MCP Lecture 10

Question 1

What are the components of metabolic syndrome?

Answer 1

1. elevated levels of insulin in blood
2. glucose intolerance
3. hypertension
4. increased tendency to clot
5. dyslipidemia
6. visceral obesity

Question 2

What is dyslipidemia?

Answer 2

hyperinsulinemia stimulates TRIglyceride biosynthesis which increases the clearance of HDL-cholesterol

Question 3

Define insulin resistance

Answer 3

failure of blood glucose levels to decline normally in a glucose tolerance test despite the presence of elevated levels of circulating insulin

Question 4

What causes insulin resistance?

Answer 4

release of substances from adipose tissues in obese individuals reduces glucose uptake, cuases gluconeogenesis and glucose release by liver, and causes impaired glucose uptake into skeletal muscle

Question 5

What causes progression from insulin resistance to T2DM?

Answer 5

apoptosis of insulin-producing islet cells

Question 6

What substances released from adipose tissue induce insulin resistance in skeletal muscle and liver?

Answer 6

free or nonesterified fatty acids (NEFA), leptin, other signaling molecules called adipokines

Question 7

What is lipotoxicity?

Answer 7

elevated circulating NEFA that promotes metabolic derangements in muscle and liver

Question 8

What does adipose tissue release to stimulate Beta-oxidation?

Answer 8

adiponectin and leptin

Question 9

What is the relationship between obesity and adiponectin levels?

Answer 9

decreases with increasing obesity

Question 10

What is the relationship between adipose tissue and macrophages in obesity?

Answer 10

expanded adipose tissue releases proinflammatory cytokines = body wide low-grade inflammation

hypertrophy of fat cells = reduced oxygenation and cell death = macrophage infiltration (5% in normal, 50% in obese) = TNF-alpha, IL-6, PAI1 release

Question 11

How does insulin resistance occur in muscle?

Answer 11

substances released from fat cells interfere with insulin-dependent glucose disposal in muscle - downstream signaling pathways are impairesd

Question 12

How does insulin resistance occur in liver?

Answer 12

insulin is less effective in blocking expression of gluconeogenic enzymes - liver produces more glucose and releases it into the blood

Question 13

How does insulin resistance occur in adipose tissue?

Answer 13

down stream signaling again

decreased glucose uptake - effects of IR in adipose tissue on blood glucose mostly indirect

Question 14

What inhibits insulin signaling?

Answer 14

DIacylglycerol (DAG) - build up of DAG inhibits translocation of GLUT4 to muscle cell membrane and also inhibits the glycogen synthase and activates gluconeogenic enzymes in liver

Question 15

What causes DAG accumulation in muscle cells of obese individuals?

Answer 15

accumulate in skeletal muscle and liver when the rate of FA delivery exceeds the rate of intracellular fat oxidation
Causes:
1. excessive caloric intake
2. defects in adipocyte metabolism
3. gene variation in apolipoprotein C3 (reduces lipoprotein lipase and therefore lipid storage)
4. defects in mitochondrial function - reduced FA Beta oxidation
5. reduced AMP-actived protein kinase signaling

Question 16

What is most likely the primary cause of DAG over-accumulation?

Answer 16

lower rate of Beta-oxidation which is controlled by the AMPK (which integrates many signals including energy status and adipokines)

Question 17

What is the basis behind the inflammation theory?

Answer 17

excessive adiposity activates a diverse range of stress-response and inflammatory signaling pathways which directly inhibits insulin signaling in the local adipocytes as well as liver and muscle
-fat increases production of cytokines such as TNFalpha, IL6, PAI1 by macrophages - activate stress kinases, phosphorylate IRS1 on inhibotr serine residues = reduced insulin signaling

Question 18

How does AMPK modulate insulin sensitivity?

Answer 18

stimulating fatty acid oxidation during times of low energy (AMP)

Question 19

What activates AMPK?

Answer 19

adiponectin and insulin

Question 20

What is metformin?

Answer 20

pharmaceutical that activates AMPK for treatment of metabolic syndrome

Question 21

What is the role of mitochondria in insulin resistance?

Answer 21

genetically determines and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly affect FA oxidation - leads to DAG accumulation and insulin resistance

Question 22

How do fructose and alcohol contribute to insulin resistance?

Answer 22

1. metabolized for energy within liver
2. metabolism is not insulin regulated
3. do not have a mechanism for to form glycogen for storage

-highly lipogenic = increase intrahepatic lipid deposition

Question 23

What is thiazolidinedione (TZDs)?

Answer 23

class of antidiabetic drugs - increase body weight while improving insulin sensitivity - increase FA uptake and storage as TG

Question 24

Why is visceral fat worse than subcutaneous fat?

Answer 24

1. direct drainage to liver
2. increased NEFA release (more beta3-adenergic receptors, decreased response to insulin inhibits lypolysis)
3. increased secretion of proinflammatory molecules

Question 25

What are PPARs? Examples?

Answer 25

drugs that target transcriptional activators - regulate genes involved in lipid metabolism
-Fibrates and TZDs

Question 26

What are fibrates?

Answer 26

drugs that upregulate enzymes involved in beta oxidation - lower triglycerides and raise HDL_cholesterol and lower LDL cholesterol