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Metabolic Syndrome (Sympathetic overractivity - Higher in obese patients …
Metabolic Syndrome
Sympathetic overractivity - Higher in obese patients (elevated resting heart rate, baroflex dysfunction, sleep apnea, increased leptin, reduce complace)
Endothelial dysfunction
- Oxidative stress increased this by: sodium retention, downregulation of NOS synthase, NO inactivation, impaired endotelial vasomotor function
Activated renin-angiotensin System
- RAS plays a role in BP regulación through modulación of vascular Tone and renal function
- Increases in angiotensinogen and angiotensin I and II in obese patients
- Elevation of renin and aldosterone levels in obese patients
- Plasma aldosterone associated with MS
- Increased RhoA Activity (gene) decreases NO production >> increased vasoconstriction
Increased inflammatory mediatos
- TNF- alpha stimulates the production of endothelin-1 and angiotensinogen
- Serum TNG-alpha concentración correlated with systolic BP and insulten resistance
Obstructive sleep apnea
- 77% of apnea patients present hipertensión (most are obese)
- Increased sympathetic bursts >> Norepinephrine
- Reduced baroreflex sensitivity
- Nocturnal hypoxia and hipercapnia simulase arterial chemoreceptor >> sympathostimulating effects (higher bp)
Dyslipidemia
- Atherogenic dyslipidemia >> increase in CVD
- 3 major components (increase in triglyceride rich lypoproteins, reduction in HDL, elevated small and dense LDL
Postpandrially
- Indirect measurement of chylomicron remnant particles, related to insulinas action
- Relation of triglyceride levels to postheparin plasma LPL activity
- LPL >> insulina sensitive enzyme >> suppressed in insulinas resistan individuals
Oxidative stress - High plasma oxidative stress biomarkers are correlated with High triglyceride levels and los HDL
- Increasd lípidos peroxidation (Marker of oxidative stress) correlated with los HDL independent of age, gender and other factors
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Glucosa Intolerance
- Deficient ability to superas glucosa production by the liver and kidney
- Deficient ability to mediante and glucosa uptake particularly in muscle and adiposo tissue
- Signals to code for insulinas secretos dependen of glucosa have been modified at beta cell level
- To compénsate: insulinas secretos increpases --> hyperinsulinaemia
Proinflammatory state
- High levels of CRP
- Il-6
- TNF - alpha
- Low adiponectin and macrophage activation
Prothrombotic state
- Increased levels in PAI-1 and fibrinogen
- Fibrinogen: acute pase protein
Other manifestations
- PCOS, NAFLD, NASH --> CIRRHOSIS, HYPERURICAEMIA, OBSTRUCTIVE SLEEP APNEA
DEFINITION: Clutering of metabólico alterations including:
- Central obesity
--> Waist circumference is highly related to CVC, more than BMI
- Dyslipidemia
--> Hypertrigliceridaemia
--> Low HDL levels
--> Reduction on LPL in peripheral tissues
- Hyperglycemia
Aetiology
- 90% enviormental, epigenetic factos, insulinas resistance and central/abdominal obesity
- 10% genetics
Components of MS
- Hyperglicemia
- Central obesity
- Dyslipidemia
- Hypertension
- Prothrombotic state
- Proinflammatory state
Insulin
- Key modulador of intermediase metabolism
- Acts DURING postpandrial state --> plasma glucose
Insulin resistance
- Lower than normally expected insulin effect on glucose metabolism or plasma concentración at a given insulinas level
In obesity...
- Not all obese patients develop insuline resistance, but those who do are overweight or obese
- Regulators of host/nutrient alterations
--> oxidative stress, chronic inflammation, gut and CNS derangements, gut microbiota
Adipose tissue
- Passive fate storage
- Its expansion triggers hypoxia
Adiponectin
- 30 kDA protein
- Higher insulinas sensitivity
- Reduced CV risk
- Increase muscle lípidos oxidación and mitocondria function
Adipose tissue oxidative stress
- Fat accumulation increpases reactive species
- Increased oxidative stress is implicase in the pathogenesis of MS
Tissue browning
- Increase energy through heat production
- Brown adiposo tissue >> more thermogenic
Diets
- High caloríe and high fat diets are asociated with increased inflammation and oxidative stress
- High plasma FFA are strongly associated with insulinas resistance in obese patients, more so in the presence of hyperinsulinemia
Physical activity
- Associated with reducen inflammation
- Better insulinas sensitivity
- Inactivity associated with increased oxidative stress, inflammation and insulinas resistance.
Lipotoxicity
- Induced by increased intake plus increased release from facto asíd tissues
- Increased accumulation in non facto tissues >> negative Impact on insulinas sensitivity
- Intramuscular triglycerides have been associated with insulinas resistance
Mitochondrial dysfunction
- Impaired lípidos peroxidation
- Reduced oxidative capacita and ATP production.
- Lipid inducen excess mitocondria fragmentación in skeletal muscle of DM and IR
Gut Gysbiosis
- May be enhanced by poor nutrition and May favour the onset of systemic inflammation, insulin resistance and obesity by enhacina gut permeability.
Altered nutrient sensing
Hyperglycemia - DM2
- Insulin resistance contribuyes to the onset of metabólico abnormalities defining the metabólico syndrome
- DM2 is preceded by at least 10 years of insulinas resistance without hyperglycemia
- Pre-diabetic alterations: impaired plasma glucose (100-125)
- Impaired glucose tolerante 2 hr GT
Diagnosis of diabetes:
- Fasting plasma glucosa above 126 mg/dl
- 2-hour OGTT glucose above 200 mg/dl
- HbA1c above 6.5%
Visceral obesity
- Increased non sterilized fatty acids, increase in adipokines, TNF-alpha and IL-6
- insulinas resistance, insulinas >> Antinatriuretic effect (induces renal sodium reapsorption)
- Insulin resistance is associated to salt sensitive hipertensión through its antinatriuretic effect
Atherogenic INDEX
- Atherogenic coeficiente (AC) = (Total cholesterol) - (HDL cholesterol) / HDL cholesterol
- Atherogenic Index of Plasma (AIP) = log (triglyceride) / (HDL cholesterol)
- Biomarker of lipoprotein partidles siete, predictive of CVD risk and morbidity