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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