Glucose kinetics and exercise tolerance in mice lacking the GLUT4 glucose transporter

Fueger, Patrick T.; Li, Candice Y.; Ayala, Julio E.; Shearer, Jane; Bracy, Deanna P.; Charron, Maureen J.; Rottman, Jeffrey N.; Wasserman, David H.

doi:10.1113/jphysiol.2007.132902

Cited by 58 publications

(54 citation statements)

References 46 publications

(57 reference statements)

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“…[17][18][19][20][21][22][23][24]. In response to an 18-hour fast, hepatic ATP, ADP, and AMP levels were decreased, unchanged, and increased, respectively, resulting in a nearly 6-fold increase in AMP/ATP ratios compared with fed mice and mice fasted for 5 hours ( Figure 1A).…”

Section: Metabolic Stress Induces Dramatic Changes In Hepatic Adeninementioning

confidence: 98%

“…Our goals, therefore, were to test the hypotheses that (a) reductions in the hepatic energy state are a physiological phenomenon not isolated to exhaustive exercise and (b) glucagon receptor activation mediates a lowered hepatic energy state sufficient to activate AMPK through a process requiring cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). The foundation for this latter hypothesis is that a rise in plasma glucagon is characteristic of metabolic stress (17)(18)(19)(20)(21)(22)(23)(24) and increased hormone levels are shown to amplify phosphorylation of AMPK in vitro and in perfused liver (25,26). Studies in vivo have also shown that hepatic glucagon action is the primary determinant of gluconeogenesis via PEPCK-C and stimulation of coupled pathways, including fatty acid activation and ureagenesis, which are required to offset higher glucose use in the body during exercise (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

“…Skeletal muscle was removed after the liver in each experiment, and adenine nucleotides deviated little, if any, in response to a variety of conditions and a variety of models. Glucagon action was considered a mechanism to explain changes in the hepatic energy state based on independent evidence that glucagon levels rise during metabolic stress (17)(18)(19)(20)(21)(22)(23)(24), activate AMPK (25,26), and potently stimulate energy-requiring processes in the liver (27)(28)(29)49). Glucagon binding to its receptor increases adenosine cAMP levels in the liver, leading to stimulation of PKA activity.…”

Section: Figurementioning

confidence: 99%

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Hepatic energy state is regulated by glucagon receptor signaling in mice

et al. 2009

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The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor-null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism. IntroductionThe energy state in the cell is defined by adenine nucleotide levels and is critically coupled to nearly all metabolic processes (1). In the cell, the adenine nucleotides ATP, ADP, and AMP are tied directly or indirectly to all energetic pathways and allosterically control numerous regulatory enzymes (2-6). Changes in adenine nucleotides typically occur such that ATP and AMP deviate in reciprocal directions, while ADP remains constant (1). Such changes are the basis for using the ratio AMP/ATP (1, 7) or the equation for cellular energy charge ([ATP + (0.5 × ADP)] / [ATP + ADP + AMP]) (8, 9) as indices of the metabolic environment. Metabolic stress is thus characterized by a rise in AMP paired with a fall in ATP levels, reflecting a decrease in energy state. A fall in energy state is of considerable importance, in part due to the regulatory role of AMP/ATP ratios on AMPK activity (10). AMPK is a metabolic switch sensitive to high AMP/ATP ratios and functions to protect the energy state by inhibiting ATP-consuming processes while stimulating ATP-producing processes. (10).In most tissues, the environment is controlled to maintain a high energy state (low AMP/ATP ratio). In skeletal muscle, for example, creatine kinase limits reductions in ATP during conditions such as exercise, when energy utilization is accelerated (11,12). The liver, in contrast, lacks creatine kinase, and exercise has been shown to markedly decrease the hepatic energy state and increase the phosphorylation of AMPK (11, 13). The regulatory...

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Section: Metabolic Stress Induces Dramatic Changes In Hepatic Adeninementioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Hepatic energy state is regulated by glucagon receptor signaling in mice

et al. 2009

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“…The insulin clamp protocol can also be modified to allow for glucose levels to fall to relative hypoglycemia to assess counter-regulatory response 2,23,24 . Arterial catheterization can also be used to assess the dynamics of glucose metabolism during exercise [25][26][27][28][29][30] . This is significantly advantageous over conventional approaches conducted at single time points pre-and post-exercise or in isolated muscles ex vivo.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

Ayala

Bracy

Malabanan

et al. 2011

JoVE

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Type 2 diabetes is characterized by a defect in insulin action. The hyperinsulinemic-euglycemic clamp, or insulin clamp, is widely considered the "gold standard" method for assessing insulin action in vivo. During an insulin clamp, hyperinsulinemia is achieved by a constant insulin infusion. Euglycemia is maintained via a concomitant glucose infusion at a variable rate. This variable glucose infusion rate (GIR) is determined by measuring blood glucose at brief intervals throughout the experiment and adjusting the GIR accordingly. The GIR is indicative of whole-body insulin action, as mice with enhanced insulin action require a greater GIR. The insulin clamp can incorporate administration of isotopic 2[ 14 C]deoxyglucose to assess tissue-specific glucose uptake and [3-3 H]glucose to assess the ability of insulin to suppress the rate of endogenous glucose appearance (endoRa), a marker of hepatic glucose production, and to stimulate the rate of whole-body glucose disappearance (Rd).

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“…The R g response to exercise was diminished in mice with a partial HK II knockout . A heterozygous deletion of GLUT4 did not impair R g in working muscle (Fueger et al, 2004b); however, a complete deletion of GLUT4 prevented the increase in R g with exercise and led to marked hyperglycemia (Fueger et al, 2007b). We tested the hypothesis that if the glucose phosphorylation barrier in GLUT4 knockout mice was lowered by HK II overexpression, muscle would then be sensitive to reduced transport capacity.…”

Section: Glucose Phosphorylation Within the Working Muscle Cellsmentioning

confidence: 99%

The physiological regulation of glucose flux into musclein vivo

Wasserman

Ayala

et al. 2011

Journal of Experimental Biology

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Summary Skeletal muscle glucose uptake increases dramatically in response to physical exercise. Moreover, skeletal muscle comprises the vast majority of insulin-sensitive tissue and is a site of dysregulation in the insulin-resistant state. The biochemical and histological composition of the muscle is well defined in a variety of species. However, the functional consequences of muscle biochemical and histological adaptations to physiological and pathophysiological conditions are not well understood. The physiological regulation of muscle glucose uptake is complex. Sites involved in the regulation of muscle glucose uptake are defined by a three-step process consisting of: (1) delivery of glucose to muscle, (2) transport of glucose into the muscle by GLUT4 and (3) phosphorylation of glucose within the muscle by a hexokinase (HK). Muscle blood flow, capillary recruitment and extracellular matrix characteristics determine glucose movement from the blood to the interstitium. Plasma membrane GLUT4 content determines glucose transport into the cell. Muscle HK activity, cellular HK compartmentalization and the concentration of the HK inhibitor glucose 6-phosphate determine the capacity to phosphorylate glucose. Phosphorylation of glucose is irreversible in muscle; therefore, with this reaction, glucose is trapped and the uptake process is complete. Emphasis has been placed on the role of the glucose transport step for glucose influx into muscle with the past assertion that membrane transport is rate limiting. More recent research definitively shows that the distributed control paradigm more accurately defines the regulation of muscle glucose uptake as each of the three steps that define this process are important sites of flux control.

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Glucose kinetics and exercise tolerance in mice lacking the GLUT4 glucose transporter

Cited by 58 publications

References 46 publications

Hepatic energy state is regulated by glucagon receptor signaling in mice

Hepatic energy state is regulated by glucagon receptor signaling in mice

Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice

The physiological regulation of glucose flux into musclein vivo

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