#337 – Insulin resistance masterclass: The full body impact of metabolic dysfunction and prevention, diagnosis, and treatment | Ralph DeFronzo, M.D.

Metabolic disease as a foundational driver of chronic illness [4:00]

• People who listen to Peter are familiar with him talking about these 4 horsemen:
  • Cardiovascular disease and cerebrovascular disease
  • Cancer
  • Neurodegenerative and dementing diseases
  • Metabolic disease
    • This one is the squishiest because it’s not the one that shows up on the most death certificates, but in many ways, it’s the foundational one that is amplifying the risk of all of those other causes of death
    • Spanning the spectrum from hyperinsulinemia to insulin resistance to fatty liver disease, all the way out to type 2 diabetes
• It seems very important that we should have a really thorough discussion of that foundational metabolic disease, and there’s no one better than Ralph to have that discussion

Briefly tell folks what you’re doing at UT San Antonio and why you’ve spent the last 50 years working on this problem 

• Ralph has been in this field of metabolic disease for a long time
• He may be the longest consecutively funded NIDDK investigator (53 years)
• He actually started even long before that when he was a medical student at Harvard
• He had this fantastic teacher, Professor Cahill, who gave the lectures on intermediary metabolism, and Ralph decided this is what he wanted to do
• He worked each summer with Professor Cahill

“Sometimes in life you meet the right person, the right opportunity and it changes everything you do.”‒ Ralph DeFronzo

• What Ralph does now, he attributes directly to George
• When he gave the Banting Lecture in 2008
  • People usually put a picture of their mother, and father, and children
  • Ralph loves his mother, and father, and children, but he only showed one picture and that was Professor Cahill because he’s really the person who’s ended up directing him to where he is today

People who are listening, who are particularly astute, might recall that Peter has referenced a number of Cahill’s papers 

• One of the more interesting studies he did, was the 40-day starvation study in the mid-60s
• A group of students at Harvard did a water-only fast for 40 days, and he followed all the metabolites

One of the things that was interesting to Peter was that even under a period of extreme starvation, the brain never gave up its dependency on glucose 

• Even though ketone bodies began to service the brain by about day 7-10 as the majority of the fuel, glucose was still providing about ⅓ of the brain’s energy
• The brain did switch over to ketone metabolism
• Ralph was not one of the people who did the 40-day fast, but he did fast for 5-7 days
  • If you fasted for 3 days you could get paid $50, and Ralph thought he was the richest guy in the world from this study
  • He can assure you that the physical specimens in this study were phenomenal

The interesting thing you realize is that we have so much energy stored into human body 

• Who would’ve thought that a lean type person can fast for 40 days? 

⇒ The real problem is at some point you start to break down muscle

• And then if you start to break down cardiac muscle, prolonged fasting at that point becomes a problem
• But you have a lot of energy stored in fat and you can starve for a long time
• And obese people easily can go for 3, 4 months with all of the reserves that are in the body

Defining insulin resistance: effects on glucose, fat, and protein metabolism, and how it varies between healthy, obese, and diabetic individuals [8:15]

Insulin resistance is a term that gets thrown around constantly, explain what it is from a technical standpoint 

• Every time you eat a meal and your blood sugar level goes up, you’re going to release insulin

⇒ Insulin is a master regulator for all biochemical processes in the body 

• 1 – One of the things insulin is going to do, it’s going to talk to your muscles and say, “Take up glucose and burn that glucose.”
• What we need to know is, when you infuse insulin, how much of the glucose is taken up by the muscle
• We can compare a normal person, someone who is overweight, and someone who is diabetic

“I actually developed the gold standard technique which is the insulin clamp technique to look at this.”‒ Ralph DeFronzo

• Comparing an overweight person to a lean person ‒ obese people are very insulin resistant in terms of muscle glucose uptake 
• In a diabetic, they’re even more insulin resistant

There are many processes that insulin controls

• 2 – Insulin regulates how much fat is released from your fat cells
• Unfortunately, insulin keeps the fat in your fat cell
• But in obese people insulin doesn’t work so well
  • So instead of keeping the fat in the fat cell, even though your insulin is high, you’re breaking down the fat

You have to look at each individual process that insulin is controlling ‒ insulin resistance is a general term because insulin controls many things 

• For that process, we know how a normal person should respond and how a diabetic responds
  • And the diabetic is much more insulin resistant
• 3 – Insulin controls protein metabolism ‒ it’s important in helping you build protein
• Ralph did a study infusing insulin and carbon-labeled leucine to define how insulin promotes protein metabolism in a normal healthy person
  • He could do the same study in an obese person, and we know they don’t respond to insulin as well in terms of aggregating protein metabolism  

Peter asks, “Does that translate not just to structural proteins such as enzymes or cellular structural proteins but also macrostructural proteins such as muscle?”

• Absolutely
• You can look at specific enzymes within the cell or muscle in terms of muscle as a bulk

There are many ways you could define insulin resistance, but whatever the particular process you’re looking at, you’re comparing what would be the normal response in a normal healthy person compared to what might happen in a diabetic person or an obese individual 

Peter’s takeaway on insulin resistance 

• It’s a vague term and it’s non-specific because the actions of insulin are so many
• It has an action in the liver
• It has an action in the muscles
• It has an action with response to glucose
• It has an action with response to amino acids
• It has an action with response to fat, both in the liberation of fat, lipolysis, and presumably in response to oxidation

The historical significance of the development of the euglycemic clamp technique for measuring insulin resistance [11:45]

Explain how the euglycemic clamp test is done

What would happen in a healthy individual? 

• When Ralph was a fellow, at that time there was not a good measure of insulin sensitivity
  • You do an oral glucose tolerance test and the insulin level would go up
  • Some people would look at how much insulin comes out compared to the rise in glucose, and that’s a measure of ꞵ-cell function
  • Then someone would just turn it around and look at how much the rise in glucose was per insulin, and that’s a measure of insulin resistance
• It was very clear to Ralph that this was insane
  • You can’t take 2 variables and then, just depending upon how you want to look at them, switch denominator and numerator
• Ralph wanted to develop something more specific
• Unfortunately, clinicians are not able to do euglycemic clamps
  • They are still looking at oral glycemic tolerance tests: giving people oral glucose, and sampling glucose and insulin every 30 minutes, and trying to impute what we can
  • [we will come back to what you can learn from an OGTT at the end of the episode]
• Ralph developed a technique where you could take 100 people and infuse insulin (initially as a priming dose) and then just clamp the insulin level
  • [and infuse enough glucose to keep it at 80; discussed further shortly]

Give a prime continuous insulin infusion: raise their insulin level by 100 micro units per ml, and do that for 2 hours

Figure 1. The euglycemic insulin clamp technique and examples of data obtained. Image credit: Obesity 2022 

• Now you know that the insulin stimulus, whether you’re lean, whether you’re obese, or whether you’re diabetic, whatever particular process that you want to look at
  • Maybe you wanted to look at how insulin shut down a part of glucose production
  • Ralph’s group was the first to ever use radioisotopes to trace this, and show that in normal people insulin shut down glucose production by the liver very quickly 
  • But obese people and diabetics were very, very resistant to the insulin

{end of show notes preview}