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Nutr 4210 > 11. Obesity (1) - insulin resistance > Flashcards

11. Obesity (1) - insulin resistance Flashcards

(43 cards)

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1
Q

Difference between peripheral and central obesity

A

Peripheral

  • subcutaneous fat
  • excess below the waist (hips, butt, thighs)
  • NOT likely a major health risk factor

Central (Abdominal) Obesity

  • visceral fat (surrounds heart, liver, intestines, kidney)
  • very strong predictor of health risk
  • pro-inflammatory, IR, diabetes risk, heart disease
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2
Q

Easiest way to measure Visceral Fat

  • male and female measure
  • other ways to measure
A

waist circumference

  • men > 102 cm
  • women > 88 cm

others

  • MRI and CT
  • $$$
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3
Q

key independent predictor of all cause mortality

- some basic measurements

A

visceral fat

  • 0.5kg normal
  • 1.0kg 2 fold higher risk for mortality
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4
Q

Why is increased visceral fat a potential health risk?

A

associated with

  • increased lipolysis
  • increased plasma FFAs
  • increased secretory products (adipokines -> inflammatory mediator)
  • *increased insulin resistance**
  • less glucose uptake into cells
  • increased blood glucose levels
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5
Q

what do adipokines do?

A

inflammatory mediator

adipo = fat
kines = signal molecules
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6
Q

what is insulin resistance?

  • how does it impair normal response
  • result in skeletal muscle
A

inability of insulin to produce a “normal” response at a given tissue

  • defect in insulin signalling leads to impaired GLUT4 translocation to membrane
  • reduced insulin stimulated glucose uptake in muscle
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7
Q

hyperinsulinemia definition

A
  • high levels of insulin in the blood

- result from over production of insulin in the pancreas in order to compensate for insulin resistance

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8
Q

stages in the development of T2D

- is it reversible?

A

1) impaired glucose tolerance
- obesity causes insulin resistance and impaired glucose tolerance directly
- hyperinsulinemia -> over production of insulin to compensate for resistance

2) early diabetes
- decreased insulin secretion
- result from beta cell defect
- cells exhausted and damaged from overproduction

3) late diabetes
- beta cells fail
- no insulin produced

** can be reversible with lifestyle change depending on stage -> only lived with it for a few years

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9
Q

clinal signs of T2D

A

Glucose
- fasting hyperglycemia (>7mM)

Insulin

  • dependent on stage of diabetes
  • impaired gluc tolerance -> high levels
  • early diabetes -> low levels
  • late diabetes -> no insulin
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10
Q

clinical tests used to assess diabetes

A

1) oral glucose tolerance test

2) euglycemic / hyperinsulinemic clamp

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11
Q

diabetes NOT associated with diabetes

A

Type 1 diabetes
(aka juvenile or insulin-dependent diabetes)
- autoimmune disease
- children
- genetics or exposure to certain virusis
- no cure (irreversible)

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12
Q

OGTT

A

Oral Glucose Tolerance Test
- measures acute metabolic response to glucose ingestion at whole body level

Method

  • 75g glucose beverage (Trutol)
  • measured 2hrs after ingestion (should return to near normal levels)
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13
Q

OGTT clinical diagnostic measurements

A

Diagnostic criteria after 2hrs from ingestion

  • 7.8mM = impaired glucose tolerance
  • 11.1mM = T2D
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14
Q

OGTT response to “glucose” in lean, obese and T2D

A

Normal

  • fasting ~4-5mM
  • peak at 1hr ~6-7mM
  • return to normal after 2hr
  • obese without diabetes similar response*

T2D

  • impaired fasting glucose ~6-7mM
  • huge spike glucose response (peak at 1hr)
  • diagnosed with disease at 11.1mM after 2hr
  • > 3hrs to return to normal
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15
Q

OGTT response to “insulin” in lean, obese and T2D

A

Fasting insulin - similar for all health states (~10mM but highly variable between individuals)

Lean (healthy)

  • peak after 30min ~40mM
  • slow/steady decline

Obese (healthy)

  • “huge”peak after 30min ~90mM (hyperinsulinemia)
  • indicates insulin resistance
  • pancreas works hard not to become diabetic

Obese T2D

  • peak after 1.5hr* (much longer)
  • peak response between obese and lean ~50-60mM
  • pancreas exhausted, fewer cells to secrete amount needed

Lean T2D

  • little to no response
  • similar to type 1
  • pancreas likely severely damaged
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16
Q

Euglycemic definition

A

normal blood glucose level

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17
Q

Gold standard for measuring whole body insulin sensitivity

A

hyperinsulinemia euglycemic clamp

  • measures responsiveness to insulin
  • used in lab, not clinically ($$$)
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18
Q

hyperinsulinemic euglycemic clamp procedure

Study These Flashcards
A

raise insulin levels to supra-physiological levels via infusion

  • monitor glucose infusion rate (GIR) required to maintain normal/steady blood glucose levels
  • check every 5-10min
19
Q

hyperinsulinemic euglycemic clamp measures

Study These Flashcards
A

High GIR
- >7.5mg/min = very insulin sensitive (athletes)

20
Q

GIR definition

Study These Flashcards
A

glucose infusion rate

  • measured during hyperinsulinemic euglycemic clamp
  • high amounts of insulin infused
  • muscle responds by absorbing resting blood glucose
  • glucose infused at a certain rate to maintain normal glucose levels (euglycemia)
21
Q

Effect of elevated levels of free fatty acids on insulin resistace

Study These Flashcards
A

can induce insulin resistance “in only 4-6hrs”

22
Q

Fatty acid uptake in lean, obese and T2D

- palmate transport rate into muscle

Study These Flashcards
A

HUGE improvement in FA uptake ability in obese and T2D patients (compared to lean and overweight)

23
Q

How does fatty acid uptake improve in obese and T2D patients?

Study These Flashcards
A

FAT/CD36 “redistribution” to plasma membrane

  • huge increase at the plasma membrane
  • NO CHANGE in whole muscle content (homogenate)
24
Q

intergral membrane protein involved in FA transport

Study These Flashcards
A

FAT/CD36

fatty acid translocase / cluster of distribution 36

25
Zucker Rats
model for obesity - mutation in the "leptin" gene - shortened leptin receptor - impaired insulin stimulated glucose uptake - BUT contraction stimulated glucose uptake normal
26
Effect of obesity/T2D on glucose uptake into muscle | - 2 methods of glucose uptake
1) insulin stimulated glucose uptake - impaired 2) contraction stimulated glucose uptake - no change* - ATP turnover to induce AMPK activation can still promote GLUT4 translocation to membrane * * plasma membrane GLUT4 concentration same levels with exercise
27
IMTG definition
Intramuscular triglycerides | - marker of FA storage
28
Athletes paradox | - what does this tell us?
General - declining insulin sensitivity = increase IMTGs Athletes - high insulin sensitivity and high IMTGs Significance * IMTGs are an "inert" metabolite unlikely to directly interfere with insulin action * does not cause insulin sensitivity
29
IMTG can be used as a marker for what?
FA-derived metabolites with negative effects - diacylglycerol (DAG) - cytosolic long chain fatty acyl CoA (LCFACoA) - ceramine * *athletes paradox - not bad for them - if not used, turned into bad metabolites associated with insulin resistance
30
function of DGAT
rate limiting step in TG synthesis - catalyzes the formation of triglycerides from diacylglycerol (DAG) and acyl-CoA *remember: "DAG" and cytosolic long chain fatty "acyl-COA" are bad metabolites that cause insulin resistance (diglyceride acyltransferase)
31
result of over expressing DGAT | - what is the significance?
improve insulin sensitivity - synthesizes TG significance - TG is the "inert" storage form - synthesis of TG is protective - other bad metabolites of FA produce cause insulin resistance
32
what is a better predictor for insulin sensitivity/resistance than IMTG
LCFACoA (long chain fatty acyl CoA) - inverse relationship - increase LCFACoA = decrease insulin sensitivity
33
how do fatty acid metabolites suppress insulin signalling cascade?
DAG and LCFACoA - activate PKC (protein kinase C) - phosphorylates serine and theonine residues at IR and IRS-1 (inhibits signalling) Ceramine - inhibits akt/PKB and GLUT4 translocase * * DAG and ceramides do not always coincide with insulin resistance * * LCFACoA very reactive, suppress insulin signalling and influence fuel supply to mitochondria
34
Key points about LCFACoA | other than insulin signalling
1) Inhibits adenine nucleotide translocase (ANT) - influence fuel supply to mitochondria - atp from mitochondria to cytosol (out) - adp from cytosol to mitochondria (in) 2) Promotes reactive oxygen species (ROS) formation - oxidative stress * ** Disease state only - ANT "not" inhibited during exercise - LCFACoA during chronic state of over eating is in the absence of ADP - does not move through system -> builds up
35
What form do we want to store fat
IMTG
36
Study: Weight loss in morbidly obese (BMI ~50kg/m2) - bariatric surgery 142kg -> 80kg in one year Results? - insulin sensitivity and lipid storage type
Large improvement in insulin sensitivity - 25% blood gluc reduction - 75% insulin reduction Change in lipid type - LCFACoA reduced - mostly palmitoyl CoA and stearyl CoA (saturated FAs) - other LCFACoA not as sign
37
Study: weight loss morbidly obese - 2 year post bariatric surgery Is fat oxidation improved with weight loss?
NO - impairment in skeletal muscle fatty acid oxidation persists - may contribute to weight re-gain
38
Study: T2D men and women weight loss - 16 weeks moderate-intensity exercise - caloric restriction Results? - insulin stimulated glucose disposal
weight loss improved insulin stimulated glucose disposal in those with T2D - non oxidative glucose disposal significant increase - glycogen formation
39
Study: NO weight loss - moderate intensity exercise for 8 weeks Results - insulin sensitivity and lipids
1) Improved insulin sensitivity - decreased blood glucose and insulin levels 2) Improved CPT1 activity in mitochondria - allows entry into mitochondria => increased beta oxidation 3) DAGs and ceramides decreased 25-30% - especially saturated lipid species - due to FA oxidation? (unknown) Side notes - CPT1 catalyzes acyl-CoA + carnatine => Acyl-Carnatine - converted back to acyl-CoA once crossing the membrane before going through beta oxidation
40
Differences in the benefits of weight loss through exercise vs bariatric surgery
Both improved insulin sensitivity Bariatric surgery - LCFACoA declined - impaired fatty acid oxidation still persisted Exercise (even with NO weight loss) - improved CPT1 activity in mitochondria (increased FA oxidation) - DAGs and ceramides decreased 25-30%
41
Conclusions on the problems with lipid metabolism in obesity / diabetes?
Not any one thing wrong - imbalance between FA uptake and FA oxidation leads to accumulation - both transport and oxidation involved in the impairments that occur - likely LCFACoA, DAG or ceramides cause problem (not TAG) - not fully understood
42
most important component of 'aerobic' training to improve "insulin sensitivity"
longest duration best - regardless of intensity or volume - all types benefit
43
resistance training and insulin sensitivity | non obese women - 6 month study
improved insulin sensitivity - when corrected for lean mass => no change * * improvement due to increase lean muscle mass - main tissue for glucose disposal

Nutr 4210 (16 decks)

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