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Winter 2014 > KIN 404 3 > Flashcards

KIN 404 3 Flashcards

1
Q

Is obesity a result of hypertrophy or hyperplasia?

A

Adipocyte number increases in childhood and adolescence then levels off and remains constant in adulthood in both lean and obese (early onset) individuals.

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2
Q

What does weight loss from bariatric surgery stem from?

A

Major weight loss by bariatric surgery results in a significant decrease in cell volume but fails to reduce adipocyte cell number

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3
Q

What is fat mass determined by?

A

Both adipocyte number and size

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4
Q

Steps in the development of obesity (process through hypertrophy and hyerplasia)

A

1) Mesenchymal cells 2) preadipocytes 3) adipocytes filled with small lipid droplets 4) adipocyte with one large lipid droplet encompassing greater than 90% of the entire cell body 5) Adipocytes can enlarge up to 1000 times their original size (hypertrophy) and once it reaches a certain size it triggers other preadipocytes to differentiate, increasing the number of adipocytes (hyperplasia)

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5
Q

Once a preadipocyte becomes an adipocyte can it become anything else?

A

Nope…the change is permanent

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6
Q

How many adipokines does adipose tissue secrete?

A

50+ adipokines

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7
Q

What are the adipokines that contribute to insulin resistance in an obese state?

A

TNF-alpha, IL-6, FFA, MCP-1, TIMP-1, and RBP4

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8
Q

What 2 body masses cause type 2 diabetes?

A

Both obesity and lipodystrophy cause severe defects in lipid and glucose homeostasis resulting in peripheral insulin resistance and type 2 diabetes

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9
Q

Steps in the mechanism is which fatty acids cause insulin resistance T2D

A
  1. Positive net energy balance leads to TG accumulation in many tissues 2) Increased TG in adipose tissue leads to increased lipolysis by a mass effect which in association with adipocyte insulin resistance leads to 3. net spillover of fatty acids to nonadipose tissue which leads to the 4. insulin resistant state and type 2 diabetes
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10
Q

What is normal insulin signaling and the regulation of glucose and lipid homeostasis like in a healthy state?

A

Insulin is released from the pancreas in response to elevated blood glucose following a meal. It decreases hepatic glucose output and lipolysis in adipocytes, while increasing glucose uptake into muscle and liver and increasing fatty acid synthesis in adipocytes.

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11
Q

What is metabolic flexibility?

A

Ability to switch fuel use (fat vs. carb) under appropriate nutritional condition (fast vs. fed)

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12
Q

How are obese people/T2Diabetics metabolically inflexible?

A

They primarily use glucose (high RER) in a fasted state when they should be oxidizing fat (low RER), so in response to insulin, they can’t increase carbohydrate metabolism

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13
Q

What is the role of insulin in the stimulation of adipose tissue fatty acid uptake, esterification and storage?

A

It inhibits HSL, which decreases lipolysis. It increases lipoporitein lipase activity and fatty acid uptake. It increases glucose uptake (for glycerol-3-P). It may also increase DGAT activity. All of this leads to increased intracellular TG and decreased lipolysis.

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14
Q

What are the 2 ways that glucose is transported into muscle?

A

Insulin-stimulated and contration-stimulated

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15
Q

Muscles stimulated with supramaximal insulin plus exercise have greater transport than either alone…what does this illustrate?

A

Insulin and exercise use distinctive mechanisms to increase glucose transport in muscle

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16
Q

What activates PI3K?

A

Insulin

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17
Q

What activates AMPK?

A

Exercise

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18
Q

PI3K inhibitor blocks effects of….

A

insulin but not exercise

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19
Q

Muscles from ZUcker rats are insulin resistant but…

A

have normal contraction stimulated glucose transport

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20
Q

Mice with expression of inactive AMPK…

A

contractile glucose uptake is inhibited but insulin mediated is fine

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21
Q

LKB1 knockout mice…

A

contractile inhibited, but insulin mediated is fine

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22
Q

Insulin receptor knockout…

A

decreased insulin mediated glucose uptake but contractile mediated stays the same

23
Q

Does insulin induce phosphorylation of the insulin receptor or IRS1?

A

NO

24
Q

Would AICAR and contraction induced glucose transport be inhibited by wortmannin?

A

NOPE

25
Q

Would insulin mediated glucose uptake be inhibited by Wortmannin?

A

yes

26
Q

What is wortmannin?

A

a fungal metabolite that inhibits insulin mediated glucose uptake by decreasing PI3K activity

27
Q

What is AICAR?

A

WHen added to muscle it gets phosphorylated and becomes ZMP (a mimetic of AMP) —> turns on AMPK

28
Q

Steps in the signaling pathway involved in GLUT4 translocation from insulin in skeletal muscle

A

1) Insulin binds to its receptor, which causes a conformational change that activates a tyrpsine kinase that autophosphorylates Tyr residues on the beta subunit 2) The kinase of the insulin receptor recruits and phosphorylates IRS1 3) Phosphorylated IRS1 recruits and binds to the p85 regulatory subunit of PI3K which actiavtes p110 catalytic subunit of PI3K 4) Activation of PI3K increases production of PIP3 from PIP2 within the plasms membrane which initiates rectruitment and activation of PDK1 5) Akt/PKB is recruited in association with PDK1 and is phosphorylated by PDK1 but full activation of Akt requires additional phosphorylation by the Rictor-mTOR kinase 6) PKD1 also activates PKC which along with Akt can phosphorylate AS160 and inhibit GTPase activity of RAB which leads to increased movement and fusion of GLUT-4 storage vesicles (GSV)

29
Q

When is the only time that PDK1 works?

A

When it is actiavted by PIP3

30
Q

Where do the insulin and the contraction mediated glucose uptake pathways converge?

A

At phosphorylation/inactivation of As160…AS160 becomes phosphorylated in response not only to insulin but also to contractile activity and pharmacological activation of AMPK with AICAR…therefore, AMPK is a potential therapuetic target for insulin resistnace

31
Q

What prohibits GLUT4 translocation to the sarcolemms at rest?

A

At rest, AS160 has an active Rab GAP which hydrolyzes GTP to GDP. Rab GDP is not able to transport GSV to the sarcolemms

32
Q

How does contraction increase GLUT4 translocation?

A

Contraction/exercise activate AMPK, which directly inactivates AS160 by phosphorylating it

33
Q

In addition to increasing glucose uptake into muscle, what does insulin and muscle contraction do?

A

Increase fatty acid transport to sarcolemms because FAT/CD36 ahd FABP(pm) are also found in GSV

34
Q

Acute infusion of fatty acids in humans induces insulin resistance how fast?

A

4-5 hours

35
Q

What about the accumulation of TGs in muscle leads to insulin resistance?

A

An increase in TGs leads to an increase in fatty metabolites (fatty acyl-CoA, ceramides and DAGs) and/or a reduction in fatty acid oxidation impairs insulin signalling and recruitment of GLUT4 to the cell surface

36
Q

Lipid accumulation in muscle can be attributed to?

A

1) increased circulating plasma fatty acid concetrations 2) increased rate of fatty acid transport into muscle 3) decreased rates of fatty acid oxidation

37
Q

What is the paradox to the relationship between increased intramyocellular TG and insulin resistance?

A

Type I (oxidative) skeletal muscle fibres have a 3-fold higher content of intramyocellular TG than type II (glycolytic) muscle fibres, yet, type I fibres are more insulin sensitive than type II fibres. Endurance trained athletes have higher concentrations of intramyocellular TG than sedentary and/or diabetic individuals, yet, because of their training these athletes are far more insulin sensitive than sedentary individuals

38
Q

What explains the paradox of to the relationship between increased intramyocellular TG and insulin resistance?

A

Rates of FA oxidation are high in Type I fibers and in muscles of endurance athletes due to increased mitochondria. In contrast, FA oxidation is impaired in obese and T2Diabetic…athletes have a greater turn over of TG than obese people.

39
Q

What allows for more rapid entry of FA into skeletal muscle in moderate obesity and Type 2 diabetes?

A

Redistribution of FAT/CD36 from intracellular pools into plasma membrane in insulin resistant muscle which allows more rapid entry of fatty acids into cell

40
Q

What happens to mitochondria in skeletal muscle as Type 2 diabetes advances?

A

Mitochondria begins to become dysfunctional, which leads to a huge increase in TGs and therefore a greater increase in DAGs, ceramides and LC Fatty-acyl CoA

41
Q

What is the mechanism of fatty-acid induced insulin resistance in skeletal muscle?

A

Decrease in mitochondrial density –> decreased beta-oxidation –> increased LCCoA –> increased DAG –> increased PKC pheta –> phosphorylates Ser/Thr residues –>no Tyr residue phosphorylation –> decreased in IRS-1 phosporylation –> decreased in PI3K –> decrease in PIP3 –> decrease in AKT2 –> decreased GLUT-4 translocation and decreased phosphorylation of GSK3 –> decreased GS activity –> decreased glycogen synthesis

42
Q

When GSK3 is active is it phosphrylated or not, and what does it do?

A

Active - NOT phosphorylated. Adds a phosphate group to glycogen synthase which INHIBITS it, os no glycogen synthesis

43
Q

Accumulation of excess intramyocellular lipids in muscle could occur due to:

A

1) increased circulating FFA with obesity and adipocyte insulin resistance 2) Increased capacity for FFA uptake into muscle due to the increased presence of FAT/CD36 at the cell surface 3) Decreased capacity to oxidize fat

44
Q

What activations PKC pheta, leading to serine phosphorylation and inactivation of IRS-1?

A

Fatty acid metabolites (DAG and ceramides)

45
Q

What does insulin resistance at the liver?

A

Reduces the ability to turn off glucose production by the liver after a meal

46
Q

What happens in the liver after a meal?

A

Liver glucose output is suppressed within 30 min after an oral glucose load and the liver takes up glucose to replenish glycogen stores

47
Q

What is fasting hyperglycemia a result of?

A

Related to increased rates of endogenous glucose production (~25%) which could be due to increased gluconeogensis and/or increased glyocgenolysis

48
Q

What does the reduced liver glycogen concentration baseline in Type 2 Diabetic indicate?

A

A defect in liver glycogen synthesis

49
Q

What is the increased liver glucose production in Type 2 Diabetics a result of?

A

The reduction in glyocogen synthesis leads to lower rates of glycogenolysis and ~60% increase in gluconeogenesis so the increase in liver glucose production in type 2 diabetes in entirely due to increased gluconeogensis

50
Q

Mechanisms of Fatty-Acid induced insulin resistance in liver?

A

increased de novo lipid synthesis and decreased beta-oxidation –> increased LCCoA –> increased DAG –> increased PKC theta –> Ser/Thr residue phosphorylation –> decreased Tyr phosphorylation on IR –> decreased IRS2 phosphorylation –> decreased PI3K –> decreased PIP3 –> decreased Akt2 –> decreased phosphorylation of GSK3 which leads to decreased glycogen synthesis and decreased phosphorylation of FOXO, which leads to increased transcription of genes involved in gluconeogenesis

51
Q

What does loss of long-chain fatty acid elongase do in the liver?

A

Improves onsulin signalling even in fatty livers…it’s what you do with the fat that matters!

52
Q

Steps in the chronic inflammation in adipose tissue that increases FA spillover from adipocytes and triggers IR in skeletal muscle

A

Small adipocytes gain TG and hypertrophy into an obese state.At a certain point, adipocytes begin secreting MCP-1 and inflammation occurs. MCP-1 attracts TNF-alpha to adipocyte which causes insulin resistance and accumulation of TG into muscle?

53
Q

In what ways does TNF-alpha impair TG storage in adipocytes?

A

It downregulates Peroxisome Proliferator-Activates Receptor-Gamma, which impairs TG storage in adipocytes. It activates NF-kB, which stops transciption of PPAR mRNA. It actiavtes MAP4K4 which decreases PPAR protein translation. TnF-alpha also activates caspases which degrade any PPAR protein.

54
Q

Activation of skeletal muscle glucose by AICAR… a) involves activation of AMPK b) involves translocation of GLUT-4 to the sarcolemma c) is blocked by PI3K inhibitor Wortmanin d) all the above e) a and b

A

e) a and b

Winter 2014 (5 decks)

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