11. Obesity (1) - insulin resistance Flashcards Preview

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Difference between peripheral and central obesity

- 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


Easiest way to measure Visceral Fat
- male and female measure
- other ways to measure

waist circumference
- men > 102 cm
- women > 88 cm

- MRI and CT
- $$$


key independent predictor of all cause mortality
- some basic measurements

visceral fat
- 0.5kg normal
- 1.0kg 2 fold higher risk for mortality


Why is increased visceral fat a potential health risk?

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


what do adipokines do?

inflammatory mediator

adipo = fat
kines = signal molecules


what is insulin resistance?
- how does it impair normal response
- result in skeletal muscle

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


hyperinsulinemia definition

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


stages in the development of T2D
- is it reversible?

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


clinal signs of T2D

- fasting hyperglycemia (>7mM)

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


clinical tests used to assess diabetes

1) oral glucose tolerance test
2) euglycemic / hyperinsulinemic clamp


diabetes NOT associated with diabetes

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



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

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


OGTT clinical diagnostic measurements

Diagnostic criteria after 2hrs from ingestion
- 7.8mM = impaired glucose tolerance
- 11.1mM = T2D


OGTT response to "glucose" in lean, obese and T2D

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

- 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


OGTT response to "insulin" in lean, obese and T2D

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


Euglycemic definition

normal blood glucose level


Gold standard for measuring whole body insulin sensitivity

hyperinsulinemia euglycemic clamp
- measures responsiveness to insulin
- used in lab, not clinically ($$$)


hyperinsulinemic euglycemic clamp procedure

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


hyperinsulinemic euglycemic clamp measures

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



GIR definition

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)


Effect of elevated levels of free fatty acids on insulin resistace

can induce insulin resistance "in only 4-6hrs"


Fatty acid uptake in lean, obese and T2D
- palmate transport rate into muscle

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


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

FAT/CD36 "redistribution" to plasma membrane

- huge increase at the plasma membrane
- NO CHANGE in whole muscle content (homogenate)


intergral membrane protein involved in FA transport


(fatty acid translocase / cluster of distribution 36)


Zucker Rats

model for obesity
- mutation in the "leptin" gene
- shortened leptin receptor
- impaired insulin stimulated glucose uptake
- BUT contraction stimulated glucose uptake normal


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


IMTG definition

Intramuscular triglycerides
- marker of FA storage


Athletes paradox
- what does this tell us?

- declining insulin sensitivity = increase IMTGs
- high insulin sensitivity and high IMTGs

* IMTGs are an "inert" metabolite unlikely to directly interfere with insulin action
* does not cause insulin sensitivity


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


function of DGAT

rate limiting step in TG synthesis
- catalyzes the formation of triglycerides from diacylglycerol (DAG) and acyl-CoA

"DAG" and cytosolic long chain fatty "acyl-COA" are bad metabolites that cause insulin resistance

(diglyceride acyltransferase)


result of over expressing DGAT
- what is the significance?

improve insulin sensitivity
- synthesizes TG

- TG is the "inert" storage form
- synthesis of TG is protective
- other bad metabolites of FA produce cause insulin resistance


what is a better predictor for insulin sensitivity/resistance than IMTG

LCFACoA (long chain fatty acyl CoA)

- inverse relationship
- increase LCFACoA = decrease insulin sensitivity


how do fatty acid metabolites suppress insulin signalling cascade?

- activate PKC (protein kinase C)
- phosphorylates serine and theonine residues at IR and IRS-1 (inhibits signalling)

- 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


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


What form do we want to store fat



Study: Weight loss in morbidly obese (BMI ~50kg/m2)
- bariatric surgery 142kg -> 80kg in one year

- 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


Study: weight loss morbidly obese
- 2 year post bariatric surgery

Is fat oxidation improved with weight loss?

- impairment in skeletal muscle fatty acid oxidation persists
- may contribute to weight re-gain


Study: T2D men and women weight loss
- 16 weeks moderate-intensity exercise
-caloric restriction

- insulin stimulated glucose disposal

weight loss improved insulin stimulated glucose disposal in those with T2D
- non oxidative glucose disposal significant increase
- glycogen formation


Study: NO weight loss
- moderate intensity exercise for 8 weeks

- 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


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%


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


most important component of 'aerobic' training to improve "insulin sensitivity"

longest duration best
- regardless of intensity or volume
- all types benefit


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