Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle.

Stenbit, Antine E.; Burcelin, Rémy; Katz, Ellen B.; Tsao, Tsu‐Shuen; Gautier, Nadine; Charron, Maureen J.; Marchand-Brustel, Y. Le

doi:10.1172/jci118833

Cited by 70 publications

(85 citation statements)

References 37 publications

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“…Similar findings in EDL muscle were made in generalized GLUT-4(Ϫ/Ϫ) mice (35). They are, however, at variance with recent observations showing that in EDL muscle of both female and male GLUT-4(Ϫ/Ϫ) mice glycogen content is decreased (30).…”

Section: Discussionsupporting

confidence: 82%

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Increased muscle fatigability in GLUT-4-deficient mice

Gorselink¹,

Drost

Brouwer³

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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plays a predominant role in glucose uptake during muscle contraction. In the present study, we have investigated in mice whether disruption of the GLUT-4 gene affects isometric and shortening contractile performance of the dorsal flexor muscle complex in situ. Moreover, we have explored the hypothesis that lack of GLUT-4 enhances muscle fatigability. Isometric performance normalized to muscle mass during a single tetanic contraction did not differ between wild-type (WT) and GLUT-4-deficient [GLUT-4(Ϫ/Ϫ)] mice. Shortening contractions, however, revealed a significant 1.4-fold decrease in peak power per unit mass, most likely caused by the fiber-type transition from fast-glycolytic fibers (IIB) to fast-oxidative fibers (IIA) in GLUT-4(Ϫ/Ϫ) dorsal flexors. In addition, the resting glycogen content was significantly lower (34%) in the dorsal flexor complex of GLUT-4(Ϫ/Ϫ) mice than in WT mice. Moreover, the muscle complex of GLUT-4(Ϫ/Ϫ) mice showed enhanced susceptibility to fatigue, which may be related to the decline in the muscle carbohydrate store. The significant decrease in relative work output during the steady-state phase of the fatigue protocol suggests that energy supply via alternative routes is not capable to compensate fully for the lack of GLUT-4. skeletal muscle; electrical stimulation GLUCOSE IS A major fuel for contracting muscle fibers (6,20). This substrate is supplied to the muscle fiber from extra-and intracellular sources, i.e., blood glucose pool and intracellular glycogen (12,25). The uptake of glucose by skeletal muscle cells is facilitated by a family of membrane-associated glucose transporters (GLUTs; see Refs. 1, 6, and 16). Basal glucose uptake is mediated via the GLUT-1 isoform, whereas the bulk of glucose is primarily transported across the sarcolemma by the insulin-and contraction-regulatable glucose transporter 9,18,24,28,29). After uptake, glucose is metabolized to generate ATP or is stored as glycogen (2). During the initial phase of moderate-intensity exercise, skeletal muscle uses the intracellular glycogen store to meet its energy demand (23). It was recently shown that, during electrical stimulation, blood-borne glucose also serves as a suitable substrate during moderate-intensity exercise in mice (27). To enable detailed studies on the specific role of GLUT-4 in glucose homeostasis in general and in muscle mechanical performance in particular, mice with the GLUT-4 gene disrupted [GLUT-4(Ϫ/Ϫ)] were generated (17,36).Despite the importance of regulatable glucose transporters for muscle energy metabolism, information on the impact of GLUT-4 deficiency on muscle contractile behavior is scarce. It was recently reported that developed isometric tension during in vitro electrical stimulation of isolated extensor digitorum longus (EDL) muscle did not differ between wild-type (WT) and GLUT-4(Ϫ/Ϫ) mice (27). Extrapolation of these findings to the in vivo situation, however, should be done with caution, since the muscle fibers were studied isolated from their natural surroundings, and onl...

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Section: Discussionsupporting

confidence: 82%

“…However, in female GLUT-4(Ϫ/Ϫ) mice the glycogen content in soleus muscle was significantly increased (30). Muscle-specific GLUT-4 knockout mice showed a normal resting glycogen level in both soleus and EDL muscle (22).…”

Section: Discussionmentioning

confidence: 99%

Increased muscle fatigability in GLUT-4-deficient mice

Gorselink¹,

Drost

Brouwer³

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…It is therefore possible that GLUT12 can act as a substitute for GLUT4 in fetal tissues and allow increased uptake of glucose into cells in the presence of insulin or IGF-I. In adult GLUT4 global knockout mice, glucose homeostasis is essentially normal and glucose uptake is normal or increased in soleus muscle (Katz et al 1995;Stenbit et al 1996). It was suggested that expression of another glucose transporter protein compensated for the lack of GLUT4.…”

Section: Discussionmentioning

confidence: 99%

Expression during rat fetal development of GLUT12 – a member of the class III hexose transporter family

et al. 2003

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Glucose is an essential molecule for most mammalian cells, and is particularly important during fetal development, when cells are rapidly dividing and differentiating. In rats, GLUT1 is present at high levels in most fetal tissues, with levels decreasing after birth. We used immunohistochemistry to localise GLUT12 protein, a recently identified member of the sugar transporter family, and GLUT1 during rat fetal development. GLUT12 staining was observed in heart muscle from gestational days 15 to 21. GLUT12 staining in skeletal muscle increased from gestational days 17 to 21, and GLUT12 was also detected in brown adipose tissue. The expression of GLUT12 in insulin-responsive tissues supports a potential role for GLUT12 in the provision of glucose to these tissues before the appearance of GLUT4. GLUT12 protein was also expressed in fetal chondrocytes from gestational day 15 onward, in kidney distal tubules and collecting ducts from day 19, and in lung bronchioles from day 19. The specific pattern of expression observed in the rat fetus suggests that GLUT12 may be important in hexose delivery to developing tissues.

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“…Overall the unexpected non-diabetic phenotype of GLUT4-null mice has suggested a compensatory mechanism or unmasking of a novel glucose transporter activity. Indeed in vitro analysis demonstrated a 2.3-fold increase in basal glucose uptake in GLUT4-null male and normal basal levels with a significant increase following insulin stimulation in GLUT4-null female oxidative soleus muscles [116]. The possibility that overexpression of GLUT1 and/or ectopic expression of other canonical GLUTs occurred in GLUT4-null soleus muscle was ruled out [32,116].…”

Section: Glut4mentioning

confidence: 99%

“…Indeed in vitro analysis demonstrated a 2.3-fold increase in basal glucose uptake in GLUT4-null male and normal basal levels with a significant increase following insulin stimulation in GLUT4-null female oxidative soleus muscles [116]. The possibility that overexpression of GLUT1 and/or ectopic expression of other canonical GLUTs occurred in GLUT4-null soleus muscle was ruled out [32,116]. As a result, expression of a novel GLUT4-independent glucose transport activity was proposed [32,108,116].…”

Section: Glut4mentioning

confidence: 99%

What we know about facilitative glucose transporters: Lessons from cultured cells, animal models, and human studies

Gorovits

Charron

2003

Biochem Molecular Bio Educ

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Glucose uptake by all cells in the organism by glucose transport proteins is among the most essential processes in life. The process of glucose uptake into tissues is performed by glucose transporters. This review focuses on the biology of facilitative glucose transporters (GLUTs). The knowledge that has accumulated for more than a decade with respect to the regulation of GLUT expression and function in various experimental conditions points to the great potential for GLUTs to be utilized as targets for designing therapies for treatment of diseases related to impaired regulation of glucose homeostasis including type 2 diabetes.Keywords: Glucose uptake, GLUT, insulin action, diabetes.The entry of glucose into cells is a crucial step in lifesupporting processes since glucose is the main monosaccharide in nature that provides carbon and energy for almost all cells. The passage of glucose into cells depends on different parameters, including expression of the appropriate glucose transporters in the target tissues and hormonal regulation of their function. Single cell eucaryotes such as Saccharomyces cerevisiae possess 20 genes encoding glucose or glucose-like transporters and express the glucose transporters most appropriate for the amount of glucose available [1]. In mammalian cells a tight regulation of blood glucose levels is needed to meet the energetic demands of the brain, a tissue that uses glucose as its primary energy source [2,3]. Adequate glucose flux into tissues provides maintenance of glucose homeostasis that is critical in well being. Transport of glucose across the plasma membrane is accomplished by two families of glucose transporters: sodium-glucose co-transporters (SGLT 1 1-3), mainly expressed in the apical membrane of renal and intestinal absorptive epithelial cells that transport glucose against its concentration gradient and utilize ATP (for a review, see Ref. 4), and facilitative glucose transporters (GLUTs) that are expressed in all cells that transport glucose down a concentration gradient [5][6][7]. Until now the search for the mammalian facilitative glucose transporters has yielded 12 carriers including GLUT1-5 and the recently discovered GLUT6 -12. GLUT1-4 share greater than 40% homology [8], and GLUT5, which is a fructose transporter, exhibits 42, 40, 38, and 41.6% identity with GLUT1, GLUT2, GLUT3, and GLUT4, respectively [9]. All GLUTs have been predicted to have 12 membrane-spanning domains (helices) connected by hydrophilic loops, the first of which is exofacial and contains an N-glycosylation site in GLUT1-5 (Fig. 1) [8,10]. Both the amino and carboxyl termini of GLUTs reside on the cytoplasmic side of the cell membrane [11]. The carboxyl termini of all GLUTs have unique amino acid sequences that have been utilized for development of reagents. The common sensitivity of the GLUT family to the inhibitory action of the fungal metabolite cytochalasin B has been reported widely and is utilized in studies of hexose transporters [12]. Substrate selectivity of GLUTs is dictated by conserve...

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Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle.

Cited by 70 publications

References 37 publications

Increased muscle fatigability in GLUT-4-deficient mice

Increased muscle fatigability in GLUT-4-deficient mice

Expression during rat fetal development of GLUT12 – a member of the class III hexose transporter family

What we know about facilitative glucose transporters: Lessons from cultured cells, animal models, and human studies

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