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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