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Skeletal Muscle Pathways of Contraction-Enhanced Glucose Uptake

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Muscle contraction acutely increases glucose transport in both healthy and type 2 diabetic individuals. Since glucose uptake during muscle contraction has been observed in the absence of insulin, the existence of an insulin-independent pathway has been suggested to explain this phenomenon. However, the exact mechanism behind the translocation of GLUT4 vesicles through the sarcolemma during muscle contraction is still unknown. Some substances, such as AMPK and calcium activated proteins, have been suggested as potential mediators but the exact mechanisms of their involvement remain to be elucidated. A hypothetical convergence point between the in-

Introduction
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accepted after revision January 21, 2008

Bibliography DOI 10.1055/s-2008-1038404 Published online April 9, 2008 Int J Sports Med 2008; 29: 785 794 Georg Thieme Verlag KG Stuttgart New York ISSN 0172-4622 Correspondence Prof. Jose Alberto Duarte University of Porto CIAFEL, Faculty of Sports Rua Dr. Plcido Costa, 91 4200-450 Porto Portugal Fax: + 35 12 25 50 06 89 jarduarte@fade.up.pt

The prevalence of diabetes has progressively increased during the last few decades; epidemiologic data suggest that at least 171 million people worldwide suffered from diabetes in 2000. It is expected that this number will reach 366 million in 2030 [119]. One main reason for this increasing prevalence is the staggering increase in obesity rates. Obesity is considered an important contributor to the pathogenesis of diabetes mellitus type 2 (DMT2) which represents 90 95% of all diabetic cases. Together with obesity (particularly the accumulation of visceral fat), factors such as physical inactivity and stress associated with age and genetic influences also appear to contribute to the epidemic character of DMT2 [2, 74, 77]. All these factors will favor the development of an impaired glucose tolerance, which may result from pancreatic b cell dysfunction and/or from the increase of insulin resistance in target tissues, such as skeletal muscle and adipose tissue [90].

The resulting chronic hyperglycemia, which is the main characteristic of diabetes mellitus, may negatively influence the structure and function of many organ systems, particularly the cardiovascular, the nervous, and the renal system [90]. The state of insulin resistance, which is the initial malfunction for the development of DMT2, is also linked with atherosclerosis, hyperlipidemia, and hypertension. These patients consequently have a higher risk of myocardial infarction, of cerebral and peripheral arterial diseases, and of limb amputation [9,120]. The therapeutic approaches towards DMT2 and its secondary complications include the daily control of hyperglycemia and the improvement of insulin sensitivity [77]. Their goal is an increased glucose uptake in skeletal muscle, which accounts for ~ 80 % of glucose disposal under insulin-stimulated conditions in healthy subjects [99]. A considerable amount of research has revealed that an acute bout of physical exercise enhances skeletal muscle glucose uptake and that regular physical activity improves the ability of insulin to stimulate the glucose transporters at

Santos JM et al. Skeletal Muscle Pathways Int J Sports Med 2008; 29: 785 794

This is a copy of the authors personal reprint

Key words " insulin l " diabetes mellitus l " GLUT4 l " AS160 l " aPKC l

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J. M. Santos 1, S. B. Ribeiro 1, A. R. Gaya 1, H.-J. Appell 2, J. A. Duarte 1
1 2

CIAFEL, Faculty of Sports, University of Porto, Portugal Department of Physiology & Anatomy, German Sport University, Cologne, Germany

Abstract
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sulin cascade and the potential pathways triggered by muscle contraction has been suggested. Therefore, the earliest concept that two different routes exist in skeletal muscle has been progressively modified to the notion that glucose uptake is induced by muscle contraction via components of the insulin pathway. With further consideration, increased glucose uptake and enhanced insulin sensitivity observed during/after exercise might be explained by a metabolic- and calcium-dependent activation of several intermediate molecules of the insulin cascade. This paper aimed to review the literature in order to examine in detail these concepts behind muscle contraction-induced glucose uptake.

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The Insulin Dependent Cascade

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Glucose Transport in Skeletal Muscle

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Glucose is carried across the cell membrane by a family of specialized transporter proteins called glucose transporters (GLUT) [120]. Skeletal muscle contains different isoforms of GLUT, of which GLUT4 is the most important [1]. These proteins are mainly located in the membrane of intracellular vesicles, which are situated in the perinuclear compartment during the quiescent state. The quick cellular translocation of these vesicles to the sarcolemma, and consequently the redistribution of GLUT4 " Fig. 1), is stimulated by a through the plasma membrane (l complex intracellular cascade [59, 64,101]. Insulin and muscle contractions are the most important stimuli for GLUT4 mobilization through the plasma membrane. This effect is trigged by muscle contraction and seems to provide a higher rate of glucose transport in cells, which only contain GLUT4 [40]. Nevertheless, apart from insulin and contraction, other factors like hypoxia [78], pharmacologic agents [133], and K+ depolarization [110,118] may also increase the amount of surface GLUT4, and consequently of glucose uptake.

In skeletal muscle fibers, insulin triggers the dependent cascade by binding to insulin receptors (IR) at the cell membrane " Fig. 2). The IR is a tetrameric protein with two a- and two b(l subunits functioning as allosteric enzymes, with the a-subunit inhibiting the tyrosine kinase activity of the b-subunit. Insulin binding to the a-subunit activates the kinase activity in the bsubunit followed by the transphosphorylation of the receptor [3,16, 88,101]. The activated IR phosphorylates tyrosine residues of the insulin receptor substrate family (IRS 1 to 4) to initiate the " Fig. 2). Upon so called classical insulin cascade [15, 36,101] (l tyrosine phosphorylation, IRS proteins interact with the p85 regulatory subunit of phosphatidylinositol (PI)-3-kinase (PI3K), which activates the p110 catalytic subunit of this enzyme, with the membrane phospholipids as the main target [16, 88]. This key component of the classical insulin cascade generates the lipid product phosphatidylinositol 3,4,5-trisphosphate (PIP3), which regulates the activity of downstream proteins, especially of the 3-phosphoinositide-dependent protein kinase (PDK). The PDK activates two protein kinases that have been postulated to be essential key factors for insulin-stimulated glucose transport:

Santos JM et al. Skeletal Muscle Pathways Int J Sports Med 2008; 29: 785 794

This is a copy of the authors personal reprint

rest [45, 95,111]. This increased skeletal muscle glucose transport and insulin sensitivity induced by exercise may be a key mechanism to explain the strong epidemiological evidence that the practice of regular exercise prevents or delays the onset of DMT2 [46, 59,102]. However, the intracellular mechanism mediating this phenomenon is not yet well understood. For instance, it is not clear whether the increase in muscle glucose uptake in response to exercise in vivo requires the involvement of molecular components of the insulin cascade. In fact, several research groups have suggested an insulin-independent pathway to enhance glucose uptake [26,113]. On the other hand, this insulinlike effect may also be explained by molecular changes in muscle fibers during contraction, with an enhancement of several metabolic substances that are, simultaneously, key elements in the insulin-signalling cascade. Therefore, those substances triggered by insulin may also be activated during muscle contraction even in the absence of this hormone. The objective of this review is to examine candidate substances related to the process of signalling of the glucose transport during muscle contraction, and to simultaneously analyze, whether such substances act in an insulin-dependent or independent fashion.

Fig. 1 Insulin and muscle contraction stimulate the redistribution of isoform 4 of glucose transporter (GLUT4) from the membrane of cytoplasmic vesicles through the sarcolemma, allowing the muscular uptake of glucose.

In the absence of insulin, muscle contraction in vitro increases the glucose transport to a degree similar to that described during exercise in vivo [13,19, 26, 35, 83,113]. Additionally, many studies have reported a synergistic effect of contraction-dependent and of insulin-induced glucose uptake trigged by multiple signalling cascades [13, 25, 26, 46, 96,113]. It is, however, currently unknown, whether the intracellular mechanism generated by exercise in vivo is completely independent of the insulin-induced mechanism for glucose uptake. During a marathon run, for instance, the intracellular mechanism trigged by exercise has been shown to be effective enough to maintain glucose transport in diabetes type 1 subjects [14]. However, previous data suggest a reduced potential of exercise to increase glucose transport in type 1 diabetic subjects compared to normal individuals [91]. It is therefore more reasonable to assume that exercise triggers an additional effect on the insulin cascade for enhanced glucose uptake probably through one or more components of the insulin cascade. For a comprehensive discussion of the effect of contraction mechanisms on the insulin cascade it is necessary to briefly discuss the isolated insulin effect on glucose transport in muscle.

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protein kinase B (PKB or AKT) [108,114] and atypical protein kinase C-z/l/i (aPKC) [5, 6, 62, 68]. AKT is a signalling protein for several insulin actions, including the activation of glycogen synthesis, protein synthesis, and GLUT4 translocation, thereby increasing glucose transport [11]. The AKT substrate, with 160KD (AS160) [11, 28, 61], links the in" Fig. 2), and the activsulin signal with GLUT4 trafficking [27] (l ity of this substrate is diminished in DMT2 patients [63]. The aPKC is also considered an important factor for the translocation of GLUT4 vesicles, acting in parallel with AKT and AS160 [39, 74, 101]. The aPKC appears to activate motor proteins, such as kinesins, which contribute to vesicle migration to the sarcolemma [55]. The binding between IR and insulin also stimulates the mitogen activated protein kinases (MAPK), which include the extracellular signal-regulated kinases (ERK) and p38 MAPK [34]. This event results in the stimulation of different transcription factors, which initiates the program that leads to cell proliferation or differentiation [101]. Such transcriptional-dependent adaptations also should have the potential to indirectly modify glucose up" Fig. 2). take (l

Mechanisms of Glucose Transport Induced by Muscle Contraction

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Despite the endocrine [8, 67,116] and paracrine [49, 66] influence on glucose uptake in skeletal muscle during exercise, the intracellular mechanism triggered by muscle contraction appears to be mainly responsible for acting directly on the enrichment of surface GLUT4 levels. Two main intracellular mechanisms have been suggested to explain the contraction-dependent glucose transport. The first one is based on the assumption that glucose transport might be related to the metabolic strain imposed on skeletal muscle during exercise [31, 71], and the second one explains an enhanced glucose uptake due to the depolarization of the sarcolemma and of T-tubule membranes via calcium-mediated second messengers [127].

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Metabolism-dependent mechanisms

Fig. 2 Signal transduction in insulin action: The autophosphorylation of the insulin receptor (IR) catalyzes the phosphorylation of IRS 1/2 (insulin receptor substrates) that activates PI3K (phosphatidylinositol 3-kinase), which interacts with AKT/ AS160 (protein kinase B/AKT substrate of 160 KD) and aPKC (atypical protein kinase C). The IR activation also triggers MAPK (mitogen-activated protein kinase) pathways. These pathways act in regulating GLUT4 (glucose transporter isoform 4) vesicle trafficking.

This is a copy of the authors personal reprint

An important step in understanding the molecular events of how muscle contraction affects glucose transport was the identification of adenosine-5-monophosphate as an activator of protein kinase, which resulted in the name AMPK to describe this link [42]. In the past decade, much research has been conducted associating the role of this enzyme in contraction-stimulated glucose transport in vivo [79, 93], in situ [52] and in vitro [44]. AMPK is a heterotrimeric protein consisting in one a-subunit and two non-catalytic subunits b and g. Two isoforms of the a-subunit have been identified, a1 and a2, which are differently distributed among tissues, with the highest expression of a2 in skeletal muscle [65,106]. In addition, a pharmacologic activator of AMPK, namely 5-aminoimidazole-4-carboxamide-riboside (AICAR), activates the glucose transport in resting rat muscle [30, 47, 71, 80]. This drug mimics the effect of AMP on AMPK without alterations of ATP stores or using earlier steps of the insulin cascade [75, 80, 82]. Apart from AICAR, also hypoxia and metformin, an oral antidiabetic [21, 53], seem to act on glucose uptake through AMPK " Fig. 3). [81,133] (l In ob/ob rats (obese and insulin resistant), a subcutaneous administration of AICAR has been shown to be associated with a decrease in glucose intolerance [73]. The same phenomenon has been reported with the use of AICAR in different models of insulin resistance (KKAy-CETP mice and Zucker rats) [12, 29]. In agreement with these animal studies, Musi et al. [81] observed a correlation between the increase in AMPK activity and glucose transport in DMT2 patients after exercise [79]. An augmentation of AMPK expression has also been reported after metformin treatment [76]. These studies suggest that insulin resistance does not inhibit the effect of AMPK on glucose transport. Recent findings convincingly propose the tumor suppressor kinase LKB1 (serine/threonine kinase 11) as the major upstream regulator of AMPK in skeletal muscle. The development of a muscle-specific LKB1 knockout mouse by Sakamoto et al. [100] has substantiated the role played by this enzyme in AMPK activation. These authors have demonstrated that the glucose uptake and AMPK a2 activation induced by AICAR, by phenformin (a metformin analogue), and by muscle contraction were diminished in LKB1 deficient extensor digitorum longus (EDL) muscle

Santos JM et al. Skeletal Muscle Pathways Int J Sports Med 2008; 29: 785 794

This is a copy of the authors personal reprint

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[100]. In addition, different methodologies have also emphasized the role of LKB1 as a dependent molecule for AMPK-induced glucose transport [105,109]. Therefore, LKB1 seems to catalyze the phosphorylation of the AMPK a-subunit, turning it into " Fig. 3). Thus, convincing findings active AMPK complexes [41] (l support the role of LKB1 in AMPK activation, but it is still unknown whether LKB1 is the only kinase responsible for AMPK activation. In spite of the well-known role of AMPK in contraction-induced glucose uptake, the association between this protein and glucose uptake does not appear to be simply dose-dependent. It should thus be suggested that a component of the insulin cascade may be a downstream regulator of the AMPK pathway for increasing glucose uptake. The majority of investigations have failed to demonstrate an association between earlier components in the insulin cascade such as IR, IRS, and PI3K and the mechanisms of contractionstimulated glucose transport. In vivo studies have demonstrated that PI3K expression is decreased some minutes after exercise [86,122]. It has further been observed in isolated muscle that wortmannin (a PI3K inhibitor) does not influence contraction and AICAR-stimulated glucose transport but, on the other hand, impairs the insulin action [35,104,115,123]. This suggests that muscle contraction through AMPK affects a step beyond PI3K action. Consistent findings have established a convincing connection between AS160 and AMPK: Contraction and AICAR, as well as insulin, stimulate AS160 phosphorylation in isolated epitrochlearis muscle [11]. Additionally, Kramer et al. [69] have shown a synergic effect of contractile activity, of AICAR and of insulin on AS160 phosphorylation, without wortmannin impairment [69]. The combination of AICAR and contraction in AMPK (/) transgenic mice impairs AS160 phosphorylation, which also is indicative for the necessity of AMPK for AS160 activation [112]. Supporting studies using an in vitro methodology have also observed an enhancement of AS160 activation in human vastus lateralis muscle after endurance training [24]. Such approaches strongly propose AS160 to be an important AMPK downstream regulator and also a signalling key point in the integration of insulin- and contraction-stimulated glucose uptake. As stated above, the aPKC is activated by lipid binding (e.g., to phosphatidylinositol trisphosphate or phosphatidic acid). In regard to contraction-induced glucose uptake, studies have consistently shown that the aPKC activity is higher in contracting

Fig. 3 Phosphorylation of adenosine monophosphate-activated protein kinase (AMPK-p) dependent of LKB1 (serine/threonine kinase 11), with AMPK upstream and downstream regulators (ATP adenosine 5-triphosphate; ADP adenosine diphosphate; AMP adenosine monophosphate). Possible interaction between aPKC (atypical protein kinase C) and AS160 (160 KD substrate of protein kinase B) on GLUT4 (glucose transporter isoform 4) translocation.

muscle [7, 85, 92, 98], but the second messenger required to activate this protein is still unknown. In contrast to AS160, little research has been conducted with the aim to analyze the association between AMPK and aPKC. Chen et al. [17] suggested that AICAR and muscle contraction activate aPKC in the absence of PI3K. Instead, aPKC activity induced by AMPK appears to depend on the praline-rich tyrosine kinase-2, MAPK-ERK, which activates phospholipase D (PLD) to generate phosphatidic acid (PA) that itself directly activates aPKC [17]. In agreement with this concept, recent data has demonstrated, in skeletal muscle of DMT2 subjects, that metformin therapy also affects aPKC, suggesting a common effect of this protein and of AMPK for glucose uptake in skeletal muscle [76]. Furthermore, like AS160 assumably does, aPKC may also represent a point of convergence in insulin and contraction pathways, although additional research is required to address this hypothesis adequately. A prior activation of AMPK also seems to play a key role in the activity of the p38MAPK protein, which is a component of the insulin pathway [97,117]. Indeed, two pioneer studies [103,129] using a p38 inhibitor (SB203580) in rat skeletal muscle [107], suggested that p38 might partially regulate contraction-stimulated glucose uptake. Additionally, an insulin impairment to activate p38 has been described in insulin-resistant rats (ob/ob) without affecting the contraction-induced activation of this protein in soleus muscle and EDL in vitro [73]. In the same sense, p38 activity has been significantly increased in isolated mouse muscle in response to physiological bouts of isometric contractions, suggesting that changes in ATP-free energy homeostasis could activate this kinase [22]. It has furthermore been demonstrated that AICAR has the same effect on p38MAPK like muscle contraction [72]. In addition, an increase of p38 activity after metformin administration has also been observed in insulin resistant muscle fibers [70]. These data suggest that this protein may be a key molecule that mediates AMPK signalling to enhance glucose transport. However, it is important to keep in mind that the idea about the probably acute contribution of p38 on muscle glucose uptake induced by both, insulin or muscle contraction, is not unanimously accepted in the literature. In fact, it is nowadays assumed that SB203580, beyond its role as a p38 antagonist, also acts as a competitive inhibitor of glucose transport through a direct interaction with GLUT [94]. This should compromise the conclusions of previous studies supporting an acute role of p38 on glucose uptake [72,110]. Furthermore, the overexpression of a dominant negative p38 mu-

This is a copy of the authors personal reprint

Santos JM et al. Skeletal Muscle Pathways Int J Sports Med 2008; 29: 785 794

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Fig. 4 Calcium activated proteins (PKC protein kinase C; CaMK Ca/ calmodulin-dependent protein kinase; CaMKK Ca/calmodulin-dependent protein kinase kinase) act on glucose transport parallel and/or connected to the AMP-activated protein kinase (AMPK) pathway (ATP adenosine 5-triphosphate; AMP adenosine monophosphate; LKB1 serine/threonine kinase 11).

Calcium dependent mechanisms

The increase in cytoplasmic calcium concentration due to membrane depolarization also seems to activate several substances involved in the translocation of GLUT4 vesicles. Several studies have shown that glucose transport is increased in mammalian muscle, when cytoplasmic calcium concentrations are elevated, independent of insulin or of the energy status [18, 48, 56,130]. Two proteins have been identified in this context: the Ca/calmodulin-dependent protein kinase (CaMK) and the protein kinase C (PKC) [87,126,128]. In an attempt to demonstrate the mechanisms dependance simply on calcium in the absence of muscle contraction, studies have used pharmacological calcium activators and inhibitors such as caffeine and KN-62, respectively [10, 128]. CaMK seems to integrate the pathway by which calcium stimulates the translocation of GLUT4 vesicles [33, 89,124]. Wright et al. [128] in vitro analyzed the interaction between muscle contraction, AICAR, and caffeine, and described a synergistic effect of these factors on glucose transport. Additionally, the combination of these two drugs increased glucose transport rates to the same degree as did muscle contraction [128]. In concordance, the role of CaMK has been suggested to parallel AMPK independent mechanisms [20,127]. Based on experiments with steady state exercise resulting in a modest activation of AMPK, Ojuka [87] proposed that the primary adaptive stimulus for GLUT4 vesicles translocation may be linked to the rise in cytoplasmic calcium. On the other hand, intensive exercise results in a more

powerful stimulus for GLUT4 expression and translocation by " Fig. 4) [87,132]. activating both, CaMK and AMPK (l In contrast to the idea of an AMPK independent pathway, several recent studies have shown that calcium may activate AMPK by CaMK kinase (CaMKK) [43, 58,125]. It has been demonstrated that the inhibition of Ca/calmodulin-regulated protein kinases potently inhibits AMPK phosphorylation, independent of the influence of LKB1 in muscle at rest and during contraction [58]. The same group has demonstrated in isolated soleus muscle that a caffeine-induced glucose uptake through a Ca+2 pathway also depends on the activation of AMPK a1 [57]. These data, supporting the concept of CaMKK as an upstream regulator of AMPK, suggest that calcium and AMPK signals for glucose uptake are at least partially connected rather than exclusively parallel. This assumption, however, has been partially contradicted by Witczak et al. [121] using an innovative methodology with electroporated vectors containing constitutively active CaMKK. Thus, the resulting overexpression of CaMKK increased the in vivo glucose transport in wild strain and in AMPK deficient animals, demonstrating that CaMKK-stimulated glucose uptake may act independently of AMPK through one or more unknown components [121]. The apparent contradiction between the studies of Witczak et al. [121] and of Jensen et al. [57, 58] may only be explained on the basis of the different methodologies used. Nevertheless, it is important to keep in mind that, although the ex vivo muscle contraction model remains a valuable tool to study the components of contraction signalling, it is unknown whether such findings entirely mimic the conditions and expectable results of in vivo studies.

Santos JM et al. Skeletal Muscle Pathways Int J Sports Med 2008; 29: 785 794

This is a copy of the authors personal reprint

tant in skeletal muscle does not seem to affect glucose transport [4], and p38 overexpression is correlated with a decreased GLUT4 expression in hindlimb muscles after stimulation [50]. In opposition to the possible link between AMPK and p38, a recently published study [51] has clearly dissociated the signalling pathways of these two proteins. Transgenic mice (inactive vs. active forms of AMPK subunits) have been submitted to different protocols of AICAR administration and/or muscle contraction, and the authors [51] came to the conclusion that p38 can be activated by muscle contraction, but AMPK is not an essential upstream regulator of this MAPK signalling. As a result of these findings, the association between p38 and AMPK on contraction-induced glucose uptake appears less likely; however, the role of p38 as a potential convergence point for glucose uptake induced either by insulin or muscle contraction is still a controversial matter. A valuable approach to elucidate the molecular mechanisms of contraction-induced glucose transport in vivo has originated from studies on transgenic mice [78] with an inactive (dominant-negative) AMPK protein, thereby expressing an inhibitory effect on the AMPK a2-subunit. With this model, a reduction of only 30 % in the glucose transport in response to contraction by electrical stimulation has been observed [78]. Additionally, in knockout mice for a1 or a2 AMPK isoforms, the contraction-induced glucose transport in isolated muscle is not altered despite the inability of AICAR to stimulate glucose transport in a2 knockout mice [60]. These important findings suggest that a small activation of AMPK may be sufficient to induce normal glucose uptake and, moreover, it may only be a part of the mechanisms leading to contraction-stimulated glucose transport. It should therefore be feasible to imagine the existence of parallel or compensatory pathways acting independently of this enzyme, which may be triggered by a calcium dependent mechanism " Fig. 4) [23, 32, 80]. (l

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To our best knowledge, the association between the earlier insulin cascade components and calcium-activated proteins has received little attention in the literature. It has been observed in vitro that KN-62, a specific Ca/calmodulin-dependent protein kinase inhibitor, induces a decrease in glucose transport triggered by hypoxia and insulin, without parallel alterations in the expression or activity of PI3K and AKT [10]. These data suggest that the association between CaMK and GLUT4 may not be explained by an interaction with AKT or PI3K. It is, however, important to highlight that CaMK might interact within a cascade step below which these substances start to act. Since its identification, AS160 has been assumed to be a candidate for the convergence point between CaMK and insulin cascade components. Further findings have, however, rejected this hypothesis. In one of the first studies to test this hypothesis, it was demonstrated that Ca/calmodulin is not a downstream regulator for AS160 in adipocytes [61]. In agreement with that, an increase of AS160 phosphorylation in skeletal muscle has also not been observed with CaMKK overexpression, suggesting that CaMKK triggers metabolic reactions, such as glucose uptake, independent of AS160 [121]. Additional research is certainly required to identify the link between Ca/calmodulin-regulated protein kinases and components of the insulin cascade. In addition to atypical PKC, the other nine isoforms, i.e., conventional PKC (a, b, g) and new PCKs (d, e, h, u, , q), have also been associated with the translocation of GLUT4 vesicles [84]. Although PCKq negatively affects GLUT4 translocation [37, 38, 93,131], the other new PCK isoforms have indeed been associated with the promotion of glucose uptake. Using a PKC inhibitor (Calphostin C), a decrease of glucose transport has been observed after muscle contraction, suggesting a major role of conventional and novel (c/n) PKCs in glucose uptake. However, this result should be interpreted with caution, because Calphostin C unspecifically inhibits all PKC isoforms [54]. With the aim to find a possible candidate for PKC downstream regulation, Thong et al. [110] have demonstrated that (n/c) PKC activation due to K+ depolarization increases AS160 phosphorylation, which contributes to the regulation of the GLUT4 traffic in cultured L6 cells

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Concluding Remarks
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Fig. 5 Proposed pathways to explain the increase of glucose transport triggered by muscle contraction (PI3K phosphatidylinositol 3-kinase; GLUT4 glucose transporter isoform 4; CaMK Ca/calmodulin-dependent protein kinase; CaMKK-Ca/calmodulin-dependent protein kinase kinase; AMPK adenosine monophosphate-activated protein kinase; ERK extracellular signal-regulated kinase; AS160 160 KD substrate of protein kinase B; n/cPKC novel and conventional protein kinase C; IRS 1/2 insulin receptor substrate; ATP adenosine 5-triphosphate; ADP adenosine diphosphate; AMP adenosine monophosphate).

This is a copy of the authors personal reprint

[110]. Thus, there is in fact a possibility that PKC stimulated by muscle contraction acts on glucose transport through AS160. It will therefore be important to clarify in further studies, whether the calcium-induced glucose transport is related to any components of the insulin cascade.

According to the revised literature, the glucose uptake induced by muscle contraction might depend on components of the insulin cascade. The same pathway leading to insulin dependent glucose uptake also seems to be triggered by other stimuli such as muscle contraction. Thus, the insulin action is facilitated by an enhancement of several intermediate components within that " Fig. 5). Research over the past decades has established route (l a convincing connection between AMPK, calcium stimulated proteins, and glucose transport activated by muscular contraction. However, the isolated effect of these substances on GLUT4 signalling is still unknown. The recent amount of experimental data consistently suggests the interaction between AMPK and AS160, which could explain the absence of an impaired exercise-induced glucose uptake in subjects with insulin resistance. Future research should focus its attention on the role of aPKC as a potential point of convergence among the mechanisms of muscle contraction and insulin signalling. Moreover, the exact link between CaMK and (n/c) PKC to GLUT4 still waits to be elucidated.

Acknowledgements
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The first author acknowledges FCT for her PhD grant (SFRH/BD/ 15844/2005).

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