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Table 3 Multiple metabolic toxicities in ms and t2dm: the a-flight acronym

From: Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation

  Initiator Metabolic Defect Metabolic mediator Functional mediator Consequence ROS
A AMYLIN (Co-secreted – Co-packaged within the insulin secretory granule) by the islet Beta cell. Insulin's "Fraternal Twin" Elevated in MS, PD, and Early T2DM) Hyperamylinemia Activation of ANG II PKC Signal Transduction Islet Amyloid IAPP Islet aggregation and deposition. Beta cell apoptosis – Beta cell defect. ROS IAPP Amyloid in islets contributing to Beta Cell defect. Possible deposition in the intima, mesangium, neuronal unit, and myocardial. REMODELING
  ANG II Via RAAS activation In MS, PD, and T2DM Ang II Excess Ang II Excess Most potent stimulus for: Activation of Vascular membrane bound NAD(P)H Oxidase Enzyme PKC Signal Transduction. Superoxide production. Uncoupling of the eNOS reaction. TGF beta-1 activation ROS NAD(P)H oxidase Derived Superoxide Myocardial, Renal, Intimal, Retinal, and Neuronal remodeling
  AGE Advanced Glycation Endproducts AFE Advanced fructosylation endproducts AGE / AFE See Glucotoxicity (G) RAGE activation Receptor for AGE Protein Cross – linking / Dysfunction RAGE Receptor for AGE Matrix Defects Signal Transduction Matrix Defects Signal Transduction ROS Myocardial, Renal, Intimal, Retinal, Neuronal– Endoneurial Fibrosis
  Advanced Lipoxidation Endproducts (ALE) ALE Protein Cross – linking Matrix Defects Signal Transduction ROS Matrix Remodeling
  Antioxidant Enzymes : Antioxidant reserve compromised Reduced – Dysfunctional eNOS, SOD, GPx, GSH, Catalase, and Vit. C. Decreased NO Decreased NO REDOX STRESS ROS REDOX STRESS
  Antioxidant Enzymes : Absence of antioxidant network IMPAIRED eNOS L-arginine BH4 Decreased NO Decreased NO ROS Decreased NO
  AGING : Accumulation of multiple metabolic toxicities → ROS Increased Ox-LDL-C, TNFalpha, Capase 3, Glomerulosclerosis. Decreased NO: Decreased NO ROS Inflammation, Apoptosis
  Atherosclerotic Nephropathy ROS beget ROS Atheroscleropathy Decreased NO Self perpetuating Decreased NO Decreased NO Athero – emboli Activated Platelets See Thrombotic Tox. ROS beget ROS Decreased NO
F Free fatty acid toxicity Elevated FFA LC acyl -CoA's Mitochondrial Defects ROS Cytotoxicity
L Lipotoxicity Lipid Triad FFA ALE Long chain acyl-COA's Increased VLDL – VLDL Triglycerides and Small dense atherogenic LDL-Cholesterol with Decreased HDL-Cholesterol LIPID TRIAD LC acyl -CoA's Fat Accumulation Non Adipose Accumulation of Fat (LC acyl -CoA's) in Adipose and Non Adipose Tissue ROS Accumulation of fat in non adipose tissues resulting in Ceramide induced: Cytotoxicity
I Insulin toxicity ENDOGENOUS Insulin Resistance Hyperinsulinemia Hyperamylinemia in: MS, PD, EARLY T2DM Glut 4 is NO dependent Redox sensitive pathway Ang II Increase # AT-1 receptors Cross-talk with AT-1 Increase FFA Increase PAI-1 Increase Sympathetic tone and activity Increased Na+ and H2O reabsorption Increase Volume and Blood Pressure Hypertension HypeR NAD(P)H REDOX STRESS SIGNAL PATHWAYS PI3 Kinase / Akt (Protein kinase B) → MAP Kinase Shunt ROS ROS ROS Extracellular Matrix Remodeling Islet, intimal, renal, myocardial, and neuronal.
  Inflammation toxicity. "Inflammatory Cycle" Activation of the innate immune system: IL-6, IL-8, TNF alpha Macrophage (MPO) → Hypochlorous Acid Superoxide O2• Acute Phase Reactants: C-Reactive Protein Serum Amyloid A Fibrinogen NF kappa B Cellular Adhesion Molecules: ICAM, VCAM, and MCP-1 ROS Inflammation begets Inflammation " INFLAMMATORY CYCLE " ROS beget ROS
  Insulin deficiency OVERT T2DM GLUCOTOXICITY POLYOL SORBITOL PATHWAY REDUCTIVE STRESS NADH > NAD+ PSEUDOHYPOXIA ROS
G Glucotoxicity Glycation / AGE See above See above See above
    Protein inactivation Receptor-ligand defects Dysfunctional Signal Transduction
    NO quenching Vasoconstriction Ischemia/Hypoxia ROS
    Macrophage Activation Increased Cytokines, TGF-Beta Cytotoxicity ROS
    Free Radical Formation REDOX STRESS Cytotoxicity ROS
   Auto-oxidation Free Radical Formation REDOX STRESS Cytotoxicity ROS
  ORIGIN OF REDUCTIVE STRESS ! REDUCTIVE STRESS ! Polyol Sorbitol Pathway (eNO inhibits Aldose Reductase) Increased NADH Lactate REDUCTIVE STRESS REDOX STRESS Decreased NO Pseudohypoxia Cytotoxicity ROS Ischemia/ Hypoxia
    Decreased Taurine REDOX STRESS ROS Cytotoxicity
   Increased DAG Increased PKC Signal Transduction REDOX STRESS Ischemia ROS
  Glucotoxicity Glucotoxicity Polyol – Sorbitol Pathway PAS + material Interstitium, Basement Membrane Remodeling – CHF Diastolic Dysfunction
H Hypertension Toxicity Homocysteine Toxicity RAAS activation Hyperhomocysteinemia NO quenching and NEW: PPAR interaction. Ang II Decreased GPx, DDAH with resultant ^ ADMA NAD(P)H REDOX STRESS ^ ROS, O2', ONOO', nitrotyrosine ROS Decreased NO, Endothelial Cell toxicity, dysfunction, and apoptosis
T Triglyceride Toxicity Thrombotic Toxicity Taurine (antioxidant) depletion Triglyceride – FFA exchange See FFA – Lipotoxicity above eNOS uncoupling REDOX STRESS Activated Platelets PAI-1 elevation Fibrinogen elevated. Decreased NO ROS Athero-emboli ROS
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