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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
	AntioxidantEnzymes: Antioxidant reserve compromised	Reduced – Dysfunctional eNOS, SOD, GPx, GSH, Catalase, and Vit. C.	Decreased NO	Decreased NO REDOX STRESS	ROS REDOX STRESS
	AntioxidantEnzymes: 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

Table 4