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