Table 4 MULTIPLE METABOLIC TOXICITIES IN MS AND T2DM: THE A-FLIGHT ACRONYM
| Â | Initiator | Metabolic Defect | Metabolic mediator | Functional mediator | Consequence |
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 |
| Â | 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 |
| Â | 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 Hype | 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" (figure 5) | 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 " (figure 5) ROS beget ROS |
| Â | Insulin deficiency | OVERT T2DM | GLUCOTOXICITY POLYOL SORBITOL PATHWAY | REDUCTIVE STRESS NADH > NAD+ PSEUDOHYPOXIA | ROS |
G | Glucotoxicity | Glycation / AGE | See above | See above | See above |
| Â | Â | Â | Protein inactivation | Receptor-ligand defects | Dysfunctional Signal Transduction |
| Â | Â | Â | NO quenching | Vasoconstriction | Ischemia/Hypoxia ROS |
| Â | Â | Â | Macrophage Activation | Increased Cytokines, TGF-Beta | Cytotoxicity ROS |
| Â | Â | Â | Free Radical Formation | REDOX STRESS | Cytotoxicity ROS |
| Â | Â | Auto-oxidation | Free Radical Formation | REDOX STRESS | Cytotoxicity ROS |
| Â | 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 |
| Â | Â | Â | Decreased Taurine | REDOX STRESS | ROS Cytotoxicity |
| Â | Â | Increased DAG | Increased PKC | Signal Transduction | Ischemia ROS |
|  | Glucotoxicity | Glucotoxicity | Polyol – Sorbitol Pathway | PAS + material Interstitium, Basement Membrane | Remodeling – Cardiomyopathy CHF Diastolic Dysfunction |
H | Hypertension Toxicity Homocysteine Toxicity | RAAS activation HHcy 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 |