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Am J Physiol Endocrinol Metab 291: E867-E877, 2006. First published July 5, 2006; doi:10.1152/ajpendo.00207.2006
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INVITED REVIEWS

AMP-activated protein kinase and the regulation of glucose transport

Nobuharu Fujii,1 Niels Jessen,1,2 and Laurie J. Goodyear1

1Research Division, Joslin Diabetes Center and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and 2Medical Research Laboratory and Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark


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The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated by acute increases in the cellular [AMP]/[ATP] ratio. In skeletal and/or cardiac muscle, AMPK activity is increased by stimuli such as exercise, hypoxia, ischemia, and osmotic stress. There are many lines of evidence that increasing AMPK activity in skeletal muscle results in increased rates of glucose transport. Although similar to the effects of insulin to increase glucose transport in muscle, it is clear that the underlying mechanisms for AMPK-mediated glucose transport involve proximal signals that are distinct from that of insulin. Here, we discuss the evidence for AMPK regulation of glucose transport in skeletal and cardiac muscle and describe research investigating putative signaling mechanisms mediating this effect. We also discuss evidence that AMPK may play a role in enhancing muscle and whole body insulin sensitivity for glucose transport under conditions such as exercise, as well as the use of the AMPK activator AICAR to reverse insulin-resistant conditions. The identification of AMPK as a novel glucose transport mediator in skeletal muscle is providing important insights for the treatment and prevention of type 2 diabetes.

skeletal muscle; heart; LKB1 drug target; exercise

IN DECEMBER OF 1997, the American Journal of Physiology-Endocrinology and Metabolism published a paper by Winder and colleagues [Merrill et al. (79)] showing that perfusion of hindlimb skeletal muscle with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, enhanced glucose transport in the presence of insulin. Several months later, our laboratory, in collaboration with Dr. Winder, reported that direct incubation of isolated rat muscles with AICAR increased glucose transport, an effect that was independent of insulin (47). One year later, Bergeron et al. (10) showed that infusion of AICAR in vivo was also effective in increasing glucose transport into multiple rat skeletal muscles. These papers provided the first evidence that AMPK can regulate glucose metabolism in skeletal muscle and began an intense period of investigation aimed at studying the relationship between AMPK activity and insulin-independent mechanisms to increase glucose transport in this tissue and others. In fact, since those first studies, more than 400 papers have been published examining the relationship between AMPK and glucose metabolism in mammalian cells. In this review, we focus on studies testing the hypothesis that AMPK regulates glucose transport in skeletal muscle and touch briefly on the potential role of AMPK in regulating glucose transport in the heart.

AMPK: a Cellular Fuel Sensor

AMPK was first identified as a kinase for hydroxymethylgutaryl-CoA reductase (HMG-CoA) and acetyl-CoA carboxylase (ACC), key regulatory enzymes of steroid and fatty acid synthesis, respectively (reviewed in Ref. 40). AMPK is a serine/threonine kinase that is part of a multiprotein family of kinases that extends from plants to mammals. The mammalian homolog of AMPK in Saccharomyces cerevisiae is the SNF-1 protein kinase, critical for the adaptation of yeast to nutrient stress (40, 82, 113). The AMPK heterotrimer consists of a catalytic {alpha}-subunit and regulatory beta- and {gamma}-subunits (15, 40, 64). There are multiple isoforms for each subunit ({alpha}1 and {alpha}2, beta1 and beta2, and {gamma}1, {gamma}2, and {gamma}3) with tissue-specific distribution. In skeletal muscle, {alpha}2 (19, 84), beta2 (17, 116), and {gamma}1 (19) or {gamma}3 (78) are the major isoforms expressed and form the majority of AMPK heterotrimer complexes. In heart, all isoforms have been reported to be expressed (39). The {alpha}-subunit of AMPK is an ~63-kDa protein that exhibits catalytic activity. The {alpha}1 isoform is widely expressed, whereas the {alpha}2 isoform has its highest levels of expression in liver, heart, and skeletal muscle (114). The beta- and {gamma}-subunits appear to be important in substrate specificity and maintenance of heterotrimer stability (40, 64). The beta-subunit acts as a scaffold for the binding of the {alpha}- and {gamma}-subunits (125) and, by virtue of having a putative glycogen binding domain, may also function in the regulation of glycogen metabolism (52, 90). The {gamma}-subunit appears to be involved in AMP binding and has also been implicated in regulating glycogen metabolism, since mutations in the CBS domains of {gamma}-subunit lead to altered glycogen metabolism in both skeletal muscle and heart (6, 19, 23, 81).

AMPK has been called the "fuel gauge" of the mammalian cell, activated by a mechanism that involves allosteric modification and phosphorylation (40). When cells sense decreased ATP, AMPK acts to switch off ATP-consuming pathways and switch on alternative pathways for ATP regeneration. One hypothesis is that decreases in intracellular ATP and concomitant increases in AMP increase the AMP/ATP ratio (15, 40, 64), causing a conformational change in the AMPK complex and phosphorylation of the {alpha}-subunit by one or more upstream kinases (15, 40, 64). Thr172 is the major regulatory phosphorylation site within the {alpha}-subunit (42), and its phosphorylation is essential for catalytic activity (21, 115). Recently, LKB1 (41, 50, 107) and Ca2+/calmodulin kinase kinase (CaMKK) (43, 53, 124) have been identified as enzymes that phosphorylate Thr172 of the {alpha}-subunit. In skeletal muscle, LKB1 appears to be the major kinase that regulates AMPK{alpha}2 activity in vivo, as our recent work with a muscle-specific LKB1 knockout (68) or in comparing a hypomorphic LKB1 knockout with a muscle LKB1 knockout (102) show ablation of AMPK{alpha}2 activity under basal and stimulated conditions. Interestingly, AMPK{alpha}1 activity was not significantly reduced (68, 102).

A major physiological stimulus that changes the ATP/AMP ratio is contraction of skeletal muscles during exercise. Thus, as would be expected from a change in cellular energy status, AMPK activity increases in rat skeletal muscle with exercise in vivo (93, 94), sciatic nerve-stimulated muscle contractions in situ (54, 119), and contraction of isolated muscles in vitro (46, 47, 56). The degree of force production generated by contraction (56) as well as the intensity of treadmill exercise (94) are directly related to the level of AMPK activation. Human studies have shown that both moderate- and high-intensity exercise increase skeletal muscle AMPK activity and/or Thr172 phosphorylation (18). In addition to exercise and contractile activity, AMPK activity increases in skeletal muscle and cultured muscle cells during other forms of cellular stress, including hypoxia (46, 83) and hyperosmolarity (30, 46, 87) and by uncouplers of the mitochondrial respiration chain (46, 87).

Since AMPK was initially identified as an HMG-CoA and ACC kinase, in the early years of AMPK research AMPK was thought to regulate cellular metabolism by virtue of affecting steroid and fatty acid metabolism. However, as will be discussed later in this review, it is likely that the stimulation of glucose transport is also an important mechanism by which AMPK regulates cellular energy status. Because glucose transport is the rate-limiting step in glucose utilization and is permissive for ATP generation under most physiological conditions, this hypothesis has greatly expanded the importance of AMPK in cellular energetic homeostasis. Given the dramatic worldwide increase in the prevalence of type 2 diabetes and associated muscle insulin resistance, understanding whether and how AMPK functions in insulin-independent muscle glucose transport has great potential for translation into novel therapies.

AICAR Increases Glucose Transport in Skeletal Muscle and Several Cell Lines

As mentioned briefly above, early studies showing a relationship between AMPK and glucose transport in skeletal muscle and heart were done using AICAR, a compound taken up into skeletal muscle and metabolized by adenosine kinase to form 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranotide (ZMP), the monophosphorylated derivative that mimics the effects of AMP on AMPK (47, 79). In addition to studies from the Winder, Goodyear, and Shulman laboratories, numerous other groups subsequently demonstrated that AICAR increases glucose transport in rat skeletal muscle, a phenomenon that is now universally accepted. The magnitude of AICAR-stimulated glucose transport is dependent on nutritional status (3) and muscle fiber type (3, 7, 63). Interestingly, in isolated rat soleus muscles, AICAR incubation does not increase glucose transport (3, 7, 63), but AICAR also does not increase AMPK activity (Refs. 3 and 63; Fujii N and Goodyear LJ, unpublished observations). In mouse skeletal muscle, AICAR incubation increases glucose transport in both extensor digitorum longus (EDL) (7, 33, 61, 83, 99) and soleus (7, 61). AICAR also increases glucose transport and GLUT4 translocation in vastus lateralis muscle strips from healthy subjects, an effect that was partially impaired in patients with type 2 diabetes (69). AICAR is also effective in increasing glucose transport in a number of cell lines, including Clone 9 cells (1, 127), 3T3-L1 preadipocytes (1), and several muscle cell lines such as L6 (16, 103), C2C12 (1), and H-2Kb (30, 31). Hindlimb perfusion studies in rats revealed that AICAR-induced increases in skeletal muscle glucose transport are mediated by the translocation of GLUT4 to the plasma membrane (74), and AICAR increased GLUT4 translocation in incubated ventricular papillary muscles and hearts perfused in vivo (96).

Limitations of Studies Using AICAR

Although experiments using AICAR as an AMPK activator have generated a wealth of information on AMPK function, there are limitations to this approach, and conclusions based on using this compound as a surrogate for other stimuli must be treated cautiously. AICAR does not have strict specificity to AMPK, activating all enzymes directly activated by AMP; and AICAR can also have systemic effects when administered in vivo (37, 131). Specific activation and inhibition of AMPK by pharmacological agents would be a valuable approach to more clearly define the role of AMPK in glucose transport and other metabolic effects, but unfortunately, such compounds are not currently available. Two putative AMPK inhibitors, iodotubercidin and araA, are not specific to AMPK, and although these compounds inhibit AICAR-induced activation of AMPK, they fail to inhibit contraction-induced AMPK activation in skeletal muscle (85). Compound C, which can inhibit AMPK activity in hepatocytes (132), is ineffective in attenuating AMPK activity in skeletal muscle (Musi N, Hirshman MF, and Goodyear LJ, unpublished observations). To overcome these limitations, nonpharmacological approaches have been used to activate and inhibit AMPK activity in vivo, including studies using transgenic and knockout mice and expression of adenoviral mediated constructs as discussed below.

Does AMPK Regulate Contraction-Stimulated Glucose Transport?

Much of the initial interest in examining AMPK and glucose transport was focused on testing the hypothesis that AMPK is the signaling mechanism necessary for contraction-stimulated glucose transport. This has always been an important question, given the physiological relevance of exercise in the regulation of glucose transport and control of glucose homeostasis in healthy people and those with type 2 diabetes. Contraction and insulin are two major stimuli that activate glucose transport in skeletal muscle, and there are several lines of evidence that the underlying mechanisms leading to contraction- and insulin-induced glucose transport are distinct (36). AICAR-stimulated glucose transport was not affected by inhibition of phosphatidylinositol (PI) 3-kinase using wortmannin (10, 47), similar to numerous other insulin-independent stimuli that increase glucose transport. The combination of a maximal AICAR stimulus with a maximal insulin treatment had partially additive effects on glucose transport, suggesting that signaling to glucose transport by these two stimuli was via different mechanisms. In contrast, there was no additive effect on glucose transport with the combination of AICAR plus contraction (47), providing evidence that AMPK may be the long-elusive signaling mechanism regulating exercise-stimulated glucose transport. Bergeron et al. (10) also reported similar findings and further demonstrated that AICAR-stimulated glucose transport is not affected by an adenosine receptor inhibitor that diminishes contraction-induced glucose transport, suggesting that the AICAR effect is directly due to AMPK activation and not to adenosine receptor activation. In H-2Kb skeletal muscle cells, overexpression of constitutively active AMPK stimulates glucose transport accompanied by GLUT1 and GLUT4 translocation, also indicating that AMPK-mediated glucose transport involves glucose transporter translocation (30). Contraction of isolated muscle was shown to activate AMPK in a dose-dependent manner and at a similar rate compared with increases in glucose transport in skeletal muscle (85).

Despite considerable enthusiasm for the idea that AMPK is part of the signaling pathway responsible for mediating contraction-stimulated glucose transport in skeletal muscle, not all findings have been consistent with this hypothesis. To evaluate the contribution of AMPK to glucose transport in skeletal muscle, Mu et al. (83) generated transgenic mice that express a dominant-negative form of AMPK{alpha}2 in skeletal muscle by using the muscle-specific creatine kinase promoter. Consistent with the hypothesis that AMPK regulates glucose transport in rat skeletal muscle, they found that AICAR- and hypoxia-stimulated increases in AMPK activity and glucose transport were completely inhibited. This result provides evidence that AMPK activity is necessary for AICAR-stimulated glucose transport. On the other hand, contraction-induced glucose transport was reduced by only 30–40% in the muscles from the transgenic mice. These results provided the first direct evidence that AMPK is involved in the regulation of contraction-induced glucose transport but that AMPK is not the sole intermediary of the contraction effect.

Although the data from Mu et al. suggest that AMPK may be partially regulating glucose transport in contracting skeletal muscle, Jørgensen et al. (61) came to a different conclusion. Using either {alpha}1 or {alpha}2 whole body AMPK knockout mice, they found that contraction-induced glucose transport in isolated muscles was normal. Because the {alpha}2 knockout mice had a two- to threefold increase in {alpha}1 expression and a twofold increase in contraction-stimulated {alpha}1 activity, as the authors state, it is possible that the upregulation of {alpha}1 compensated for the loss of {alpha}2 function with regard to glucose transport. We generated muscle-specific transgenic mice carrying cDNAs of inactive {alpha}1 and {alpha}2 and crosses of these animals (33). Surprisingly, despite 20-fold greater expression of the {alpha}1 transgene (compared to wild type), the {alpha}1 transgenic mice had only partially reduced AMPK{alpha}1 activity, suggesting that there may be very little {alpha}1 expressed in skeletal muscle. AICAR- and contraction-stimulated AMPK{alpha}2 activity were fully inhibited in these mice, but only AICAR-stimulated glucose transport was fully ablated (33). For glucose transport measured in isolated muscle contracted in vitro, we found that, similar to Mu et al, there was an ~20–30% decrease in the transgenic mice. However, with careful characterization of muscle force generation with contraction, we determined that the entire decrease in glucose transport could be accounted for by a reduction in force production (33). Thus our data are consistent with the hypothesis that AMPK is not essential for contraction-stimulated glucose transport in skeletal muscle.

Another approach to addressing the question of whether AMPK is necessary for contraction-stimulated glucose transport would be to disrupt the upstream kinase for AMPK. Recently, the serine/threonine kinase LKB1, in complex with the two accessory subunits STRAD and MO25, has been identified as an upstream kinase for AMPK (41, 50, 107) as well as a kinase for 11 of the 12 proteins in the AMPK family (76, 112). Phosphorylation of the Thr172 site on the {alpha}1 and {alpha}2 catalytic subunits is essential for AMPK activity (21, 115). To study LKB1 function in skeletal muscle and its putative role in contraction-stimulated glucose transport, our group (68) has generated a muscle-specific LKB1 knockout mouse (MLKB1KO), where Sakamoto et al. (102) have studied a hypomorphic LKB1 mouse that has a 70–80% loss of LKB1 throughout all tissues in the body and complete ablation of LKB1 in skeletal muscle. In contrast to studies in AMPK whole body knockout mice and our muscle-specific AMPK{alpha}2-inactive transgenic mice, contraction-stimulated glucose transport was partially inhibited in these two LKB1 knockout models, a finding that could not be attributed to a reduced force production during contraction. As AMPK{alpha}2 knockout mice and AMPK{alpha}2 transgenic mice have normal contraction-stimulated glucose transport (33, 61), the decrease in contraction-stimulated glucose transport in MLKB1KO mice may be a function of altered AMPK{alpha}1 activity, although the majority of data suggest that there may be little AMPK{alpha}1 activity in muscle. Alternatively, or in addition, another LKB1 substrate may be necessary for contraction-stimulated glucose transport. The fact that our MLKB1KO mice did not fully inhibit contraction-stimulated glucose transport demonstrates that LKB1 is necessary for a normal response, but it also suggests that there are additional signals involved in the regulation of this process.

If AMPK{alpha}2 activity is not essential for contraction-stimulated glucose transport, how can one explain the many findings that led to the hypothesis that AMPK regulates glucose transport in skeletal muscle? For example, if increasing AMPK activity using AICAR increases muscle glucose transport, why would increasing AMPK by muscle contraction not have the same physiological outcome? Furthermore, the combined effects of a maximal AICAR treatment and contraction on glucose transport are not additive, strongly suggesting that these two stimuli work through the same mechanism. The most likely explanation is that there are multiple contraction-stimulated signals that simultaneously contribute to an increase in glucose transport and that there is redundancy in the system (33). In recent years, there has been accumulating evidence that calcium-mediated signaling, including regulation of the calcium/calmodulin kinases, is involved in the contraction effect (20, 59). Therefore, it may be that contraction-stimulated glucose transport is regulated by multiple signals that originate from reductions in energy states of the muscle fibers, redox changes, and calcium release for the sarcoplasmic reticulum. It is also possible that signals emanating from mechanical stress to the muscle fibers could also contribute to changes in glucose transport, although such signals have yet to be linked to the transport process.

AMPK as a Mediator of Multiple Insulin-Independent Stimuli of Glucose Transport

Exercise and contractions have drawn a great deal of attention as stimulators of an insulin-independent stimulus of glucose transport because of the obvious clinical benefits of exercise in metabolic disorders like type 2 diabetes. However, numerous metabolic stressors, like hypoxia, hyperosmolarity, the chemical uncoupler 2,4-dinitrophenol (DNP), and the electron transport inhibitor rotenone can all increase glucose transport independently of insulin (46). The discovery of the differences in the involvement of AMPK in AICAR- and contraction-induced glucose transport has made it clear that several pathways may exist leading to an insulin-independent stimulus of glucose transport.

Hypoxia, rotenone (a complex I inhibitor), and DNP (a mitochondrial uncoupler) activate AMPK through energy depletion and result in an increase in glucose transport (46). Comparable results are seen when L6 and H-2kb cells are incubated with DNP (31, 87). When muscles from mice expressing AMPK{alpha}2 dominant-negative isoforms are subjected to hypoxia or incubated with rotenone, the increase in glucose transport is completely abolished (33, 83). These results indicate that there is no compensatory effect on {alpha}2 function by {alpha}1 and strongly support the idea that AMPK{alpha}2 represents the predominant, if not the only, regulator of hypoxia- and rotenone-stimulated glucose transport. Interestingly, AMPK does not seem to be involved in insulin (33, 61), phorbol ester (30), or passive stretch (56, 57) -stimulated glucose transport, which occurs without decreases in intracellular energy status. Interestingly, AMPK{alpha}1 activity, although partly diminished by ~40%, was still significantly increased by rotenone (33). There is a discrepancy in whether osmotic stress activates AMPK by decreases in energy status in cells. Although increased AMPK activity after osmotic shock induced by sorbitol was associated with decreased intracellular ATP, phosphocreatine, and glycogen content in isolated rat epitrochlearis muscles (46), there was no effect of sorbitol on the ATP/AMP ratio in H-2kb cells (30). Unlike rotenone and hypoxia, but similar to contractions, glucose transport induced by osmotic shock was not affected in muscles from AMPK dominant-negative mice (33). This is unlike H-2Kb cells, where osmotic shock-stimulated glucose transport is completely abolished by adenoviral mediated overexpression of the AMPK{alpha} dominant-negative mutant (30). Hyperosmolarity-induced glucose transport in skeletal muscles may therefore be regulated by a mechanism in which AMPK{alpha}2 is one of multiple signaling pathways. Nevertheless, it is clear that in skeletal muscle, AMPK{alpha}2 activation is essential for some, but not all, insulin-independent stimuli of glucose transport.

Signaling Intermediaries for AMPK Effects on Glucose Transport

Although it is now well documented that activation of AMPK using various stimuli can increase glucose transport in skeletal muscle and other tissues, the downstream signals that mediate glucose transport have remained elusive. Akt substrate of 160 kDa (AS160) has recently been identified as a protein that modulates GLUT4 trafficking in insulin-sensitive 3T3-L1 adipocytes (105) and L6 myoblasts (62). In the nonphosphorylated state, AS160 prevents the translocation of GLUT4 to the cell surface (26, 80), and when AS160 is phosphorylated by Akt on several phospho-motifs (12, 62) GLUT4 translocates. However, it is not known whether AS160 phosphorylation is mandatory for GLUT4 translocation in skeletal muscle. The substrate motifs of AMPK and Akt show similarities, and both kinases can phosphorylate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase on Ser466 (91). AS160 might also be a shared substrate and thereby serves as a point of convergence and integration for multiple effectors of glucose transport. Bruss et al. (12) reported that, in rat epitrochlearis muscles, contraction and AICAR treatment increase AS160 phosphorylation in muscle samples in vitro when probed with a phospho-Akt substrate (PAS) antibody. However, because AICAR is not a specific AMPK activator it is still not possible to conclude that AS160 is a substrate for AMPK. To determine whether AS160 mediates AMPK signaling, our laboratory has assessed AS160 phosphorylation in AMPK{alpha}2-inactive transgenic mice after various stimuli (70). We saw that AICAR-stimulated phosphorylation of AS160 phosphorylation was fully inhibited in AMPK{alpha}2-inactive transgenic mice, whereas contraction-stimulated AS160 phosphorylation was only partially reduced. Contraction activates Akt (101), and this activation can be inhibited by wortmannin (101). However, combined AMPK{alpha}2 and Akt inhibition by wortmannin treatment of AMPK{alpha}2 transgenic mice did not fully ablate contraction-stimulated AS160 phosphorylation. Similar to glucose transport, AMPK{alpha}2 activity is essential for AS160 phosphorylation by AICAR, but AMPK is not indispensable for the entire effects of contraction on AS160 phosphorylation. These results indicate that AMPK can be upstream of AS160, but whether AS160 phosphorylation is obligatory for the AMPK signal to glucose transport is not known, and several other proteins activated by AMPK have also been suggested as mediators.

Studies in Clone 9 cells identified the stress-activated protein kinase p38 as a mediator of AMPK-induced glucose transport. Addition of the p38 inhibitor SB-203580 and overexpressing of a dominant-negative p38 mutant inhibited AICAR-induced glucose transport in these cells (127). The p38 inhibitor SB-203580, was also shown to diminish contraction-stimulated p38{alpha} and -beta activities and concomitantly reduced glucose transport in isolated rat EDL and soleus muscles (110). However, recent data show that SB-203580 acts as a competitive inhibitor of glucose transport through direct interaction with the glucose transporter (95), and overexpression of dominant-negative p38 mutants in skeletal muscle does not affect glucose transport (5). These results are supported by work from our laboratory, where we find that another p38 inhibitor, SB-202190, nonspecifically diminishes both contraction- and insulin-induced glucose transport without inhibition of p38 activation (Boppart MD and Goodyear LJ, unpublished findings, and Ref. 34) and that AICAR activates only AMPK but not p38 in L6 myotubes (48). Taken together, a role of p38 as a mediator of the signal from AMPK to glucose transport in skeletal muscles therefore seems unlikely.

On the basis of studies using treadmill running of mice and L6 myotubes, Chen et al. (16) proposed a new hypothesis that the effects of exercise on glucose transport are mediated by sequential activation of AMPK, Pyk2, Grb2, SOS, Ras, Raf, MEK1, ERK, PLD, and aPKCs. This signaling pathway has also been suggested to explain osmotic stress-stimulated glucose transport in L6 cells (100). However, Pyk2 does not seem to be activated by exercise in human skeletal muscle with contraction (120) and by contraction in rat muscle in vitro (126). ERK inhibition using the MAP kinase kinase inhibitor PD-98059 does not affect glucose transport either in slow-twitch fiber-rich muscles, such as soleus (44, 45, 123), nor in fast-twitch fiber-rich muscles, such as red gastrocnemius (123) and white gastrocnemius muscles in rats (123). Furthermore, the role of Grb2 in muscle contraction-induced ERK pathway activation has been ruled out (109). It is also suggested that genestein, an agent used to inhibit tyrosine kinase by Chen et al. (16), may have a direct effect on GLUT4 (8) and GLUT1 (2). Roles for PLD (71, 72) and aPKCs (27) in glucose transport in skeletal muscle have been reported, although the association between AMPK activation and the function of these molecules has not been elucidated.

Collectively, it is clear that, despite intense research, no obvious mediators of the signal from AMPK to glucose transport have emerged. Future investigation is needed to determine the role of newly discovered regulators of GLUT4 trafficking, such as AS160, in glucose transport. The development of tissue-specific transgenic animal models might help shed new light on the role of these regulators in AMPK-mediated glucose transport.

AMPK and Insulin Sensitivity for Glucose Transport

It is well established that the period after exercise is characterized by an increase in the sensitivity of the muscle to insulin. This phenomenon is not fully understood, but recently it has been hypothesized that AMPK may be part of the mechanism for enhanced insulin action in skeletal muscle after exercise. Fisher et al. (29) found that prior incubation of isolated rat epitrochlearis muscles with AICAR for 1 h enhanced insulin-stimulated glucose transport twofold. This AICAR-induced increase in insulin sensitivity was not inhibited by addition of cycloheximide, an inhibitor of protein synthesis, and was thus not dependent on increased expression of glucose transporters. More recently, this group has used Compound C, an AMPK inhibitor, to show that the insulin-sensitizing effects of both AICAR and hyperosmotic stress in C2C12 myotubes is dependent on AMPK. On the other hand, studies in primary human muscle cells have shown no effect of prior AICAR treatment on insulin-stimulated glucose transport (4), but incubation of these cells with AICAR also did not increase glucose transport (4). Why these reports come to different conclusions is not clear, and further studies in this area are essential.

One mechanism for enhanced insulin action induced by AICAR may be through direct regulation of components of the insulin-signaling pathway. Purified AMPK from rat liver phosphorylated IRS-1 on Ser789 in a cell-free assay (58). In C2C12 myotubes, activation of AMPK by AICAR caused Ser789 IRS-1 phosphorylation, whereas preincubation of these cells with AICAR increased IRS-1-associated PI 3-kinase activation by insulin (58). This study raised the intriguing possibility that IRS-1 phosphorylation on Ser789 may be involved in the mechanism of increased insulin sensitivity associated with AMPK activation. However, the effect of AMPK activation on insulin-stimulated PI 3-kinase activity was independent of changes in IRS-1 tyrosine phosphorylation or binding of p85 to IRS-1 in the myotubes (58), and studies of adult intact skeletal muscles have shown that AICAR preincubation does not enhance insulin-stimulated phosphotyrosine-associated PI 3-kinase activity (29). Furthermore, it is unlikely that phosphorylation of IRS-1 by AMPK plays a role in the insulin-sensitizing effects of exercise, because prior contraction of rat hindlimb skeletal muscles actually causes a decrease in insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS-1 and in IRS-1-associated PI 3-kinase activity (35, 122). Moreover, it has been suggested that Ser789 may play a role in attenuating insulin signaling in insulin-resistant rodent models (106), and AMPK is not involved in serine kinases that phosphorylate the IRS-1 Ser789 site in liver (92). Evidently, further work is required to clarify the importance of IRS-1 Ser789 in insulin sensitivity and the function of AMPK in the regulation of IRS-1.

AMPK and Insulin Resistance in Skeletal Muscles

AMPK has also been suggested as a key component in the more prolonged insulin-sensitizing effect of chronic exercise training, where increased expression of proteins involved in glucose transport plays a key role. Holmes et al. (49) administrated five daily doses of AICAR to Sprague-Dawley rats. Twenty-four hours after the last AICAR treatment, they saw accumulation of glycogen in the muscles together with increases in the expression of GLUT4 and hexokinase (49), very similar to well-established effects of endurance exercise training. Using the same protocol, Buhl et al. (14) showed increased insulin-stimulated GLUT4 translocation and glucose transport in isolated rat muscles. Besides the increase in GLUT4 and hexokinase expression, AICAR treatment also increased the insulin-stimulated activity of the insulin-signaling cascade (60). These observations imply that the increase in insulin sensitivity following endurance training may be mediated by AMPK in skeletal muscle. However, when administrated in vivo, the effects on muscles could also be secondary to AICAR effects on fat and glucose metabolism in other tissues, such as the liver.

Based on the numerous studies showing that a single AICAR treatment can increase muscle glucose transport, lower blood glucose concentrations, and increase insulin sensitivity, there have been many investigations examining the effects of AMPK activation on specific insulin-resistant conditions. In obese Zucker rats, insulin was ineffective in increasing glucose uptake, whereas a 90-min infusion of AICAR activated AMPK and increased glucose uptake in gastrocnemius muscle of obese and lean rats, and to a similar degree (9). Furthermore, in insulin-resistant high-fat-fed rats, administration of a single injection of AICAR increased whole body, liver, and muscle insulin action measured 24 h after AICAR was administrated (55). These studies showed that pharmacological activation of AMPK decreases blood glucose concentrations in an animal model of insulin resistance.

In addition to the short-term studies in insulin-resistant rats, several long-term studies have been conducted in both mouse and rat models of insulin resistance. In KKAy-CETP mice, administration of AICAR intraperitoneally for 7 days decreased the abnormally elevated glucose and insulin concentrations and improved glucose and insulin tolerance tests (28). However, insulin-stimulated glucose transport into isolated muscles did not increase. In ob/ob mice, subcutaneous administration of AICAR for 7 days corrected the hyperglycemia and improved glucose tolerance (111). Similar to the KKAy-CETP mice, in ob/ob animals AICAR had no effect on insulin-stimulated glucose transport measured in muscles removed 24 h after the last in vivo dose; however, glucose transport did increase normally during in vitro isolated muscle incubations with the compound. Similar to the effects of AICAR in ob/ob mice, this compound also lowered glucose concentrations acutely in db/db mice (38).

In these insulin-resistant mice (28, 38, 111), although 7–8 days of AICAR treatment improved glucose and insulin concentrations, it also caused an increase in free fatty acid and triglyceride concentrations, an effect that could be detrimental. Buhl et al. (13) studied the effect of AICAR treatment for 7 wk in Zucker rats. AICAR caused a decrease in glucose and insulin levels and improved glucose tolerance. Moreover, after 7 wk of treatment, AICAR-treated animals had improvements in their lipid profile and systolic blood pressure. Similarly, 8 wk of AICAR-treatment in the Zucker diabetic fatty rat, an animal model characterized by a progressive beta-cell loss and development of diabetes, prevented or delayed the onset of diabetes without any increases in plasma lipids (89). Hyperinsulinemic euglycemic clamp studies of these animals showed that the improved insulin sensitivity was due mainly to an increased glucose transport in skeletal muscle (89). AICAR treatment also preserved beta-cell mass (89), but it is not known whether this was due to a direct effect of AICAR on the beta-cells or whether it was a result of the improved insulin sensitivity in the peripheral tissues.

Whether the differences between the studies in insulin-resistant mice vs. rats are due to species differences or to duration of treatment needs to be investigated. Furthermore, given the nonspecificity of AICAR and the inconsistent findings discussed here, in future studies it will be important to use AMPK knockout or transgenic mice, especially muscle specific, to determine whether AMPK activation is necessary for postexercise enhancement of insulin sensitivity for glucose transport.

AMPK and Glucose Transport in the Heart

Ischemia is a potent activator of AMPK in the heart (73), and it has been suggested that AMPK mediates the ischemia-induced increase in glucose transport (reviewed in Ref. 104). During cardiac ischemia, the glucose transporters GLUT1 and GLUT4 translocate to the sarcolemma and facilitate glucose transport into the heart (25, 98, 118). In vitro incubation of rat papillary muscles with AICAR increased GLUT4 translocation and glucose transport in a PI 3-kinase-independent manner (96). However, AICAR has been shown to have AMPK-independent effects on glucose metabolism in the heart (77). To determine a causal relationship between AMPK and glucose transport in the heart, Dr. Tian's group, in collaboration with our laboratory, generated a heart-specific AMPK{alpha}2-inactive transgenic mouse [Xing et al. (128)]. During in vitro perfusion, the ischemia-induced increase in glucose transport was partly reduced in the AMPK{alpha}2-inactive hearts (128), providing evidence that AMPK plays a critical role in glucose transport during ischemia. This observation was supported by the findings of Russell et al. (97) in a different AMPK transgenic mouse model. In those mice, activation of both the {alpha}1- and {alpha}2-isoforms of AMPK was inhibited, and hypoxia completely failed to augment glucose transport in the hearts (97). Together, these studies clearly demonstrate the importance of AMPK in ischemia-induced glucose transport in the heart.

The mechanisms by which AMPK stimulates GLUT4 translocation in the heart are unknown. Similar to skeletal muscle, nitric oxide synthase (NOS) and p38 MAPK have been suggested as possible mediators, but the findings have been inconsistent. Li et al. found that incubation of rat papillary muscles with the two NOS inhibitors NG-nitro-L-arginine methyl ester and NG-monomethyl-L-arginine (L-NMMA) partly inhibited AICAR-induced glucose transport, whereas the NO donors sodium nitroprusside and S-nitroso-N-acetyl-DL-penicillamine increased glucose transport (75). However, the reduction of glucose transport was only modest, and the finding is in contrast to other studies that show increased glucose transport in hearts perfused with L-NMMA (24). Further research is needed to determine the role of NOS in glucose transport by AMPK in cardiomyocytes.

p38 MAPK is activated in heart muscle during ischemia (11), and inhibition of AMPK with either araA or overexpression of a dominant-negative form of AMPK abolishes p38 phosphorylation in isolated cardiomyocytes incubated with DNP (88). When the same cells are incubated with the p38 inhibitor PD-169316, DNP-induced glucose transport is reduced by 70%, indicating a role for p38 in glucose transport in cardiomyocytes. This is an interesting hypothesis, but, due to the possible nonspecific effects of the inhibitor and the fundamental differences between cultured cells and intact cardiomyocytes, it will be important to further investigate the putative role of p38 in mediating the signal from AMPK to glucose transport in the heart in vivo.

AMPK as a Drug Target for Diabetes

The identification of AMPK as a regulator of glucose transport has made it a promising target for pharmaceutical development, supported by the discovery that metformin activates glucose transport via AMPK activation (121). Metformin is a widely used drug for the treatment of type 2 diabetes; its mechanism of action, however, had until recently not been defined. Zhou et al. (132) showed that metformin activates AMPK in primary cultures of rat hepatocytes, mediating inhibitory effects of the drug on hepatic glucose production and, in isolated rat skeletal muscle, stimulating glucose transport. The observation was recently confirmed by Shaw et al. (108), who provided strong experimental evidence for AMPK as the only therapeutic target of metformin. By generating mice with a liver-specific deletion of LKB1, they demonstrated that both phosphorylation of AMPK in hepatocytes and the blood-lowering effects of metformin were completely abolished. These results strongly suggest that, in mice, metformin primarily decreases blood glucose concentrations by decreasing hepatic gluconeogenesis. Data from human studies have shown that, besides the effects on the liver, metformin administration increases glucose disposal in skeletal muscle (22, 51, 65). This effect might also be mediated through AMPK, as it has been demonstrated by Musi et al. (86) that metformin treatment for 10 wk significantly increases AMPK{alpha}2 activity in skeletal muscles from human subjects with type 2 diabetes. Activation of AMPK therefore provides a unified explanation for the beneficial effects of metformin.

Thiazolidinediones, another group of antidiabetic drugs, have also been found to activate glucose transport in an AMPK{alpha}2-dependent manner in rat skeletal muscle in vitro (130). One of the beneficial effects of this class of drugs is the enhancement of insulin sensitivity. As described above, activation of AMPK enhances glucose transport in response to insulin stimulation. Therefore, it is likely that activation of AMPK is one of the mechanisms underlying the beneficial effects of this drug in the treatment of type 2 diabetes. Exactly how thiazolidinediones activate AMPK is unknown, but treatment of cultured muscle cells with these compounds increases the AMP/ATP ratio (32). Furthermore, treatment with thiazolidinediones increases synthesis of adiponectin, an adipokine that activates AMPK in liver (129) and muscle (117), which might in turn potentiate the effects of thiazolidinediones on AMPK in vivo.

Not only are metformin and thiazolidinediones beneficial in the treatment of type 2 diabetes, but treatment with both drugs have, similarly to regular exercise, proved effective in the prevention of the disease in high-risk populations (66, 67). Whether this effect is due to activation of the AMPK system remains to be established, but the results suggest that targeting AMPK might be a strategy to oppose the increasing prevalence of type 2 diabetes.


   SUMMARY
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AMPK stimulates glucose transport when skeletal muscle is exposed to stimuli that lower intracellular energy charge. The efficacy of AMPK to activate glucose transport is comparable to that observed with insulin in muscle, but the proximal signals mediating insulin- and AMPK-regulated glucose transport are distinct. The finding that AMPK activation elicits a novel signaling mechanism leading to enhanced glucose transport in skeletal muscle has important clinical and therapeutic implications. AMPK also enhances insulin sensitivity to glucose transport, and the mechanism for this effect is also not fully understood. To elucidate the expanding role of AMPK in the energy sensor hypothesis more comprehensively, it will be necessary to determine what signaling molecules are downstream of AMPK that are necessary for the activation of glucose transport. Furthermore, the recent data from the AMPK and LBK1 transgenic animal models have made it clear that mechanisms besides AMPK regulate insulin-independent glucose transport and that the identification of these mediators will be an important future undertaking (Fig. 1).


Figure 1
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  		Fig. 1. Schema illustrating the role of AMPK in glucose transport. Stimuli that cause an increase in [AMP]/[ATP] ratio activate AMPK and subsequently induce glucose transport. Hypoxia-induced glucose transport is probably regulated only by AMPK, whereas, exercise- and osmotic stress-induced glucose transport seem to be simultaneously regulated by both AMPK-dependent and AMPK-independent pathways. Metformin and thiazolidinediones, widely used drugs for treatment of type 2 diabetes, also activate AMPK. Some reports suggest that metformin may activate AMPK in an [AMP]/[ATP]-independent manner. Although several molecules have been suggested as intermediates of AMPK and glucose transport, the signaling mechanism remains largely undefined. The potential role of AMPK in enhancing insulin sensitivity is also poorly understood. Solid arrows illustrate more established relationships between stimuli, signals, and glucose transport; dashed arrows are used for putative interactions.

 

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Work from the authors' laboratory was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants RO1-AR-45670 and AR-42238 (to L. J. Goodyear).


   FOOTNOTES
 

Address for reprint requests and other correspondence: L. J. Goodyear, Research Division, Joslin Diabetes Center, One Joslin Pl., Boston, MA 02215 (e-mail: Laurie.Goodyear{at}joslin.harvard.edu)


   REFERENCES
TOP
 ABSTRACT
 SUMMARY
 GRANTS
 REFERENCES
 

  1. Abbud W, Habinowski S, Zhang JZ, Kendrew J, Elkairi FS, Kemp BE, Witters LA, and Ismail-Beigi F. Stimulation of AMP-activated protein kinase (AMPK) is associated with enhancement of Glut1-mediated glucose transport. Arch Biochem Biophys 380: 347–352, 2000.[CrossRef][Web of Science][Medline]
  2. Afzal I, Cunningham P, and Naftalin RJ. Interactions of ATP, oestradiol, genistein and the anti-oestrogens, faslodex (ICI 182780) and tamoxifen, with the human erythrocyte glucose transporter, GLUT1. Biochem J 365: 707–719, 2002.[CrossRef][Web of Science][Medline]
  3. Ai H, Ihlemann J, Hellsten Y, Lauritzen HP, Hardie DG, Galbo H, and Ploug T. Effect of fiber type and nutritional state on AICAR- and contraction-stimulated glucose transport in rat muscle. Am J Physiol Endocrinol Metab 282: E1291–E1300, 2002.[Abstract/Free Full Text]
  4. Al Khalili L, Krook A, Zierath JR, and Cartee GD. Prior serum- and AICAR-induced AMPK activation in primary human myocytes does not lead to subsequent increase in insulin-stimulated glucose uptake. Am J Physiol Endocrinol Metab 287: E553–E557, 2004.[Abstract/Free Full Text]
  5. Antonescu CN, Huang C, Niu W, Liu Z, Eyers PA, Heidenreich KA, Bilan PJ, and Klip A. Reduction of insulin-stimulated glucose uptake in L6 myotubes by the protein kinase inhibitor SB203580 is independent of p38MAPK activity. Endocrinology 146: 3773–3781, 2005.[Abstract/Free Full Text]
  6. Arad M, Benson DW, Perez-Atayde AR, McKenna WJ, Sparks EA, Kanter RJ, McGarry K, Seidman JG, and Seidman CE. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 109: 357–362, 2002.[CrossRef][Web of Science][Medline]
  7. Balon TW and Jasman AP. Acute exposure to AICAR increases glucose transport in mouse EDL and soleus muscle. Biochem Biophys Res Commun 282: 1008–1011, 2001.[CrossRef][Web of Science][Medline]
  8. Bazuine M, van den Broek PJ, and Maassen JA. Genistein directly inhibits GLUT4-mediated glucose uptake in 3T3-L1 adipocytes. Biochem Biophys Res Commun 326: 511–514, 2005.[CrossRef][Web of Science][Medline]
  9. Bergeron R, Previs SF, Cline GW, Perret P, Russell RR III, Young LH, and Shulman GI. Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50: 1076–1082, 2001.[Abstract/Free Full Text]
  10. Bergeron R, Russell RR III, Young LH, Ren JM, Marcucci M, Lee A, and Shulman GI. Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol Endocrinol Metab 276: E938–E944, 1999.[Abstract/Free Full Text]
  11. Bogoyevitch MA, Gillespie-Brown J, Ketterman AJ, Fuller SJ, Ben Levy R, Ashworth A, Marshall CJ, and Sugden PH. Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circ Res 79: 162–173, 1996.[Abstract/Free Full Text]
  12. Bruss MD, Arias EB, Lienhard GE, and Cartee GD. Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes 54: 41–50, 2005.[Abstract/Free Full Text]
  13. Buhl ES, Jessen N, Pold R, Ledet T, Flyvbjerg A, Pedersen SB, Pedersen O, Schmitz O, and Lund S. Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome. Diabetes 51: 2199–2206, 2002.[Abstract/Free Full Text]
  14. Buhl ES, Jessen N, Schmitz O, Pedersen SB, Pedersen O, Holman GD, and Lund S. Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes 50: 12–17, 2001.[Abstract/Free Full Text]
  15. Carling D. The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci 29: 18–24, 2004.[CrossRef][Web of Science][Medline]
  16. Chen HC, Bandyopadhyay G, Sajan MP, Kanoh Y, Standaert M, Farese RV Jr, and Farese RV. Activation of the ERK pathway and atypical protein kinase C isoforms in exercise- and aminoimidazole-4-carboxamide-1-beta-D-riboside (AICAR)-stimulated glucose transport. J Biol Chem 277: 23554–23562, 2002.[Abstract/Free Full Text]
  17. Chen Z, Heierhorst J, Mann RJ, Mitchelhill KI, Michell BJ, Witters LA, Lynch GS, Kemp BE, and Stapleton D. Expression of the AMP-activated protein kinase beta1 and beta2 subunits in skeletal muscle. FEBS Lett 460: 343–348, 1999.[CrossRef][Web of Science][Medline]
  18. Chen ZP, McConell GK, Michell BJ, Snow RJ, Canny BJ, and Kemp BE. AMPK signaling in contracting human skeletal muscle: acetyl-CoA carboxylase and NO synthase phosphorylation. Am J Physiol Endocrinol Metab 279: E1202–E1206, 2000.[Abstract/Free Full Text]
  19. Cheung PC, Salt IP, Davies SP, Hardie DG, and Carling D. Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem J 346: 659–669, 2000.[CrossRef][Web of Science][Medline]
  20. Chin ER. Role of Ca2+/calmodulin-dependent kinases in skeletal muscle plasticity. J Appl Physiol 99: 414–423, 2005.[Abstract/Free Full Text]
  21. Crute BE, Seefeld K, Gamble J, Kemp BE, and Witters LA. Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase. J Biol Chem 273: 35347–35354, 1998.[Abstract/Free Full Text]
  22. Cusi K and DeFronzo RA. Metformin: a review of its metabolic effects. Diabetes Rev 6: 89–131, 1998.
  23. Daniel T and Carling D. Functional analysis of mutations in the gamma 2 subunit of AMP-activated protein kinase associated with cardiac hypertrophy and Wolff-Parkinson-White syndrome. J Biol Chem 277: 51017–51024, 2002.[Abstract/Free Full Text]
  24. Depre C, Vanoverschelde JL, Goudemant JF, Mottet I, and Hue L. Protection against ischemic injury by nonvasoactive concentrations of nitric oxide synthase inhibitors in the perfused rabbit heart. Circulation 92: 1911–1918, 1995.[Abstract/Free Full Text]
  25. Egert S, Nguyen N, and Schwaiger M. Contribution of alpha-adrenergic and beta-adrenergic stimulation to ischemia-induced glucose transporter (GLUT)4 and GLUT1 translocation in the isolated perfused rat heart. Circ Res 84: 1407–1415, 1999.[Abstract/Free Full Text]
  26. Eguez L, Lee A, Chavez JA, Miinea CP, Kane S, Lienhard GE, and McGraw TE. Full intracellular retention of GLUT4 requires AS160 Rab GTPase activating protein. Cell Metab 2: 263–272, 2005.[CrossRef][Web of Science][Medline]
  27. Farese RV. Function and dysfunction of aPKC isoforms for glucose transport in insulin-sensitive and insulin-resistant states. Am J Physiol Endocrinol Metab 283: E1–E11, 2002.[Abstract/Free Full Text]
  28. Fiedler M, Zierath JR, Selen G, Wallberg-Henriksson H, Liang Y, and Sakariassen KS. 5-Aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside treatment ameliorates hyperglycaemia and hyperinsulinaemia but not dyslipidaemia in KKAy-CETP mice. Diabetologia 44: 2180–2186, 2002.[CrossRef][Web of Science]
  29. Fisher JS, Gao J, Han DH, Holloszy JO, and Nolte LA. Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am J Physiol Endocrinol Metab 282: E18–E23, 2002.[Abstract/Free Full Text]
  30. Fryer LG, Foufelle F, Barnes K, Baldwin SA, Woods A, and Carling D. Characterization of the role of the AMP-activated protein kinase in the stimulation of glucose transport in skeletal muscle cells. Biochem J 363: 167–174, 2002.[CrossRef][Web of Science][Medline]
  31. Fryer LG, Hajduch E, Rencurel F, Salt IP, Hundal HS, Hardie DG, and Carling D. Activation of glucose transport by AMP-activated protein kinase via stimulation of nitric oxide synthase. Diabetes 49: 1978–1985, 2000.[Abstract/Free Full Text]
  32. Fryer LG, Parbu-Patel A, and Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277: 25226–25232, 2002.[Abstract/Free Full Text]
  33. Fujii N, Hirshman MF, Kane EM, Ho RC, Peter LE, Seifert MM, and Goodyear LJ. AMP-activated protein kinase alpha2 activity is not essential for contraction- and hyperosmolarity-induced glucose transport in skeletal muscle. J Biol Chem 280: 39033–39041, 2005.[Abstract/Free Full Text]
  34. Fukuwatari T, Boppart MD, Hirshman MF, and Goodyear LJ. Insulin does not increase p38 MAP kinase activity or phosphorylation in rat skeletal muscle (Abstract). Diabetes 49, Suppl 1: A15, 2000.
  35. Goodyear LJ, Giorgino F, Balon TW, Condorelli G, and Smith RJ. Effects of contractile activity on tyrosine phophoproteins and PI 3-kinase activity in rat skeletal muscle. Am J Physiol Endocrinol Metab 268: E987–E995, 1995.[Abstract/Free Full Text]
  36. Goodyear LJ and Kahn BB. Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49: 235–261, 1998.[CrossRef][Web of Science][Medline]
  37. Gruber HE, Hoffer ME, McAllister DR, Laikind PK, Lane TA, Schmid-Schoenbein GW, and Engler RL. Increased adenosine concentration in blood from ischemic myocardium by AICA riboside. Effects on flow, granulocytes, and injury. Circulation 80: 1400–1411, 1989.[Abstract/Free Full Text]
  38. Halseth AE, Ensor NJ, White TA, Ross SA, and Gulve EA. Acute and chronic treatment of ob/ob and db/db mice with AICAR decreases blood glucose concentrations. Biochem Biophys Res Commun 294: 798–805, 2002.[CrossRef][Web of Science][Medline]
  39. Hardie DG. Minireview. The AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144: 5179–5183, 2003.[CrossRef][Web of Science][Medline]
  40. Hardie DG, Carling D, and Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu Rev Biochem 67: 821–855, 1998.[CrossRef][Web of Science][Medline]
  41. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, and Hardie DG. Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2: 28, 2003.[CrossRef][Medline]
  42. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, and Hardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271: 27879–27887, 1996.[Abstract/Free Full Text]
  43. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, and Hardie DG. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2: 9–19, 2005.[CrossRef][Web of Science][Medline]
  44. Hayashi T, Dufresne SD, Aronson D, Sherwood DJ, Hirshman MF, Boppart MD, Fielding RA, and Goodyear LJ. Intracellular signaling pathways in contracting skeletal muscle. In: Biochemistry of Exercise X, edited by Hargreaves M and Thompson M. Champaign, IL: Human Kinetics, 1999, p. 19–34.
  45. Hayashi T, Hirshman MF, Dufresne SD, and Goodyear LJ. Skeletal muscle contractile activity in vitro stimulates mitogen-activated protein kinase signaling. Am J Physiol Cell Physiol 277: C701–C707, 1999.[Abstract/Free Full Text]
  46. Hayashi T, Hirshman MF, Fujii N, Habinowski SA, Witters LA, and Goodyear LJ. Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 49: 527–531, 2000.[Abstract]
  47. Hayashi T, Hirshman MF, Kurth EJ, Winder WW, and Goodyear LJ. Evidence for 5' AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47: 1369–1373, 1998.[Abstract]
  48. Ho RC, Hirshman MF, Fujii N, Witters LA, and Goodyear LJ. Dissociation between AMPK and p38 MAPK signaling in resting and contracting skeletal muscle (Abstract). Diabetes 53, Suppl 2: A62, 2004.
  49. Holmes BF, Kurth-Kraczek EJ, and Winder WW. Chronic activation of 5'-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 87: 1990–1995, 1999.[Abstract/Free Full Text]
  50. Hong SP, Leiper FC, Woods A, Carling D, and Carlson M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci USA 100: 8839–8843, 2003.[Abstract/Free Full Text]
  51. Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, and Pedersen O. Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol (Copenh) 120: 257–265, 1989.[Abstract/Free Full Text]
  52. Hudson ER, Pan DA, James J, Lucocq JM, Hawley SA, Green KA, Baba O, Terashima T, and Hardie DG. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr Biol 13: 861–866, 2003.[CrossRef][Web of Science][Medline]
  53. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, and Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 280: 29060–29066, 2005.[Abstract/Free Full Text]
  54. Hutber CA, Hardie DG, and Winder WW. Electrical stimulation inactivates muscle acetyl-CoA carboxylase and increases AMP-activated protein kinase. Am J Physiol Endocrinol Metab 272: E262–E266, 1997.[Abstract/Free Full Text]
  55. Iglesias MA, Ye JM, Frangioudakis G, Saha AK, Tomas E, Ruderman NB, Cooney GJ, and Kraegen EW. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51: 2886–2894, 2002.[Abstract/Free Full Text]
  56. Ihlemann J, Ploug T, Hellsten Y, and Galbo H. Effect of tension on contraction-induced glucose transport in rat skeletal muscle. Am J Physiol Endocrinol Metab 277: E208–E214, 1999.[Abstract/Free Full Text]
  57. Ito Y, Obara K, Ikeda R, Ishii M, Tanabe Y, Ishikawa T, and Nakayama K. Passive stretching produces Akt- and MAPK-dependent augmentations of GLUT4 translocation and glucose uptake in skeletal muscles of mice. Pflügers Arch 451: 803–813, 2006.[CrossRef][Web of Science][Medline]
  58. Jakobsen SN, Hardie DG, Morrice N, and Tornqvist HE. 5'-AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. J Biol Chem 276: 46912–46916, 2001.[Abstract/Free Full Text]
  59. Jessen N and Goodyear LJ. Contraction signaling to glucose transport in skeletal muscle. J Appl Physiol 99: 330–337, 2005.[Abstract/Free Full Text]
  60. Jessen N, Pold R, Buhl ES, Jensen LS, Schmitz O, and Lund S. Effects of AICAR and exercise on insulin-stimulated glucose uptake, signaling, and GLUT-4 content in rat muscles. J Appl Physiol 94: 1373–1379, 2003.[Abstract/Free Full Text]
  61. Jorgensen SB, Viollet B, Andreelli F, Frosig C, Birk JB, Schjerling P, Vaulont S, Richter EA, and Wojtaszewski JF. Knockout of the alpha2 but not alpha1 5'-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside but not contraction-induced glucose uptake in skeletal muscle. J Biol Chem 279: 1070–1079, 2004.[Abstract/Free Full Text]
  62. Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, and Lienhard GE. A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem 277: 22115–22118, 2002.[Abstract/Free Full Text]
  63. Kaushik VK, Young ME, Dean DJ, Kurowski TG, Saha AK, and Ruderman NB. Regulation of fatty acid oxidation and glucose metabolism in rat soleus muscle: effects of AICAR. Am J Physiol Endocrinol Metab 281: E335–E340, 2001.[Abstract/Free Full Text]
  64. Kemp BE, Mitchelhill KI, Stapleton D, Michell BJ, Chen ZP, and Witters LA. Dealing with energy demand: the AMP-activated protein kinase. Trends Biochem Sci 24: 22–25, 1999.[CrossRef][Web of Science][Medline]
  65. Kim YB, Ciaraldi TP, Kong A, Kim D, Chu N, Mohideen P, Mudaliar S, Henry RR, and Kahn BB. Troglitazone but not metformin restores insulin-stimulated phosphoinositide 3-kinase activity and increases p110beta protein levels in skeletal muscle of type 2 diabetic subjects. Diabetes 51: 443–448, 2002.[Abstract/Free Full Text]
  66. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, and Nathan DM. Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346: 393–403, 2002.[Abstract/Free Full Text]
  67. Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, Fowler SE, Nathan DM, and Kahn SE. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 54: 1150–1156, 2005.[Abstract/Free Full Text]
  68. Koh H, Hirshman MF, Fujii N, Arnolds DE, Rogers MJ, Mukai N, Jessen N, Ho RC, and Goodyear LJ. Skeletal muscle knockout of LKB1 causes AICAR resistance but improves glucose tolerance (Abstract). Diabetes 54, Suppl 1: A384, 2005.
  69. Koistinen HA, Galuska D, Chibalin AV, Yang J, Zierath JR, Holman GD, and Wallberg-Henriksson H. 5-Amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes 52: 1066–1072, 2003.[Abstract/Free Full Text]
  70. Kramer HF, Witczak CA, Fujii N, Jessen N, Taylor EB, Arnolds DE, Sakamoto K, Hirshman MF, and Goodyear LJ. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 55: 2067–2076, 2006.[Abstract/Free Full Text]
  71. Kristiansen S, Nielsen JN, Bourgoin S, Klip A, Franco M, and Richter EA. GLUT-4 translocation in skeletal muscle studied with a cell-free assay: involvement of phospholipase D. Am J Physiol Endocrinol Metab 281: E608–E618, 2001.[Abstract/Free Full Text]
  72. Kristiansen S and Richter EA. GLUT4-containing vesicles are released from membranes by phospholipase D cleavage of a GPI anchor. Am J Physiol Endocrinol Metab 283: E374–E382, 2002.[Abstract/Free Full Text]
  73. Kudo N, Barr AJ, Barr RL, Desai S, and Lopaschuk GD. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 270: 17513–17520, 1995.[Abstract/Free Full Text]
  74. Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, and Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48: 1667–1671, 1999.[Abstract]
  75. Li J, Hu X, Selvakumar P, Russell RR III, Cushman SW, Holman GD, and Young LH. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol Endocrinol Metab 287: E834–E841, 2004.[Abstract/Free Full Text]
  76. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Makela TP, Hardie DG, and Alessi DR. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23: 833–843, 2004.[CrossRef][Web of Science][Medline]
  77. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, and Allard MF. 5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol 284: R936–R944, 2003.[Abstract/Free Full Text]
  78. Mahlapuu M, Johansson C, Lindgren K, Hjalm G, Barnes BR, Krook A, Zierath JR, Andersson L, and Marklund S. Expression profiling of the {gamma}-subunit isoforms of AMP-activated protein kinase suggests a major role for {gamma}3 in white skeletal muscle. Am J Physiol Endocrinol Metab 286: E194–E200, 2004.[Abstract/Free Full Text]
  79. Merrill GF, Kurth EJ, Hardie DG, and Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol Endocrinol Metab 273: E1107–E1112, 1997.[Abstract/Free Full Text]
  80. Miinea CP, Sano H, Kane S, Sano E, Fukuda M, Peranen J, Lane WS, and Lienhard GE. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J 391: 87–93, 2005.[CrossRef][Web of Science][Medline]
  81. Milan D, Jeon JT, Looft C, Amarger V, Robic A, Thelander M, Rogel-Gaillard C, Paul S, Iannuccelli N, Rask L, Ronne H, Lundstrom K, Reinsch N, Gellin J, Kalm E, Roy PL, Chardon P, and Andersson L. A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle. Science 288: 1248–1251, 2000.[Abstract/Free Full Text]
  82. Mitchelhill KI, Stapleton D, Gao G, House C, Michell B, Katsis f Witters LA, and Kemp BE. Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J Biol Chem 269: 2361–2364, 1994.[Abstract/Free Full Text]
  83. Mu J, Brozinick JT Jr, Valladares O, Bucan M, and Birnbaum MJ. A role for AMP-activated protein kinase in contraction-and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7: 1085–1094, 2001.[CrossRef][Web of Science][Medline]
  84. Musi N, Fujii N, Hirshman MF, Ekberg I, Froberg S, Ljungqvist O, Thorell A, and Goodyear LJ. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes 50: 921–927, 2001.[Abstract/Free Full Text]
  85. Musi N, Hayashi T, Fujii N, Hirshman MF, Witters LA, and Goodyear LJ. AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle. Am J Physiol Endocrinol Metab 280: E677–E684, 2001.[Abstract/Free Full Text]
  86. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, and Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51: 2074–2081, 2002.[Abstract/Free Full Text]
  87. Patel N, Khayat ZA, Ruderman NB, and Klip A. Dissociation of 5' AMP-activated protein kinase activation and glucose uptake stimulation by mitochondrial uncoupling and hyperosmolar stress: differential sensitivities to intracellular Ca(2+) and protein kinase C inhibition. Biochem Biophys Res Commun 285: 1066–1070, 2001.[CrossRef][Web of Science][Medline]
  88. Pelletier A, Joly E, Prentki M, and Coderre L. Adenosine 5'-monophosphate-activated protein kinase and p38 mitogen-activated protein kinase participate in the stimulation of glucose uptake by dinitrophenol in adult cardiomyocytes. Endocrinology 146: 2285–2294, 2005.[Abstract/Free Full Text]
  89. Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, Fujii N, Goodyear LJ, Gotfredsen CF, Brand CL, and Lund S. Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 54: 928–934, 2005.[Abstract/Free Full Text]
  90. Polekhina G, Gupta A, Michell BJ, Van Denderen B, Murthy S, Feil SC, Jennings IG, Campbell DJ, Witters LA, Parker MW, Kemp BE, and Stapleton D. AMPK beta subunit targets metabolic stress sensing to glycogen. Curr Biol 13: 867–871, 2003.[CrossRef][Web of Science][Medline]
  91. Pozuelo RM, Geraghty KM, Wong BH, Wood NT, Campbell DG, Morrice N, and MacKintosh C. 14-33-Affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. Biochem J 379: 395–408, 2004.[CrossRef][Web of Science][Medline]
  92. Qiao L, Zhande R, Jetton TL, Zhou G, and Sun XJ. In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents. J Biol Chem 277: 26530–26539, 2002.[Abstract/Free Full Text]
  93. Rasmussen BB, Hancock CR, and Winder WW. Postexercise recovery of skeletal muscle malonyl-CoA, acetyl-CoA carboxylase, and AMP-activated protein kinase. J Appl Physiol 85: 1629–1634, 1998.[Abstract/Free Full Text]
  94. Rasmussen BB and Winder WW. Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase. J Appl Physiol 83: 1104–1109, 1997.[Abstract/Free Full Text]
  95. Ribe D, Yang J, Patel S, Koumanov F, Cushman SW, and Holman GD. Endofacial competitive inhibition of glucose transporter-4 intrinsic activity by the mitogen-activated protein kinase inhibitor SB203580. Endocrinology 146: 1713–1717, 2005.[Abstract/Free Full Text]
  96. Russell RR III, Bergeron R, Shulman GI, and Young LH. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol Heart Circ Physiol 277: H643–H649, 1999.[Abstract/Free Full Text]
  97. Russell RR III, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, and Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114: 495–503, 2004.[CrossRef][Web of Science][Medline]
  98. Russell RR III, Yin R, Caplan MJ, Hu X, Ren J, Shulman GI, Sinusas AJ, and Young LH. Additive effects of hyperinsulinemia and ischemia on myocardial GLUT1 and GLUT4 translocation in vivo. Circulation 98: 2180–2186, 1998.[Abstract/Free Full Text]
  99. Ryder JW, Long YC, Nilsson E, Mahlapuu M, and Zierath JR. Effects of calcineurin activation on insulin-, AICAR- and contraction-induced glucose transport in skeletal muscle. J Physiol: 567: 379–386, 2005.[Abstract/Free Full Text]
  100. Sajan MP, Bandyopadhyay G, Kanoh Y, Standaert ML, Quon MJ, Reed BC, Dikic I, and Farese RV. Sorbitol activates atypical protein kinase C and GLUT4 glucose transporter translocation/glucose transport through proline-rich tyrosine kinase-2, the extracellular signal-regulated kinase pathway and phospholipase D. Biochem J 362: 665–674, 2002.[CrossRef][Web of Science][Medline]
  101. Sakamoto K, Hirshman MF, Aschenbach WG, and Goodyear LJ. Contraction regulation of Akt in rat skeletal muscle. J Biol Chem 277: 11910–11917, 2002.[Abstract/Free Full Text]
  102. Sakamoto K, McCarthy A, Smith D, Green KA, Grahame HD, Ashworth A, and Alessi DR. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J 24: 1810–1820, 2005.[CrossRef][Web of Science][Medline]
  103. Sakoda H, Ogihara T, Anai M, Fujishiro M, Ono H, Onishi Y, Katagiri H, Abe M, Fukushima Y, Shojima N, Inukai K, Kikuchi M, Oka Y, and Asano T. Activation of AMPK is essential for AICAR-induced glucose uptake by skeletal muscle but not adipocytes. Am J Physiol Endocrinol Metab 282: E1239–E1244, 2002.[Abstract/Free Full Text]
  104. Sambandam N and Lopaschuk GD. AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog Lipid Res 42: 238–256, 2003.[CrossRef][Web of Science][Medline]
  105. Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, and Lienhard GE. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278: 14599–14602, 2003.[Abstract/Free Full Text]
  106. Schmitz-Peiffer C and Whitehead JP. IRS-1 regulation in health and disease. IUBMB Life 55: 367–374, 2003.[Web of Science][Medline]
  107. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, and Cantley LC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 101: 3329–3335, 2004.[Abstract/Free Full Text]
  108. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, DePinho RA, Montminy M, and Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642–1646, 2005.[Abstract/Free Full Text]
  109. Sherwood DJ, Dufresne SD, Markuns JF, Cheatham B, Moller DE, Aronson D, and Goodyear LJ. Differential regulation of MAP kinase, p70 S6 kinase, and Akt by contraction and insulin in rat skeletal muscle. Am J Physiol Endocrinol Metab 276: E870–E878, 1999.[Abstract/Free Full Text]
  110. Somwar R, Kim DY, Sweeney G, Huang C, Niu W, Lador C, Ramlal T, and Klip A. GLUT4 translocation precedes the stimulation of glucose uptake by insulin in muscle cells: potential activation of GLUT4 via p38 mitogen-activated protein kinase. Biochem J 359: 639–649, 2001.[CrossRef][Web of Science][Medline]
  111. Song XM, Fiedler M, Galuska D, Ryder JW, Fernstrom M, Chibalin AV, Wallberg-Henriksson H, and Zierath JR. 5-Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45: 56–65, 2002.[CrossRef][Web of Science][Medline]
  112. Spicer J, Rayter S, Young N, Elliott R, Ashworth A, and Smith D. Regulation of the Wnt signalling component PAR1A by the Peutz-Jeghers syndrome kinase LKB1. Oncogene 22: 4752–4756, 2003.[CrossRef][Web of Science][Medline]
  113. Stapleton D, Gao G, Michell BJ, Widmer J, Mitchelhill K, Teh T, House CM, Witters LA, and Kemp BE. Mammalian 5'-AMP-activated protein kinase non-catalytic subunits are homologs of proteins that interact with yeast Snf1 protein kinase. J Biol Chem 269: 29343–29346, 1994.[Abstract/Free Full Text]
  114. Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, and Kemp BE. Mammalian AMP-activated protein kinase subfamily. J Biol Chem 271: 611–614, 1996.[Abstract/Free Full Text]
  115. Stein SC, Woods A, Jones NA, Davison MD, and Carling D. The regulation of AMP-activated protein kinase by phosphorylation. Biochem J 345: 437–443, 2000.[CrossRef][Web of Science][Medline]
  116. Thornton C, Snowden MA, and Carling D. Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle. J Biol Chem 273: 12443–12450, 1998.[Abstract/Free Full Text]
  117. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, and Ruderman NB. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 99: 16309–16313, 2002.[Abstract/Free Full Text]
  118. Tong H, Chen W, London RE, Murphy E, and Steenbergen C. Preconditioning enhanced glucose uptake is mediated by p38 MAP kinase not by phosphatidylinositol 3-kinase. J Biol Chem 275: 11981–11986, 2000.[Abstract/Free Full Text]
  119. Vavvas D, Apazidis A, Saha AK, Gamble J, Patel A, Kemp BE, Witters LA, and Ruderman NB. Contraction-induced changes in acetyl-CoA carboxylase and 5'-AMP-activated kinase in skeletal muscle. J Biol Chem 272: 13255–13261, 1997.[Abstract/Free Full Text]
  120. Widegren U, Jiang XJ, Krook A, Chibalin AV, Bjornholm M, Tally M, Roth RA, Henriksson J, Wallberg-Henriksson H, and Zierath JR. Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle. FASEB J 12: 1379–1389, 1998.[Abstract/Free Full Text]
  121. Witters LA. The blooming of the French lilac. J Clin Invest 108: 1105–1107, 2001.[CrossRef][Web of Science][Medline]
  122. Wojtaszewski JF, Higaki Y, Hirshman MF, Michael MD, Dufresne SD, Kahn CR, and Goodyear LJ. Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. J Clin Invest 104: 1257–1264, 1999.[Web of Science][Medline]
  123. Wojtaszewski JF, Lynge J, Jakobsen AB, Goodyear LJ, and Richter EA. Differential regulation of MAP kinase by contraction and insulin in skeletal muscle: metabolic implications. Am J Physiol Endocrinol Metab 277: E724–E732, 1999.[Abstract/Free Full Text]
  124. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, and Carling D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab 2: 21–33, 2005.[CrossRef][Web of Science][Medline]
  125. Woods A, Salt I, Scott J, Hardie DG, and Carling D. The alpha1 and alpha2 isoforms of the AMP-activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro. FEBS Lett 397: 347–351, 1996.[CrossRef][Web of Science][Medline]
  126. Wright DC, Geiger PC, Han DH, and Holloszy JO. Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport? Am J Physiol Endocrinol Metab 290: E123–E128, 2006.[Abstract/Free Full Text]
  127. Xi X, Han J, and Zhang JZ. Stimulation of glucose transport by AMP-activated protein kinase (AMPK) via activation of p38 mitogen-activated protein kinase (MAPK). J Biol Chem 276: 41029–41034, 2001.[Abstract/Free Full Text]
  128. Xing Y, Musi N, Fujii N, Zou L, Luptak I, Hirshman MF, Goodyear LJ, and Tian R. Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant-negative alpha2 subunit of AMP-activated protein kinase. J Biol Chem 278: 28372–28377, 2003.[Abstract/Free Full Text]
  129. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, and Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7: 941–946, 2001.[CrossRef][Web of Science][Medline]
  130. Yonemitsu S, Nishimura H, Shintani M, Inoue R, Yamamoto Y, Masuzaki H, Ogawa Y, Hosoda K, Inoue G, Hayashi T, and Nakao K. Troglitazone induces GLUT4 translocation in L6 myotubes. Diabetes 50: 1093–1101, 2001.[Abstract/Free Full Text]
  131. Young ME, Radda GK, and Leighton B. Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR—an activator of AMP-activated protein kinase. FEBS Lett 382: 43–47, 1996.[CrossRef][Web of Science][Medline]
  132. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, and Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108: 1167–1174, 2001.[CrossRef][Web of Science][Medline]



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