Table 4

MULTIPLE METABOLIC TOXICITIES IN MS AND T2DM: THE

    A-FLIGHT
ACRONYM

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

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 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

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

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


Hayden and Tyagi Nutrition Journal 2004 3:4   doi:10.1186/1475-2891-3-4

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