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exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface.
اكسون 1 يحتوي على تسلسل إشارة إلى أن localises المستقبلة إلى الشبكة الإندوبلازمية لنقلها إلى سطح الخلية.
besity-associated insulin resistance, with consideration of their role in an integrated physiological framework. finally, increasing recognition of the integrated nature of metabolic physiology has sparked investigation of mecha- nisms of insulin resistance that involve crosstalk between insulin-responsive tissues. inflammatory signaling has emerged as a key paracrine/endocrine driver of insulin re- sistance; for example, activated adipose tissue macrophages have been strongly linked to metabolic dysfunction (331, 446, 594). the mechanisms by which inflammation pro- motes insulin resistance are under intense investigation. ad- ditionally, the last two decades have yielded the identifica- tion of dozens of endogenous circulating bioactive peptide hormones with putative effects on insulin sensitivity and have also revealed that circulating branched-chain amino acids may be a predictive biomarker of insulin resistance (577). rather than providing a catalog entry for each of these circulating factors, section vii focuses on those with established mechanistic links to cellular mechanisms of in- sulin action and resistance: retinol binding protein-4 (rbp4), adiponectin, fetuin-a, and fibroblast growth factor 21 (fgf21). in offering this review, we hope that our comprehensive treatment of both insulin action and inaction presents a unified framework for understanding the physiology of this critically important signaling axis in health and disease and that it provides context for future discoveries that will fa- cilitate the prevention and treatment of t2d. we attempt to develop such a unified summary in section viii. ii. direct insulin action a. proximal insulin signaling: the insulin receptor and its direct substrates insulin exerts all of its known physiological effects by bind- ing to the insulin receptor (insr) on the plasma membrane of target cells (297). insr is a heterotetrameric receptor tyrosine kinase formed from two extracellular subunits, which bind insulin, and two membrane-spanning - sub- units, each of which contains a tyrosine kinase domain (343). there are two insr isoforms, a and b, but the b isoform is much more specific for insulin; is the primary isoform expressed in differentiated liver, muscle, and wat; and is thus thought to mediate most metabolic effects of insulin (44). the a isoform, differentiated by the splicing out of exon 11, is expressed highly in fetal development, when its high affinity for igf-2 is particularly useful (44). insr has two insulin binding sites but exhibits negative cooperativity, meaning that insulin binding at one site de- creases insulin binding affinity in the other site (186). thus available evidence indicates that at physiological concentra- tions, one insulin molecule binds and activates one insr (186, 343). the induced conformational change in the - subunit relieves cis-autoinhibition in the kinase activation loop and permits trans-autophosphorylation of the activa- tion loop tyrosines tyr1162, tyr1158, and tyr1163, in that order (344, 889). the - subunit, thus activated by tris- phosphorylation, undergoes further tyrosine phosphoryla- tion on residues including tyr972 in the juxtamembrane region; these additional events are important for recruit- ment of insr substrates (941). signaling events down- stream of insr activation can be grossly functionally di- vided into mitogenic and metabolic signals. the mitogenic signals primarily involve activation of the mitogen-acti- vated protein kinase (mapk) pathway common to many receptor tyrosine kinases; this signaling axis has been re- viewed extensively (41, 400, 535, 616). the insulin concen- trations necessary to stimulate metabolic responses are lower than those needed for mitogenic responses; this rela- tionship is reversed for the igf-1 receptor (41). this review focuses on the insr-activated pathways that regulate me- tabolism. in all cell types, activated insr initiates downstream met- abolic signaling by first recruiting phosphotyrosine-binding scaffold proteins, which in turn activate downstream effec- tors (figure 1) (826). this is in contrast to many other receptor tyrosine kinases, which phosphorylate cytoplasmic substrates directly. the recruitment of diverse phosphoty- rosine-binding proteins to insr permits early ramification of insulin signaling to activate multiple functional modules. insr can engage several phosphotyrosine-binding pro- teins. shc interacts through its phosphotyrosine-binding (ptb) domain with insr ptyr972 (343). sh2b1, sh2b2/ aps, grb10, and grb14 interact through their src homol- ogy 2 (sh2) domains with the activated, tris-phosphory- lated insr activation loop (190, 343). these substrates can serve critical regulatory functions (190, 343). for example, grb10 phosphorylation and stabilization by mtorc1, which is itself activated by insulin signaling, provides feed- back inhibition of insr activity (339). other insr sub- strates, such as grb2 and shc, are involved in the mito- genic arm of insulin signaling (41), while sh2b2/aps helps to initiate the metabolic insulin response, at least in some cell types (471). attenuation of this proximal phosphoty- rosine-based insulin signaling is carried out in part by re- ceptor internalization and dephosphorylation. one key reg- ulator of insr internalization is ceacam1, which is itself an insr substrate (568, 660). insr dephosphorylation is performed by protein tyrosine phosphatases (ptpases), es- pecially ptp1b. however, this attenuation likely occurs with a time delay, after insr internalization (808). imme- diately after activation, insr inhibits ptp1b activity by activating nad(p)h oxidase 4 (nox4). nox4-derived h2o2 in turn inhibits ptp1b activity, providing feedfor- ward amplification in the early phase of insulin signaling (515, 921).
