Flashcards in MCP 10 Deck (25):
elevated waist circumference. visceral obesity is the major risk factor that predisposes the metabolic syndrome
slow glucose disposal. hallmark of metabolic syndrome. manifested by hyperglycemia and hyperinsulinemia. failure of blood glucose levels to decline normally in a glucose tolerance test, despite the presence of elevated levels of circulating insulin. high fasting insulin level (done to offset hyperglycemia)
hyperinsulinemia stimulates triglyceride biosynthesis. overloading by TG increases clearance of HDL-cholesterol
speculated that high leptin level, resistance to insulin-stimulated vasodilation, obesity induced atherogenic inflammation and dyslipidemia may collectively contribute to hypertension
current model of insulin resistance
1. impaired glucose uptake into skeletal muscle
2. continued postprandial gluconeogenesis and glucose release by liver
3. reduced glucose uptake in adipose tissue, reduced lipoprotein lipase, and reduced TG storage.
4. release of adipose-derived substances from adipose tissue
progression to Type 2 Diabetes from insulin resistance
thought to result from local pathology in pancrease, leading to apoptosis of insulin producing islet cells.
what are the substances released from adipose tissue that induce insulin resistance in skeltal muscle and liver?
nonesterified fatty acids (NEFA). NEFA levels exceeds rate of storage in obese people. this may promote metabolic derangements in muscle and liver, aka lipotoxicity. Adiponectin and leptin are released too, stimulating beta oxidation in skeletal muscle which lowers lipolysis, reducing levels of free fatty acids. Adiponectin production is lowered in people with obesity! expanded adipose tissues also release proinflammatory cytokines that cause body wide inflammation. this is thought to promote insulin resistance in the liver
insulin resistance in the muscle
substances released from larger and more numerous fat cells of obese people interfere with insulin dependent glucose disposal in muscle. insulin normally binds to insulin receptors, but downstream signaling pathways are impaired
insulin resistance in liver
downstream signaling impaired. this makes insulin less effective in blocking expression of gluconeogenic enzymes. liver makes more glucose as a result
insulin resistance in adipose tissue
downstream signaling is affected again. decreased glucose uptake, decreased release of lipoprotein lipase, decreased triglyceride storage, increased lipolysis from fat storage. mostly indirect due to effects on muscle and liver
circulating NEFA released from larger and more numerous fat cells somehow interfere with glucose disposal in muscle and glucose release in the liver. this leads to more NEFA which aggravates insulin resistance
inhibits insulin signaling. inhibits translocation of GLUT4 (glucose transporter) to the muscle cell membrane. also inhibits glycogen synthase and activates gluconeogenic enzymes in the liver. accumulates when the rate of fatty acid delivery to the liver and muscle exceed the rate of intracellular fat oxidation and conversion to neutral lipid
5 causes of DAG accumulation
1. excessive caloric intake
2. defects in adipocyte metabolism
3. gene variation in apolipoprotein C3 which reduces lipoprotein lipase activity
4. defects in mitochondrial function (decreased beta oxidation)
5. reduced AMP-activated protein kinase signaling
low-grade systemic inflammation theory
excessive adiposity activates a diverse range of stress-response and inflammatory signaling pathways. activation of downstream inflammation pathways directly inhibit insulin signaling in the local adipocytes as well as in the liver and muscles. production of cytokines increase in adipocytes, leading to stress kinases activating which leads to reduced insulin signaling
AMP-activated protein kinase (AMPK)
modulates insulin sensitivity by affecting fatty acid. activated by AMP (low nutrient levels). when active, AMPK activates many energy generating pathways while inhibiting energy consuming pathways. adiponectin and leptin stimulate activity of AMPK. reduced AMPK leads to lower beta oxidation, accumulation of DAG, and insulin resistance!
stimulates AMPK. could be used as a pharmaceutical for treatment of metabolic syndrome. activated AMPK inhibits ACC1 and ACC2, stimulating beta oxidation.
mitochondrial dysfunction leading to ...?
leads to FA overload and insulin resistance. genetically determined.
how do specific macronutrients contribute to metabolic syndrome?
increasing ectopic lipid accumulation in liver. fructose and alcohol may contribute to insulin resistance. their metabolism is not insulin regulated, they are metabolized in the liver, and cannot form glycogen for storage. they are highly lipogenic
lower body obesity (pear shape)
why does visceral fat lead to type 2 diabetes
visceral fat has direct venous drainage to liver, so NEFA from visceral fat can go right to liver. visceral adipocytes have high expression of beta 3 adrenergic receptors, which increase lipolytic response to catecholamines (norepinephrine). visceral adipocytes are less responsive to insulin inihibtion of lipolysis. visceral fat may also be more active in secreting proinflammatory molecules
current recommendations for treating metabolic syndrome
1. intensified weight management and increased physical activity
2. use pharmaceuticals to treat hypertension, lower TG, and try to raise HDL
remodeling lipid metabolism
targeting transccriptional regulation pathways. PPARs, or drugs that target the transcriptional activators, can be used. PPARs are ligand activated nuclear receptors and regulate many genes involved in lipid metabolism
PPARalpha ligand. promotes upregulation of enzymes used in beta oxidation. lowers triglycerides, raises HDL, lowers LDL
PPARgamma ligands. promote insulin action and FA uptake, as well as FA storage as TG. downregulate lipolysis. decrease in circulating NEFA, increasing insulin sensitivity. used as anti-diabetic and insilin sensitizing drugs