Biomed Capstone - Metabolic Syndrome

What are the components of metabolic syndrome

5 Risk Factors:

- central obesity

- high blood pressure

- high triglycerides

- low HDL-cholesterol

- insulin resistance

(3 out of 5 qualify you for MetS)

Role of Adipose tissue

Acts as a passive energy store

What biomarker indicative of chronic inflammation

CRP

good indicator for a pro-inflammatory state

- < 95 nmol / L = low risk of CVD

- 9.5 - 28.6 nmol/ L = average risk

- > 28.6 nmol/ L = high risk

what biomarker is indicative of a pro-thrombotic state

PAI-1, fibrinogen and CRP

abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels)

What lifestyle factor strongly associated with metabolic syndrome

sedentary behaviour

- prevalance is rising worldwide due to increasing obesity

what pathophysiological mechanism contributed to endothelial dysfunction

chronic low-grade inflammation

Increased oxidative stress

Insulin resistance

What lipid profile change commonly seen (Dislipidemia)

Decreased HDL cholesterol

- Visceral Adiposity = waist circumfrance not obligated now but recommended

- Visceral Fat = highly correlated with insulin resistance, detrimental impact on arterial wall (dysregulation of metabolic factors, activation of inflammatory cascades and direct effects of adipokines)

- visceral fat macrophages = icnrease plasma levels of TNF-alpha --> release of other inflammatory cytokines (IL-6)

- hypertriglyceridemia = elevated levels of triglycerides, myocardial infarction and stroke

- low levels of HDL = low reverse cholesterol transport to liver (normally HDL reverse build-up of fatty plaques in arteries)

- hyperglycemia = to much glucose in blood

What organ most affected

Renal - Kidneys

nephropathy - any disease or damage to kidneys

- glomerular sclerosis (diffuse thickening) and fibrosis

- significant % of DM and MetS patients are at risk of CKD/ ESKD

- obesity = contributing factor

2 clinical stages of nephropathy

1. Incipient nephropathy = overtly asymptomatic; microalbuminuria ( + normal or elevated GFR)

2. Overt Nephropathy = macroalbuminuria and declining GFR

What intervention is most effective in reversing insulin resistance

Increased physical activity

- visceral fat highly correlated with insuling resistance

- increased hepatic fat promtoes insulin resistance = dyslipidaemia, and accounts for hepatosteatosis ("fatty liver")

What Cytokine is most associated with pro-inflammatory state

TNF-alpha

- Obesity leads to increased number of adipose tissue and macrophages

- switch to pro-inflammatory state, because macrophages produce adipokines (cytokines secreted by adipose tissue incl. leptin/ adiponectin) increase TNF-alpha and increase IL-6

- TNF-alpha and IL-6 important potential contributors to pathological processes leading to type 2 diabetes., hypertension and dyslipedemia

- increase plasma levels of TNF alpha --> release of other inflammatory cytokines (IL-6)

- increase TNF-alpha and IL-6 (adipose tissue) --> increase FFA and TG

What clinical sign most suggestive of early nephropathy in a patient

Microalbuminuria

Test = creatinine ratio (ACR) in spot urine sample (estimates 24 hour secretion)

how is microalbuminuria indicated

ACR of 30 - 300mg/g

repeat tests 1-2 times in 3 months - confirmed if at least 2 of the three tests are positive

if ACR positive, repeat tests, confirmed is at least 2 of the 3 tests are positive over 6 months

how is macroalbuminuria indicated

ACR > 300 mg/g

perform 24hr urine collection for quantification of protein excretion

what does an estimated GFR from serum creatinine indicate

>90 = normal kidney function

<30 = severe kidney dysfunction

What is Metabolic Syndrome

cluster of risk factors that is not benign but associated with

- 5-fold elevated risk of developing type 2 diabetes

- 2-3 fold elevated risk of developing cardiovascular disease

what are the problems/ risks for metabolic syndrome

1. public health problem = need for modification of lifestyle/ diet

2. the clinical problem = patients need to be identified in order to reduce risk factors

How to diagnose Metabolic Sydrome

1. Elevated waist circumference (population and country specific definitions)

2. elevated triglycerides (> 1.7 mmol/L)

3. Reduced HDL-C (< 1.03 mmol/L men & < 1.29mmol/L women)

4. Elevated blood pressure (systolic > 130mmHG and/ or diastolic > 85 mm Hg)

5. elevated fasting blood glucose (> 5.6 mmol/L )

Laboratory Tests for MetS

1. Glucose - fasting glucose test or oral glucose tolerance tests

2. lipid profile - HDL-C, (LDL-C), triglycerides

3. microalbuminuria

4. CRP

Afferent System in Obesity

Fat = adipocytes (energy source) = leptin

Stomach = parietal cells = gastrin

pancreas = B cells = insulin

intestines = L cells = PYY ( hormone regulating appetite and food intake by acting as a satiety signal to the brain)

Efferent System in Obesity

Exercise more = increase apeptite, lower exercise amount = decrease in apetitie

all about energy balance

Adipocyte hypertrophy

1. Positive caloric balance, genetic predisposition, sedentary lifestyle

2. Adiposity and adiposopathy ("sick fat" - adipose tissue = dysfunctional)

3. increase release of FFA, abnormal release of inflammatory factors and adipokines, and other adipose tissue dysfunction

4. Abnormalities in glucose metabolism ( increase insulin resistance), hypertension (increase mineralocorticoid activity, dyslipidemia)

5. Atherosclerosis and vascular damage, atherosclerotic plaque

Affect of CETP levels in Met S

1. CETP levels increased = increase transfer of cholesteryl esters from HDL to VDL in exchange for TG. Reduced HDL-C levels generating smaller, denser HDL particles. sdHDL more readily degraded and cleared by kidneys (net result is lower HDL levels)

2. increased formation of large TG-rich VLDL = formation of TG-rich LDL (preferred substrate for hepatic lipase) = generation of smaller dense LDL (sdLDL), can readily oxidise and penetrate the vascular epithelium

white and brown fat cells

white cells = energy storage

brown fat cells = convert chemical energy from glucose and lipids into heat

Non-Alcoholic Fatty Liver Disease (NAFLD)

condition where excess fat builds up in the liver

cause of steatosis ("fatty liver")

related to insulin resistance and MetS

steatosis

abnormal accumulation of fat within parenchymal cells

often in liver

arise following disruption of any single step of the fat metabolism pathway by hepatocytes

reversible unless cells are irreversibly damaged

pathway for liver steatosis

Fatty Acids entering hepatocyte are esterified (organic acid and an alcohol react to form an ester and water) into triglycerides

- converted to cholesterol

- incorporated into phospholipids

- converted to ketone bodies within mitochondria

secretion of triglycerides require complexing with apoprotein (lipid acceptor proteins) to form lipoproteins

Insulin resistance outcomes

Genes & Lifestyle and diet --> insulin resistance --> Normal B-cell function = compensatory hyperinsulinemia & normoglycemia

abnormal B-cell function = relative insulin deficiency & hyperglycaemia and Type 2 diabetes

Mechanism of insulin resistance in obese patients

1. decreased number of effector organ insulin receptors

2. post-receptor inactivation - failure of receptor tyr-kinase activity

3. GLUT-4 (adipose tissue, skeletal muscle, cardiac muscle) not translocated to the plasma membrane --> decreased glucose uptake

what does decreased insulin action cause

1. hyperglycaemia = failure to supress gluconeogenesis, and failure of glucose uptake in insulin sensitive tissues

2. hyperinsulinemia = to compensate insulin secretion is increased

what causes insulin resistance

increased lipolysis causing increases plasma FFA which causes insulin lipolysis insensitivity in muscle and formation of TG (instead of glycogenesis)

increased circualting glucose --> increased insulin secretion

FFA + insulin --> hypertension

Paracrine/ endocrine effects of pro-inflammatory state contribute to insulin resistance

increase TNF-alpha + IL-6 = increase FFA and TG

increase plasminogen activator (PAI-1), fibrinogen + CRP = pro thrombotic state

decrease Adiponectine (secretion from adipose tissue)

Type 1 DM

younger, leaner patient, may be a family or personal history of autoimmune disease

- weight loss

- thirst, polyuria, dehydration

- blurred vision

- infection

Type 2 DM

overweight, family history of metabolic dysfunction, hyperglycaemia

symptoms = thirst, polyuria, dehydration, blurred vision, lethargy, patient often asymptomatic

what causes renal function in MetS

increase in extracellular material --> occludes glomerular capillaries

hemodynamic changes damage glomerular epthelial cells (podocytes - need to cover larger surface area due to glomerular hypertrophy)

causes increased glomerular permeability and proteinuria

What is Calcified Aortic Atheroma

atherosclerosis in wall of aorta

disease of intimal layer in vessels (closest to where the blood flows)

How does calcified aortic atheroma occur

basophilic calcium salt deposits aggregate first in damaged mitochondria and progressively through the cell

calcification occurs in areas of cell necrosis in which activated phosphatases bind calcium ions to phospholipids in membrane

thrombus formation

develop at site of endothelial injury, can grow to block blood flow or can break off and become embolus (effect at a secondary site)

what vascular damage does Met S cause

atherosclerosis

CAD (coronary artery disease)

calcified aortic atheroma

thrombus formation

myocardial infarct

stroke

hypertension

treatment MetS

weight loss, regular exercise causes

- decrease BP

- increase insulin sensitivity

- decrease TG and LDL

- increase HDL levels

- decrease risk of CVD and stroke

drug treatment may be necessary for

- hypertension

- high cholesterol

- high glucose/ insulin resistance

Aspirin

- may be prescribed to decrease risk of blood clots

MetS medications - statins

Statins - most effective drugs to reduce LDL-C

also

- reduce cellular inflammation

- lower CRP levels

- improve the anti-oxidative properties of LDL-C

MetS medications - Fibrates

e.g., fenofibrate

effective in lowering TGs (decrease liver VLDL production) and increase HDL

MetS medications - Statins + fibrates

good combination therapy for patients with atherogenic lipids profiles

MetS medications - Bile acid sequesterants

alternative/ adjunct to use of statins

MetS medication - ACE

angiotensin converting enzyme inhibitor, ARB (angiotensin receptor blocker) medication to control BP

MetS medication - hyperglycaemia medication

metformin

- decrease hepatic gluconeogenesis

- decrease GI glucose absorption

- increase sensitivity to insulin