Expression of human GLUT4 in mice results in increased insulin action

Deems, Rhonda Oetting; Evans, Joseph L; Deacon, Richard; Honer, Christian M.; Chu, David; Bürki, Kurt; Fillers, William S.; Cohen, Diana K; Young, Douglas A.

doi:10.1007/bf00418373

Cited by 55 publications

(30 citation statements)

References 57 publications

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“…The data presented here in regard to the basal (i.e., sedentary) state are in agreement with previously published reports using GLUT4 (7,15,38) and HK II (6,12,16,27) transgenic mice. That is, GLUT4 but not HK II overexpression increases basal MGU.…”

Section: Discussionsupporting

confidence: 82%

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Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation

Fueger

Bracy

Malabanan

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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; 10.1152/ ajpendo.00309.2003.-Muscle glucose uptake (MGU) is determined by glucose delivery, transport, and phosphorylation. C57Bl/6J mice overexpressing GLUT4, hexokinase II (HK II), or both were used to determine the barriers to MGU. A carotid artery and jugular vein were catheterized for arterial blood sampling and venous infusions. Experiments were conducted in conscious mice ϳ7 days after surgery. 2-Deoxy-[3 H]glucose was administered during rest or treadmill exercise to calculate glucose concentration-dependent (R g) and -independent (K g) indexes of MGU. Compared with wild-type controls, GLUT4-overexpressing mice had lowered fasting glycemia (165 Ϯ 6 vs. 115 Ϯ 6 mg/dl) and increased R g by 230 and 166% in the gastrocnemius and superficial vastus lateralis (SVL) muscles under sedentary conditions. GLUT4 overexpression was not able to augment exercise-stimulated R g or Kg. Whereas HK II overexpression had no effect on fasting glycemia (170 Ϯ 6 mg/dl) or sedentary R g, it increased exercise-stimulated R g by 82, 60, and 169% in soleus, gastrocnemius, and SVL muscles, respectively. Combined GLUT4 and HK II overexpression lowered fasting glycemia (106 Ϯ 6 mg/dl), increased nonesterified fatty acids, and increased sedentary R g. Combined GLUT4 and HK II overexpression did not enhance exercisestimulated Rg compared with HK II-overexpressing mice because of the reduced glucose concentration. GLUT4 combined with HK II overexpression resulted in a marked increase in exercise-stimulated K g. In conclusion, control of MGU shifts from membrane transport at rest to phosphorylation during exercise. Glucose transport is not normally a significant barrier during exercise. However, when the phosphorylation barrier is lowered by HK II overexpression, glucose transport becomes a key site of control for regulating MGU during exercise.delivery; glucose transporter 4; hexokinase; exercise; 2-deoxyglucose THE CONTROL OF skeletal muscle glucose uptake (MGU) is distributed over the following three serial steps: delivery of glucose from the blood to the sarcolemma, transport across the sarcolemmal membrane, and intracellular phosphorylation by hexokinase (HK; see Ref. 42). Both blood flow and capillary recruitment are important determinants of glucose delivery. Glucose transport is mediated by the facilitated diffusion of glucose through a GLUT family member. Under basal and sedentary conditions, GLUT1 facilitates much of the transport into skeletal muscle (10,30,38); however, after stimulation by contractions (3,8,37), GLUT4 translocates from an intracellular pool to the cell surface, thereby increasing the permeability of the sarcolemma to glucose. Whether HK activity or localization and hence the functional rate of glucose phosphorylation to glucose 6-phosphate (G-6-P) changes during acute stimulation by exercise remains to be clearly determined. While one step may exert dominance in controlling MGU under one condition, the primary control step may shift with physiological stimuli (11)(12)(13)(14)34).During sedentary conditions...

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Section: Discussionsupporting

confidence: 82%

“…That is, GLUT4 but not HK II overexpression increases basal MGU. During insulin stimulation, it has been reported that GLUT4 overexpression increases whole body glucose disposal in vivo (7,39) and MGU in vitro (7,15). Hansen et al (15) go on to demonstrate that GLUT4 overexpression augments postexercise MGU.…”

Section: Discussionmentioning

confidence: 99%

Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation

Fueger

Bracy

Malabanan

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…We postulate that results that differ do so due to technical differences which generally make the preparations less physiological. These include the use of anaesthesia Lombardi et al 1997;Marshall et al 1999), in vitro preparations (Deems et al 1994;Hansen et al 1995;Tsao et al 1996;Lombardi et al 1997;Marshall et al 1999), suprapharmacological insulin doses Ren et al 1995;Marshall et al 1999) and prolonged fasting (Ren et al 1995). With regard to the latter two, it is noteworthy that, when Ren et al (1995) in marked reduction in glycogen content and weight, or suprapharmacological insulin, GLUT4 overexpression increased glucose utilization during an insulin clamp.…”

Section: Discussionmentioning

confidence: 99%

Control of muscle glucose uptake: test of the rate‐limiting step paradigm in conscious, unrestrained mice

Fueger¹,

Shearer²,

Bracy

et al. 2005

The Journal of Physiology

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The aim of this study was to test whether in fact glucose transport is rate-limiting in control of muscle glucose uptake (MGU) under physiological hyperinsulinaemic conditions in the conscious, unrestrained mouse. C57Bl/6J mice overexpressing GLUT4 (GLUT4 Tg ), hexokinase II (HK Tg ), or both (GLUT4 Tg + HK Tg ), were compared to wild-type (WT) littermates. Catheters were implanted into a carotid artery and jugular vein for sampling and infusions at 4 month of age. After a 5-day recovery period, conscious mice underwent one of two protocols (n = 8-14/group) after a 5-h fast. Saline or insulin (4 mU kg −1 min −1 ) was infused for 120 min. All mice received a bolus of 2-deoxy[ 3 H]glucose (2-3 HDG) at 95 min. Glucose was clamped at ∼165 mg dl −1 during insulin infusion and insulin levels reached ∼80 µU ml −1 . The rate of disappearance of 2-3 HDG from the blood provided an index of whole body glucose clearance. Gastrocnemius, superficial vastus lateralis and soleus muscles were excised at 120 min to determine 2-3 HDG-6-phosphate levels and calculate an index of MGU (R g ). Results show that whole body and tissue-specific indices of glucose utilization were: (1) augmented by GLUT4 overexpression, but not HKII overexpression, in the basal state; (2) enhanced by HKII overexpression in the presence of physiological hyperinsulinaemia; and (3) largely unaffected by GLUT4 overexpression during insulin clamps whether alone or combined with HKII overexpression. Therefore, while glucose transport is the primary barrier to MGU under basal conditions, glucose phosphorylation becomes a more important barrier during physiological hyperinsulinaemia in all muscles. The control of MGU is distributed rather than confined to a single rate-limiting step such as glucose transport as glucose transport and phosphorylation can both become barriers to skeletal muscle glucose influx.

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“…In a related study a high 100 μM dose of BPA stimulated an increase in the glucose transporter GLUT4 and glucose uptake into 3T3-F442A adipocytes in cell culture [112]. In a separate study of transgenic mice over expressing the GLUT4 gene, increased basal and insulin-induced glucose uptake was observed in whole body and in isolated adipocytes [113]. Whether the mouse 3T3 cell lines, which are relatively insensitive to estrogen, are an appropriate model to study the effects of BPA in vitro remains to be determined.…”

Section: Developmental Effects On Metabolismmentioning

confidence: 97%

In vivo effects of bisphenol A in laboratory rodent studies

Richter

Birnbaum

Farabollini

et al. 2007

Reproductive Toxicology

1,039

733

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Concern is mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical used in synthesis of plastics. We have reviewed the growing literature on effects of low doses of BPA, below 50 mg/kg/day, in laboratory exposures with mammalian model organisms. Many, but not all, effects of BPA are similar to effects seen in response to the model estrogens diethylstilbestrol and ethinylestradiol. For most effects, the potency of BPA is approximately 10 to 1,000-fold less than that of diethylstilbestrol or ethinylestradiol. Based on our review of the literature, a consensus was reached regarding our level of confidence that particular outcomes occur in response to low-dose BPA exposure. We are confident that adult exposure to BPA affects the male reproductive tract, and that long-lasting, organizational effects in response to developmental exposure to BPA occur in the brain, the male reproductive system, and metabolic processes. We consider it likely, but requiring further confirmation, that adult exposure to BPA affects the brain, the female reproductive system, and the immune system, and that developmental effects occur in the female reproductive system.

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Expression of human GLUT4 in mice results in increased insulin action

Cited by 55 publications

References 57 publications

Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation

Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation

Control of muscle glucose uptake: test of the rate‐limiting step paradigm in conscious, unrestrained mice

In vivo effects of bisphenol A in laboratory rodent studies

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