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skeletal muscle insulin signaling: effectors and effects skeletal muscle is an energy-consuming tissue; any energy the myocyte stores is mostly for its own later use with the exception of 3-carbon units (lactate, alanine) generated by glycolysis that are released by skeletal muscle and mostly cycled to the liver. insulin signals to skeletal muscle that glucose is abundant; accordingly, the myocyte insulin signaling cascade is specialized to promote glucose uptake and net glycogen synthesis. the absolute requirement of the myocellular insulin receptor for these processes was demonstrated by hyperinsulinemic-euglycemic clamp studies of muscle-specific insr knockout (mirko) mice, which displayed impairments in insulin-stimulated muscle glucose uptake and muscle glycogen synthesis (407). muscle-specific knockout of grb10 in mice, which results in loss of its feedback inhibition on insr as discussed previously, enhances myocellular insulin sensitivity and increases muscle size (329). although both irs1 and irs2 are expressed in skeletal muscle, the primary insr substrate in muscle appears to be irs1. irs1 knockdown, but not irs2 knockdown, causes defective insulin-stimulated glucose transport in l6 rat myotubes and human primary myotubes (87, 340, 837). additionally, isolated soleus muscles from irs2/ mice have normal dose-dependent insulin stimulation of glucose uptake (316). irs2 may be important for insulin control of lipid metabolism in the myocyte (87). both of the major isoforms of the pi3k catalytic subunit, p110 and p110, are expressed in skeletal muscle. of the five pi3k regulatory subunit splice isoforms, p85, p85, and p55 are thought to be most relevant in skeletal muscle (826), as mice with muscle-specific deletion of these isoforms have impaired (although not abolished) insulin-stimulated glucose uptake and glycogen synthesis (505). increases in membrane pip3 content cause the membrane recruitment of the ph domain-containing kinases pdk1 and akt (471). both akt1 and akt2 are present in skeletal muscle, but akt2 appears to be more important for insulin-stimulated glucose metabolism. rna interference of akt2 in primary human myotubes abrogated insulin stimulation of glucose uptake and glycogen synthesis, while akt1 knockdown had no effect on these parameters (87). in support of this paradigm, akt2/ mice are severely glucose intolerant (141), while akt1/ mice display normal glucose tolerance, although a severe growth defect complicates metabolic phenotyping in akt1/ mice (142). perhaps the best studied functional effect of the myocellular insulin signaling cascade is increased glucose transport activity. this is accomplished through highly coordinated translocation and fusion of the glucose transporter glut4, packaged in glut4 storage vesicles (gsvs), to the plasma membrane (471). current understanding of this process in muscle stands somewhat in contrast to that in adipocytes, for which pi3k-dependent and pi3k-independent pathways have been described. future research may identify insulin action and insulin resistance physiol rev • vol 98 • october 2018 • www.prv.org 2137 downloaded from journals.physiology.org/journal/physrev (041.232.128.179) on april 13, 2021. essential pi3k-independent mechanisms for insulin-stimulated muscle glucose uptake, but current evidence primarily implicates pi3k-dependent control (505, 818). unexpectedly, pik3r1/ mice displayed paradoxical increases in insulin-stimulated glucose transport, but this effect likely owed to compensation from other pi3k regulatory subunits (833). mice lacking both pik3r1 and pik3r2 in skeletal muscle (pik3r1 mko pik3r2/ mice) exhibited impaired insulin-stimulated glucose transport (505). the magnitude of this impairment in pik3r1 mko pik3r2/ mice was smaller than what would be expected if insulin-stimulated glucose transport was entirely pi3k-dependent, and pi3k activation per se may not be sufficient to cause glut4 translocation in l6 myotubes, suggesting that pi3k-independent mechanisms may be operative (352, 471, 505). however, the (incompletely specific) pi3k inhibitor wortmannin can completely abolish insulin-stimulated muscle glucose uptake (274, 818). pi3k control of glut4 translocation is mediated through parallel signaling through akt and the rho gtpase rac1 and involves the coordinated action of many proteins involved in gsv trafficking and fusion (140, 471, 818). akt phosphorylates several proteins involved in myocellular glucose uptake. the best characterized of these akt substrates are the gtpase-activating protein (gap) akt substrate of 160 kda (as160), also known as tbc1d4, and the related gap tbc1d1 (384, 727, 831). phosphorylation by akt blocks tbc1d4/tbc1d1 inactivation of small rab gtpase protein switches that control vesicle trafficking; the net effect is to promote gsv translocation (413). rab8, rab10, and rab14 have variously been implicated as targets of tbc1d4/tbc1d1 (471). tbc1d4 thr649 is a physiologically important akt substrate; mice homozygous for a thr649ala knock-in mutation have impaired insulin-stimulated myocellular glut4 translocation and are glucose intolerant (131). the physiological relevance of as160 was further confirmed by the identification of a family carrying a truncating mutation in tbc1d4 that resulted in profound insulin resistance (178). although tbc1d1 is better characterized as an amp-activated kinase (ampk) target than as an akt target (831), mice with muscle-specific tbc1d1 deletion also have impaired insulin-stimulated muscle glucose uptake (194). the relative physiological importance of tbc1d4 versus tbc1d1 for insulinstimulated gsv translocation in human muscle remains unclear and may vary by muscle fiber type (118, 540). germline deletion of both tbc1d1 and tbc1d4 in mice totally abrogates insulin-stimulated muscle glucose uptake, resulting in glucose intolerance more severe than in either tbc1d1/ or tbc1d4/ single knockout mice (118). akt also phosphorylates target proteins involved in gsv membrane targeting and fusion, but these processes are better understood in adipocytes than myocytes and thus will be discussed later. in general, akt phosphorylation of tbc1d1/tbc1d4 can be thought of as insulin “releasing the brakes” on glut4 translocation (413). the rho gtpase rac1 coordinates a second pi3k-dependent signaling mechanism for insulin-stimulated glucose uptake in skeletal muscle. rac1 signaling promotes glut4 translocation by inducing cortical actin reorganization (47, 140, 818). direct rac1 targets include the p21- associated kinase (pak); insulin promotes the gtp-bound form of rac1, which stimulates pak phosphorylation by relieving pak autoinhibition (140, 818). muscle-specific knockout of rac1 severely impairs insulin-stimulated glucose uptake despite preserved akt activation (817), and forced overexpression of constitutively active rac1 in muscle causes glut4 translocation even in the absence of insulin stimulation (858). the specific mechanisms by which rac1-mediated cortical actin reorganization promotes glut4 translocation are an area of continued investigation but may involve tethering of gsvs beneath the plasma membrane and changes in membrane tension (413). the glucose that enters the myocyte upon insulin stimulation has two major possible fates: glycolysis or glycogen synthesis. the principal pathway of insulin-stimulated glucose disposal in both healthy and type 2 diabetic human muscle is glycogen synthesis (~75%), consistent with the general teleological role of insulin as an energy storage hormone (182, 768). however, glucose oxidation also increases as increased substrate availability drives glycolytic flux; in fasting rat soleus muscle, insulin per se increases relative glucose oxidation (vpdh/vtca) from ~5 to ~60%, the remainder reflecting fatty acid oxidation (d. song, t. alves, r. perry, and g. shulman, unpublished data). although acute insulin-stimulated increases in skeletal muscle glycolytic flux and glycogen synthesis are primarily a consequence of increased glucose transport activity and subsequent allosteric regulation by glucose metabolites, insulin independently regulates both glycolysis and glycogen synthesis (152, 689, 769). insulin positively regulates the transcription of hexokinase ii, the primary skeletal muscle isoform of the first glycolytic enzyme, thus providing relatively slow, coarse control of glycolytic capacity (589). in contrast, glycogen synthesis is subject to acute regulation by insulin of both anabolic [glycogen synthase (gs)] and catabolic [glycogen phosphorylase (gp)] fluxes (158). this acute regulation occurs through both covalent modification (insulin promotes the dephosphorylation of both gs and gp) and allostery (by glucose-6-phosphate). we first consider glycogen synthase, in 1960 the first enzyme shown to be regulated by insulin (872). phosphorylation-based gs regulation by insulin occurs in part through akt phosphorylation and inactivation of glycogen synthase kinase 3 (gsk3) at ser21 and ser9 on the and isoforms, respectively, of gsk3 (157, 171, 172, 214, 813). thus inactivated, gsk3 kinase activity toward gs is diminished; de
في حين أن الكربوهيدرات، التي توفر الجلوكوز للجسم لدعم عملية التمثيل الغذائي، هي حاسمة للنظام الغذائي، تناول غير مناسب يمكن أن يؤدي إلى ارتفاع السكر في الدم، ونقص السكر في الدم، وتقلبات نسبة السكر في الدم التي تضر النتائج الصحية (الشكل 2). الشكل 2- الأرباح التي يمكن أن تتراوح بين 2 و 2 عواقب عدم توازن الجلوكوز. a. فرط السكر في الدم (ارتفاع مستوى السكر في الدم) قد تسهم في تعزيز الدهون والعضلات الأيض; بالإضافة إلى ذلك ، يفضل فرط السكر في الدم مضاعفات في حالات الأمراض الحادة بما في ذلك الجراحة والأمراض الخطيرة.