐25 of the presynaptic plasma membrane. B: Binding of the vesicular SNAREs VAMP‐2 and cellubrevin of glucose transporter (GLUT‐4)‐containing vesicles with the target SNAREs syntaxin‐4 and SNAP‐23 of muscle and fat‐cell plasma membranes. VAMP, vesicle‐associated membrane protein; SNAP, soluble N‐ethylmaleimide‐sensitive factor attachment protein; N and C, amino‐and carboxy‐terminal ends, respectively.

Figure 6. Figure 6.

Signal‐transduction pathways triggered by the occupied insulin receptor. Insulin binds to its receptor and stimulates tyrosine autophosphorylation of the intracellular β subunit of the receptor. This in turn stimulates the intrinsic tyrosine kinase activity of the β subunit toward intracellular substrates. A few main substrates are highlighted, namely, Shc and insulin receptor substrate (IRS) proteins. Insulin signaling is diversified into several pathways from the receptor, but only two well‐characterized pathways are shown. These are the IRS‐phosphatidylinositol‐3‐kinase (PI3K) axis and the Ras–Raf–mitogenactivated protein kinase (MAPK) axis. See text for details. PDK, 3‐phosphoinositide‐dependent kinase; PKC, protein kinase C; SOS, son of sevenless; GAP, GtPase‐activating protein, MEK, MAPK kinase.

Figure 7. Figure 7.

Proposed signal‐transduction pathway leading to glucose transporter translocation in muscle and fat cells. Insulin induces activation of phosphatidylinositol‐3‐kinase (PI3‐kinase) via binding to tyrosine‐phosphorylated insulin receptor substrate 1 (IRS‐1). The protein complex migrates to membrane compartments that include intracellular glucose transporter 4‐containing vesicles, priming them for translocation. The process requires an intact actin filament network.

Figure 8. Figure 8.

Signal‐transduction pathways involved in the regulation of glucose transporters (GLUTs) by acute and prolonged exposure to insulin. Activation of phosphatidylinositol‐3‐kinase(PI3K) rapidly stimulates GLUT‐4 translocation. This may also require activation of the protein kinase C (PKC) Akt and atypical PKCs. Prolonged exposure to insulin stimulates GLUT‐1 and GLUT‐3 biosynthesis, mediated, respectively, by a rapamycin‐sensitive pathway (likely p70 S6 kinase) and the Rasmitogen‐activated protein kinase (MAPK) pathway. IRS, insulin receptor substrate; SOS, son of sevenless; MEK, MAPK kinase; GAP, GTPase‐activating protein; mTOR, mammalian target of repamycin.

Figure 9. Figure 9.

Regulation of glucose transporters (GLUTs) by insulin and exercise in skeletal muscle. In resting muscle, GLUT‐1 is located at the plasma membrane and GLUT‐4 is stored intracellularly. Insulin activation of phosphatidylinositol‐3‐kinase (PI‐3‐kinase) is required for insulin‐stimulated translocation of GLUT‐4‐containing vesicles to the plasma membrane and transverse tubules. The low‐molecular‐weight G protein Rab4 is released from the vesicles upon insulin stimulation. Either electrically induced or voluntary activation of motor neurons causes neuro‐transmitter release at the motor end plate, which generates action potentials along the muscle plasma membrane and transverse tubules. This activates the voltage‐sensitive calcium channel R of the transverse tubules, which in turn determines the opening of the sarcoplasmic reticulum calcium channel, RR. Calcium ions released from the sarcoplasmic reticulum into the cytosol appear to prime a subset of GLUT‐4‐containing vesicles for translocation to the transverse tubules and plasma membrane.

Figure 10. Figure 10.

Circulating factors involved in the development of insulin resistance. Metabolic imbalances in circulating levels of glucose, insulin, free fatty acids (FFAs), or the cytokine tumor necrosis factor α (TNFα) interfere with the stimulation of glucose uptake, metabolism, and storage, leading to insulin resistance. The intracellular processes that could potentially be affected in these conditions are indicated by the symbol (‐). Hyperglycemia increases the amount of metabolites produced from the hexosamine pathway, which may mediate some of the insulin‐resistant actions of the hyperglycemic condition. The cytokine TNF‐α will activate sphingomyelinase and stimulate ceramide production, and these processes may mediate the effects of TNF‐α on insulin action. The mechanism by which insulin signaling is affected by FFA is not well understood. GLUT, glucose transporter; MAPK, mitogen‐activated protein kinase; IRS, insulin receptor substrate; PI3‐kinase, phosphatidylinositol‐3‐kinase.



Figure 1.

Tissue distribution of members of the glucose transporter (GLUT) and sodium‐dependent glucose co‐transporter (SGT) families. The distribution of the glucose transporters of the GLUT and SGT families is highlighted, with emphasis on tissues relevant to the maintenance of glucose homeostasis. Within any tissue, the most abundant glucose transporter is listed in larger type. See text for more information on each GLUT isoform. RBC, red blood cell; WBC, white blood cell.



Figure 2.

Orientation of the glucose transporter (GLUT) in the plasma membrane. Schematic representation of a generic GLUT, showing 12 transmembrane domains (M1 to M12). Amino acids that are identical for the human GLUT‐1 through GLUT‐5 proteins are indicated by single‐letter abbreviations. Chemically similar residues (D, E; Y, W, F; I, L, V, M; K, R; N, Q; S, T) are denoted by black circles. The amino‐and carboxy‐terminal domains as well as the exofacial loop between M1 and M2 differ in sequence and size among transporter isoforms.

(Reproduced with permission from ref. : Gould, G. W., and G. I. Bell, Trends Biochem. Sci. 15: 18–23, 1990, Elsevier Science Publishers, Ltd.).


Figure 3.

The glucose transporter translocation hypothesis. Insulin‐responsive fat and muscle tissues contain intracellular stores of glucose transporter proteins. Upon binding of insulin to its receptor, signals which lead to the mobilization of stored glucose transporters to the plasma membrane are generated. Insertion of glucose transporter molecules into the cell surface allows for increased glucose influx into the cell.



Figure 4.

Process for isolation of glucose transporter 4 (GLUT‐4)‐containing vesicles. Polymer beads containing a magnetizable core are covalently linked to antibodies that recognize the heavy chain of anti‐GLUT‐4 antibodies (α‐GLUT‐4). Isolated intracellular membranes from fat or muscle cells expose the cytosolic C‐terminal end of the GLUT‐4 protein to the solution, making it accessible for recognition by α‐GLUT‐4. A magnet is used to pull the loaded beads out of the suspension, thereby separating the GLUT‐4‐containing vesicles from all other membranes.



Figure 5.

Soluble N‐ethyimaleimide‐sensitive factor attachment protein (SNAP) receptors (SNAREs) mediating vesicle binding to target membranes in neuronal and insulin‐responsive cells. A: Binding of the vesicular SNAREs vesicle‐associated membrane protein 1 (VAMP‐1) and VAMP‐2 of synaptic vesicles with the target SNAREs syntaxin‐1 and SNAP‐25 of the presynaptic plasma membrane. B: Binding of the vesicular SNAREs VAMP‐2 and cellubrevin of glucose transporter (GLUT‐4)‐containing vesicles with the target SNAREs syntaxin‐4 and SNAP‐23 of muscle and fat‐cell plasma membranes. VAMP, vesicle‐associated membrane protein; SNAP, soluble N‐ethylmaleimide‐sensitive factor attachment protein; N and C, amino‐and carboxy‐terminal ends, respectively.



Figure 6.

Signal‐transduction pathways triggered by the occupied insulin receptor. Insulin binds to its receptor and stimulates tyrosine autophosphorylation of the intracellular β subunit of the receptor. This in turn stimulates the intrinsic tyrosine kinase activity of the β subunit toward intracellular substrates. A few main substrates are highlighted, namely, Shc and insulin receptor substrate (IRS) proteins. Insulin signaling is diversified into several pathways from the receptor, but only two well‐characterized pathways are shown. These are the IRS‐phosphatidylinositol‐3‐kinase (PI3K) axis and the Ras–Raf–mitogenactivated protein kinase (MAPK) axis. See text for details. PDK, 3‐phosphoinositide‐dependent kinase; PKC, protein kinase C; SOS, son of sevenless; GAP, GtPase‐activating protein, MEK, MAPK kinase.



Figure 7.

Proposed signal‐transduction pathway leading to glucose transporter translocation in muscle and fat cells. Insulin induces activation of phosphatidylinositol‐3‐kinase (PI3‐kinase) via binding to tyrosine‐phosphorylated insulin receptor substrate 1 (IRS‐1). The protein complex migrates to membrane compartments that include intracellular glucose transporter 4‐containing vesicles, priming them for translocation. The process requires an intact actin filament network.



Figure 8.

Signal‐transduction pathways involved in the regulation of glucose transporters (GLUTs) by acute and prolonged exposure to insulin. Activation of phosphatidylinositol‐3‐kinase(PI3K) rapidly stimulates GLUT‐4 translocation. This may also require activation of the protein kinase C (PKC) Akt and atypical PKCs. Prolonged exposure to insulin stimulates GLUT‐1 and GLUT‐3 biosynthesis, mediated, respectively, by a rapamycin‐sensitive pathway (likely p70 S6 kinase) and the Rasmitogen‐activated protein kinase (MAPK) pathway. IRS, insulin receptor substrate; SOS, son of sevenless; MEK, MAPK kinase; GAP, GTPase‐activating protein; mTOR, mammalian target of repamycin.



Figure 9.

Regulation of glucose transporters (GLUTs) by insulin and exercise in skeletal muscle. In resting muscle, GLUT‐1 is located at the plasma membrane and GLUT‐4 is stored intracellularly. Insulin activation of phosphatidylinositol‐3‐kinase (PI‐3‐kinase) is required for insulin‐stimulated translocation of GLUT‐4‐containing vesicles to the plasma membrane and transverse tubules. The low‐molecular‐weight G protein Rab4 is released from the vesicles upon insulin stimulation. Either electrically induced or voluntary activation of motor neurons causes neuro‐transmitter release at the motor end plate, which generates action potentials along the muscle plasma membrane and transverse tubules. This activates the voltage‐sensitive calcium channel R of the transverse tubules, which in turn determines the opening of the sarcoplasmic reticulum calcium channel, RR. Calcium ions released from the sarcoplasmic reticulum into the cytosol appear to prime a subset of GLUT‐4‐containing vesicles for translocation to the transverse tubules and plasma membrane.



Figure 10.

Circulating factors involved in the development of insulin resistance. Metabolic imbalances in circulating levels of glucose, insulin, free fatty acids (FFAs), or the cytokine tumor necrosis factor α (TNFα) interfere with the stimulation of glucose uptake, metabolism, and storage, leading to insulin resistance. The intracellular processes that could potentially be affected in these conditions are indicated by the symbol (‐). Hyperglycemia increases the amount of metabolites produced from the hexosamine pathway, which may mediate some of the insulin‐resistant actions of the hyperglycemic condition. The cytokine TNF‐α will activate sphingomyelinase and stimulate ceramide production, and these processes may mediate the effects of TNF‐α on insulin action. The mechanism by which insulin signaling is affected by FFA is not well understood. GLUT, glucose transporter; MAPK, mitogen‐activated protein kinase; IRS, insulin receptor substrate; PI3‐kinase, phosphatidylinositol‐3‐kinase.

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Amira Klip, Andre Marette. Regulation of Glucose Transporters by Insulin and Exercise: Cellular Effects and Implications for Diabetes. Compr Physiol 2011, Supplement 21: Handbook of Physiology, The Endocrine System, The Endocrine Pancreas and Regulation of Metabolism: 451-494. First published in print 2001. doi: 10.1002/cphy.cp070214