This audio clip is from “Ask Me Anything” (AMA) episode # 20 — Simplifying the complexities of insulin resistance: how it’s measured, how it manifests in the muscle and liver, and what we can do about it.
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How insulin resistance manifests in the muscle
- You eat some carbs and plasma glucose increases
- The increase in plasma glucose stimulates insulin secretion
- And insulin secretion:
- stimulates glucose uptake in muscle
- Suppresses GNG by the liver
- In a healthy individual, 80-90% of consumed glucose is stored as glycogen (in muscle and liver)
- The muscle is the predominant place where we dispose of glucose
- When Peter says “glucose disposal” he’s referring to muscle taking in glucose
What goes wrong from here?
- It’s important to understand this is a continuum — on one end of the spectrum is just becoming insulin resistant and at the other end of the spectrum is full-blown type 2 diabetes
- The first thing that really goes wrong is the muscles take in less glucose, and by extension, the plasma insulin level has to rise to force that in
- The first sign of this is normal levels of glucose going in but at a higher level of insulin (and that’s easy to miss)
- The first thing that usually shows up is higher levels of plasma glucose — and that’s because the liver is becoming resistant to insulin
- The liver being resistant to insulin means it’s not slowing down glucose production, and therefore in the presence of glucose it’s still making glucose (very problematic)
- At some point there’s not even enough insulin that the pancreas can make to overcome the resistance resulting in a person needing medication to start to overcome this problem
What is it about the muscle that fails in this process of glucose disposal?
Three fates of glucose within the muscle
1-The oxidative fate of glucose says glucose comes into a muscle and immediately gets converted into ATP through the very efficient pathway
- Glucose gets converted to pyruvate, pyruvate gets converted to acetyl CoA, and that going into the mitochondria where ATP is generated under something called oxidative phosphorylation (Krebs cycle — this is the most efficient way to generate ATP out of glucose)
2-The second potential fate of glucose is to undergo glycolysis
- Take the glucose down to pyruvate
- But instead of taking the pyruvate towards the mitochondria and going through the Krebs cycle you turn it into lactate, which yields much less ATP
3-The third fate of glucose in the muscle is it can be stored as glycogen
- Glycogen is literally a lattice of glucose.
- Glucose is a single six carbon ring, but you can join these things in rows, and rows, and rows, and rows, and sheets, and sheets, and sheets covalently and that becomes a matrix of glucose, which is a very efficient way to store it
When things go wrong…
- When things go wrong, we know that at least one of those three are not working
- The question becomes, which one?
Gerald Shulman did a study using a technique called NMR to try to answer this question.