© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms
aDepartment of Biochemistry and Molecular Biology, The University of British Columbia, Copp Building, Medical Block ‘A’, 2146 Health Sciences Mall, Vancouver, B.C., Canada V6T 1Z3
bDepartment of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, B.C, Canada
* Corresponding author. Tel.: +1 (604) 822-3810; Fax: +1 (604) 822-5227; e-mail: rogerb@unixg.ubc.ca
Received 17 December 1996; accepted 24 January 1997
KEYWORDS ACC = acetyl-CoA carboxylase; AMP-PK = protein serine/threonine kinase activated by 5'-AMP; CPT-I = carnitine palmitoyltransferase-I; CREB protein = cyclic AMP-response element binding protein; ERKs = extracellular signal-regulated kinases: the MAP kinases originally identified are now known to represent a sub-set of a wider family; the original members of the family are now referred to as ‘ERKs’ (extracellular signal-regulated kinase); other sub-types of MAP kinases are JNKs (c-Jun, N-terminal kinases) and p38/RK; p125-FAK = 125-kDa focal adhesion (protein tyrosine) kinase; Grb = growth-factor-receptor bound protein; GSK-3 = glycogen synthase kinase-3; HDL = high-density lipoprotein; IRS-1(-2) = insulin receptor substrate-1(-2); HSP = heat shock protein; MAP kinase = initially named for an insulin-stimulated protein Ser/Thr kinase able to phosphorylate microtubule-associated protein-2 (MAP-2); also commonly referred to as ‘mitogen-activated protein kinase’; MAPKAP-kinase = MAP-kinase-activated protein kinase: MAPKAP-K1 is identical to p90rsk, MAPKAP-K2 is distinct and activated downstream from p38/RK; MEKs = dual-specificity MAP kinase- or ERK-kinases (able to phosphorylate the TEY motif of the MAP kinases/ERKs; MEKKs = protein kinases able to phosphorylate and activate MEKs; other mammalian protein kinases which can fulfil this function include the c-Raf family and c-Mos; PDC (PDC-P) = pyruvate dehydrogenase complex (and the inactive phosphorylated form); PDE-III = cyclic nucleotide phosphodiesterase, ‘low Km, particulate’ isoform which is inhibitable by cyclic GMP; PKA = cyclic-AMP-dependent protein kinase; PKB = protein kinase B, also identified as the proto-oncogene akt and as RAC (protein kinase Related to A or C kinase); PKC = protein kinase C; PHAS = 22-kDa, phosphorylated, heat- and acid-stable protein; able to bind to the eukaryotic initiation factor 4, ‘cap-binding’ complex, therefore also designated as eIF-4E:Bp (eukaryotic initiation factor-4E binding protein); PI-3-kinase = phosphatidylinositol-3-OH-kinase (comprised of ‘p85’ and ‘p110’ subunits which are respectively the 85-kDa regulatory, SH2-containing and 110-kDa catalytic subunits); PTB domain = phosphotyrosine binding domain, equivalent in function to SH2 domains but with distinct structure and target-binding characteristics; p21-Ras = 21-kDa GTPase encoded by cellular homologue of rat sarcoma oncogene; Ras-GAP = GTPase-activating protein for p21-Ras; p90rsk = 90-kDa isoform of ribosomal protein S6 kinase; distinct from p70 S6K, the 70-kDa/85-kDa family of ribosomal S6 protein kinases; since p90-rsk is phosphorylated and activated by MAP kinases, it is also recognized as MAPKAP kinase-1; SH2 and SH3 domains = src-homology domains 2 and 3 (sequences related to non-catalytic domains of the protein tyrosine kinase pp60src and which function by binding, respectively, to phosphotyrosine motifs and proline-rich domains of target proteins).; Shc = adaptor protein with homologies to Src and to collagen; Sos = guanine nucleotide exchange factor (GDP-release factor) for p21-Ras, designated ‘son-of-sevenless’ and named from a Drosophila mutant manifest (in development of cell designated ‘R-seven’) due to a defect in signalling downstream from the ‘sev’ receptor tyrosine kinase; STAT = signal transducer and activator of transcription – transcription factors which have SH2 and tyrosyl-phosphorylation domains for dimerization to facilitate translocation from cytosol to nucleus upon cytokine or hormone activation; STZ = streptozotocin; Syp = SH2-containing protein tyrosine phosphatase (SH-PTP2); p60TCF = 60-kDa ‘ternary complex factor’, also designated Elk-1; TOR (mTOR) = target of rapamycin, first defined in yeast (and mammalian homologue); VAMP = vesicle-associated membrane protein; VLDL = very low density lipoprotein
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1 Introduction |
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Skeletal muscle, adipose tissue and liver are the quantitatively major targets for insulin action in vivo and regulation of critical steps in intermediary metabolism within these tissues account for many of the impacts of insulin on metabolic homeostasis. Many other tissues including the heart express insulin receptors and their functions may be importantly regulated by insulin. In this review we summarize the evidence that the heart is an important target of insulin action and that abrogation of these actions is important in disease states.
Current understanding of the molecular basis of insulin actions on its target cells is drawn from a large literature emanating from studies of the major target tissues and also from a wide range of other cell types including studies of appropriately transfected and immortalized cell lines [1–4]. We introduce the basic concepts of the molecular basis of insulin actions, not to reiterate the extensive reviews
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2 The context of insulin actions in the heart |
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2.1 Insulin actions and the mechanical demands of the heart
2.2 Calcium ions and insulin action in the heart
2.3 Insulin and additional inter-cellular control systems
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3 Indirect actions of insulin on the heart |
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3.1 The role of insulin in the supply of metabolic substrates to the heart
3.2 The role of insulin in the regulation of myocardial perfusion
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4 Direct actions of insulin on the heart |
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4.1 Glucose transport
4.2 Glycogen metabolism
4.3 Pyruvate oxidation
4.4 Glycolysis
4.5 Fatty acid metabolism
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5 Intracellular signalling pathways in insulin action |
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5.1 The insulin receptor—subunit structure and hormone binding
5.2 Activation of the insulin receptor protein tyrosine kinase
5.3 Intracellular proteins which interact with the insulin receptor
5.4 IRS proteins and multiple metabolic signalling pathways
5.5 Shc and the MAP kinase (ERK) signalling pathway
5.6 ERK-1 and ERK-2—a major role in rapid metabolic actions of insulin?
5.7 MAP kinase (ERK) signalling, myocardial gene expression and protein synthesis
5.8 Summary of the impact of signalling pathways on key metabolic proteins
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6 Clinical significance of defective insulin signalling |
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7 Concluding comments |
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