Unit 3 - Lecture 17 Flashcards
What prevents metabolic flexibility from happening?
- Insulin Resistance
- Mitochondrial Dysfunction
- Genes
____ ____ ____ is often blamed for decreased insulin sensitivity.
High Fat Diet
_______ ________ is the quantifiable measure to one’s responses to insulin.
Insulin Sensitivity
______ _________ is used to describe one’s metabolic state.
Insulin Resistance
- You are insulin resistant or not in a clinical state.
- It is less sound to say that someone’s insulin resistance goes up or down.
How does a high-fat diet impact tissue?
A high-fat diet decreases subcutaneous fat’s capacity to store, so the overspill causes an increase in visceral adipose tissue. The portal vein drains fat from the visceral adipose tissue to the liver. The increase in free fatty acids in the liver increase gluconeogenesis, VLDL, and triglycerides. The liver has trouble processing the excess FFA, so there is an increase in intrahepatic triglycerides (IHTG). There is an association as greater fat floods the liver, there is an increase in IMTG in skeletal muscle. There is also a decrease in fat oxidation (FOX) and insulin-mediated glucose uptake.
How is the muscle cell (myocyte) impacted by a high-fat diet?
- There is an increase in FFA, TG, VLDL in the bloodstream in a high-fat diet model.
- Fatty acids in the cell enter the mitochondria through CPT1 and CPT2 and through ß-Oxidation form acetyl-CoA, which goes through the TCA cycle.
- As acetyl-CoA increases, it combines with oxaloacetate to form citrate.
- Acetyl-CoA and citrate are allosteric regulators.
- As acetyl-CoA increases, it inhibits PDH from forming more acetyl-CoA.
- As citrate increases, it inhibits PFK from forming fructose-6-phosphate, which inhibits pyruvate formation.
- Since PFK is inhibited, an accumulation of glucose-6-phosphate will occur, which will inhibit HK.
- Inhibition of HK will lead to blocked glucose uptake into the muscle cell.
The net effect of excess lipid availability has been proposed to explain decreased blood glucose uptake after insulin-based scenarios.
Randle Cycle
Lipid Induced Insulin Resistance Model
Randle Cycle
People who can adapt are ______ metabolically to diet. Obesity can have ______ adaptations.
flexible; Obesity
Obese individuals have a blunted response to a high-fat diet. After 3 days of a high-fat diet, lean individuals were able to adapt by increasing palmitate oxidation, however, obese individuals were not.
After a 7 day washout, participants included a high-fat diet and exercise. Exercise increased fat oxidation in both obese and lean individuals.
Athlete Paradox
Athlete Paradox
Set-up:
- This is on a continuum from Type 2 Diabetic to an Athlete.
- T2D has the most IMTG, however, the athlete has relatively similar IMTG as T2D (but, has the capacity to use it as a fuel source - increasing insulin sensitivity/VO2max).
- Obese and lean are similar.
Results:
- A low-fat diet and exercise increase T2D insulin sensitivity and VO2max.
- When an athlete is inactive and consumes a high-fat diet, they decrease their insulin sensitivity.
- These systems ARE adaptive.
_____ and _____ are both thought to be protective from FFA-induced insulin resistance.
Fitness; Sex
Comparing an athlete and a non-athlete, the athlete does not have issues with the increased FFA availability. Insulin is still able to elicit adaptation.
GLUT4 will inhibit hepatic glucose production and stimulate muscle glucose uptake. Both things are seen in the athlete compared to the non-athlete.
Women are protected in this way compared to men (More oxidative, muscle fiber, capillary, and mitochondrial density).
Glucose concentrations can ______ insulin sensitivity.
Decrease
Glucose Induced Model of Insulin Resistance
Reverse Randall Cycle
More accurate; What has been observed is that T2D uses more CHO in the fasted state. This contraindicates the Randle Cycle.
Explain the Reverse Randle Cycle and how T2D utilizes CHO rather than fat.
- As glucose is taken up by the cell, glucose will go through a process (glycolysis) to form acetyl-CoA.
- Excess acetyl-CoA leads to the byproduct of malonyl-CoA.
- Malonyl-CoA inhibits CPT1, which inhibits FA entry into the mitochondria.
- The cell converts FA to IMTG, ceramide, diacylglycerol (DAG) as a byproduct of lipid entering into the cell.
- Insulin binds to the insulin receptor on the cell membrane, which through the IRS1/PI3K/AKT/AS160 cascade translocates GLUT4 to the cell membrane.
- Ceramide and DAG inhibit GLUT4 translocation at different steps of the process.
Glucose is blocking the entry of fat into the mitochondria and leads to insulin resistance.
Remember, this is not all or nothing. GLUT4 translocation from the response of insulin is blunted, not inhibited or blocked altogether, so glucose can still get into the cell.
Glucose can also stimulate its own uptake (GLUT1).
Assuming insulin is actually getting to the tissue. The cell may not be a problem, it may be the delivery mechanisms.
Effects of Insulin:
- Conduit Arteries (Ex. Aorta, Brachial Artery)
- Resistance Arteries
- Microvascular Circulation
Those with obesity, metabolic disease, and Type 2 Diabetes don’t have the blood flow changes seen in healthy, lean individuals.
Is it the metabolic pieces (uptake) that are the problem or is it a vascular component (delivery) that is the problem?
Probably both.
- About 40% of insulin resistance could be attributed to problems in the vasculature.
- Exercise can promote vasodilation independent of insulin resistance.
